Hysteroscopic assessment of menopausal breast-cancer patients taking tamoxifen; there is a bias from the mode of endometrial sampling in estimating endometrial morbidity?

The aim of this study is to evaluate the accuracy of hysteroscopy in detecting tamoxifen-associated endometrial morbidity. Ninety-eight menopausal breast cancer patients taking tamoxifen underwent hysteroscopy because of an endometrial thickness above 4 mm measured by Transvaginal Ultrasonography. Thirty-one women recorded uterine bleeding while 67 were asymptomatic. Hysteroscopies with operative facilities were performed, mainly in out-patient setting. Hysteroscopic findings were matched with histopathology derived from various modalities of tissue collection as suction-curettage, oriented-streak curettage, hysteroscopically-targeted biopsies or polypectomies and hysterectomies. Accuracy of hysteroscopy to estimate a normal or abnormal endometrium was calculated. Abnormal endometrium was detected in 35 patients (64.5% in symptomatic and 22.3% in asymptomatic women, P < 0.001). We found six carcinomas, 18 polyps and 11 hyperplasias. Hysteroscopy showed sensitivity and specificity of 89.2 and 98.4%, respectively. By blind sampling, tissue collection was too scant to give a diagnosis in 29.1% of patients and in 80.5% of patients in whom hysteroscopy showed cystic atrophy the pathologist failed to confirm this condition. Moreover, eight endometrial polyps (36.3%) detected by hysteroscopy were missed. Conversely, by tissue sampling under vision no inadequate specimen was sent to the pathologist and all hysteroscopies showing cystic atrophy and polyps were pathologically confirmed. From literature data, the detection-rate of endometrial pathology in tamoxifen users varies from the lowest to the highest prevalences whether blind or hysteroscopically-targeted modalities of tissue sampling were used, respectively. Hysteroscopy with targeted sampling appears to be the most effective method to assess the endometrial lining. In our experience it is safe, well tolerated and it should be considered the reference test to assess a thickened endometrium in women under tamoxifen.     

Indication of hysteroscopy in tamoxifen treated breast cancer patients

The aim of this study was to indicate the patients treated with tamoxifen for breast cancer in which hysteroscopy with biopsy should be considered mandatory. 414 breast cancer patients who underwent hysteroscopy with bioptic evaluation were enrolled in the study. 334 subjects were treated with 20 mg of tamoxifen daily as adjuvant therapy for six up to a hundred months. Of the remaining 80 control patients, which had not received tamoxifen, 30 were in premenopause (Group IA) and 50, in postmenopause (Group IIA). The tamoxifen-treated patients were subdivided in premenopausal (Group IB = 72 patients) and in postmenopausal (Group IIB = 262 patients) groups. All patients were further classified in asymptomatic or symptomatic groups considering whether uterine bleeding was absent or present. The evaluation of the endometrial mucosa was performed by office hysteroscopy. In group IIB patients presenting uterine bleeding, malignant lesions were found in 7.8% of the cases. The incidence of premalignant and malignant lesions in IIB patients treated for longer than 3 years (11.7%) was higher than that observed in IIB patients treated for less than 3 years (1.3%). There was a significant difference in terms of endometrial pathology between Group IIB (32.8%) and Group IIA (8%) (p < 0.001); and between Group IIB (32.8%) and Group IB (13.9%) women (p = 0.003). Among IA and IIA patients there were no cases of endometrial hyperplasia or cancer; on the contrary, in IB and IIB women, 2 and 22 cases of atypical hyperplasia were observed, respectively. All cases of endometrial cancer were observed in Group IIB and had a diagnosis of poor prognosis. In conclusion the hysteroscopy with biopsy should be considered the first diagnostic procedure to perform in tamoxifen-treated postmenopausal patients presenting uterine bleeding and in postmenopausal women treated for longer than 3 years. In premenopause, hysteroscopy should be proposed to women with ultrasonographic abnormalities and/or with uterine bleeding to patients at high risk for endometrial cancer.     

Endometrial thickness and risk of breast and endometrial carcinomas in the prostate,lung, colorectal and ovarian cancer screening trial

Postmenopausal women with higher circulating estrogen levels are at increased risk of developing breast and endometrial carcinomas. In the endometrium, excess estrogen relative to progesterone produces a net proliferative stimulus, which may result in endometrial thickening. Therefore, the hypothesis that endometrial thickness is a biological marker of excess estrogen stimulation that is associated with risk of breast and endometrial carcinomas was tested. Endometrial thickness was measured in 1,272 postmenopausal women, aged 55–74 years, who underwent transvaginal ultrasound (TVU) screening as part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Serial endometrial thickness measurements were available for a subset of women at 1 year (n = 1,018), 2 years (n = 869) and 3 years (n = 641) after baseline. The associations between endometrial thickness and breast (n = 91) and endometrial (n = 14) carcinoma were evaluated by estimating relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression with age as the time metric. Models incorporating baseline endometrial thickness and as a time‐varying covariate using all measurements were examined. Median follow‐up among study participants was 12.5 years (range: 0.3–13.8 years). Compared to baseline endometrial thickness of 1.0–2.99 mm, women with baseline endometrial thickness greater than or equal to 5.0 mm had an increased risk of breast (RR = 2.00, 95% CI = 1.15–3.48) and endometrial (RR = 5.02, 95% CI = 0.96–26.36) carcinomas in models adjusted for menopausal hormone use and BMI. These data suggest that increased endometrial thickness as assessed by TVU was associated with increased risk of breast and endometrial carcinomas.     

Bcl-2和Bax蛋白在正常、增生和恶性子宫内膜中的表达

Objective To investigate the expression of Bcl-2 and Bax proteins in normal, hyperplastic, and malignant endometrium. Methods Endometrial tissues were obtained from 14 proliferative endometrial samples; simple (n=30) and complex hyperplasia without atypia (n=13); complex hyperplasia with atypia (n=20) and endometrial adenocarcinoma (n=17). The expression of Bcl-2 and Bax proteins was detected by using immunohistochemical staining with appropriate antibodies. Results The intensity of Bcl-2 staining was gradually increased from proliferative to simple and complex hyperplasia, but it was gradually decreased from atypia hyperplasia to endometrial adenocarcinoma (P<0.05). The intensity of Bax staining was gradually increased from proliferative endometrium to simple and complex hyperplasia, but in atypia hyperplasia it was obviously lower than simple hyperplasia, the ratio of Bcl-2: Bax staining intensity was changed with the endometrium from proliferative, hyperplastic endometrium to endometrial adenocarcinoma. The ratio of Bcl-2: Bax staining intensity was obviously decreased in atypia hyperplasia and endometrial adenocarcinoma. Conclusion The survival time of the cells in hyperplasia expressing Bcl-2 might be prolonged. Neoplastic cells in atypia hyperplasia and adenocarcinoma might show a decreased expression of Bcl-2 and Bax, suggesting that Bcl-2 and Bax might be important indexes and prognosis factors and the expression of Bcl-2 and Bax might be correlated with carcinogenesis in the uterine endometrium of humans.     

Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in women with Lynch syndrome

In women with hereditary non polyposis colorectal carcinoma (HNPCC) an annual gynaecological surveillance has been recommended because of an increased lifetime risk of developing endometrial and ovarian carcinoma. The aim of this study was to assess the efficacy of gynaecological surveillance with regard to endometrial and ovarian carcinoma. Included were women from families that fulfilled the revised Amsterdam criteria for HNPCC or who showed a proven mutation in one of the mismatch repair genes. An annual gynaecological surveillance was performed (transvaginal ultrasound (TVU) and CA 125 assessment). From January 2006 on, routine endometrial sampling was included. In a total number of 100 women 285 surveillance visits were performed. Among these, in 64 visits routine endometrial samplings were performed: three atypical hyperplasias and one endometrial carcinoma were diagnosed. This was significantly more than the atypical hyperplasia and two endometrial carcinomas that were detected after 28 samples performed because of abnormal surveillance results in 221 visits. There were no interval carcinomas. One invasive ovarian carcinoma stage IIIC was diagnosed at ovarian surveillance. Endometrial surveillance with routine endometrial sampling in women with HNPCC is more efficient in diagnosing endometrial (pre)malignancies than TVU only. Ovarian surveillance is not capable of diagnosing early stage ovarian carcinoma. Prophylactic hysterectomy in HNPCC should be restricted to women in whom abdominal surgery for other reasons is performed and to those with particularly increased risk such as MSH6 mutation carriers and/or women with multiple relatives with endometrial carcinoma.     

Microsatellite instability and immunohistochemical analysis of MLH1 and MSH2 in normal endometrium, endometrial hyperplasia and endometrial cancer from a hereditary nonpolyposis colorectal cancer patient

Hereditary nonpolyposis colorectal cancer (HNPCC)-related endometrial cancer is associated with mutations in DNA mismatch repair genes. However, chronological changes of these genes in the endometrium have not been studied in women from HNPCC families. Tissue samples of normal endometrium, endometrial hyperplasia without atypia and endometrial cancer were collected at different times from a 41-year-old Japanese woman with a family history of HNPCC. Combined microsatellite instability (MSI) and immunohistochemical analysis of MLH1 and MSH2 predicted the presence of a mutation in MSH2 when she had endometrial hyperplasia without atypia 7 months before the diagnosis of endometrial cancer. Endometrial hyperplasia without atypia may indicate an early development of endometrial cancer in women from HNPCC families.     

Hysteroscopy and endometrial cancer diagnosis: a review of 2007 consecutive examinations in self-referred patients.

The authors reviewed 2007 consecutive outpatient hysteroscopies performed in self-referred women to assess the detection rate of uterine cancer and the validity of different selection criteria for hysteroscopy. Thirty cases of uterine cancer (29 endometrial, 1 carcinosarcoma) were detected. Abnormal uterine bleeding was the indication most commonly associated with cancer (26 of 30 cases, cancer detection rate = 2.1%), whereas the presence of cervical polyps had no predictive value. Patients age was correlated to cancer detection rate, and the investigation of uterine cancer under the age of 45 was poorly cost effective. Hysteroscopy and endometrial biopsy, performed by Permacurette or Novak curette immediately after hysteroscopy, missed respectively 8 and 2 of 30 cancers. Hysteroscopy should be employed in combination with endometrial biopsy as a standard outpatient investigation whenever endometrial cancer is suspected. These procedures are safe and accurate and rule out more aggressive and costly procedures, such as dilatation and curettage, in most cases.     

The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis

BACKGROUND: Endometrial assessment by means of biopsy or sampling of endometrial cells is a minimally invasive alternative for dilatation and curettage (D&C) or hysteroscopy. The use of this technique is believed to reduce the cost of the diagnostic work-up for abnormal uterine bleeding without reducing accuracy. Because the authors were not aware of any systematic review of this test, they performed a meta-analysis to assess the accuracy of endometrial sampling devices in the detection of endometrial carcinoma and atypical hyperplasia. METHODS: The authors searched the literature for studies published between 1966 and 1999 comparing the results of endometrial sampling with findings at D&C, hysteroscopy, and/or hysterectomy. They found 39 studies that included 7914 women. For each study, the fraction of patients was calculated in which endometrial sampling failed. Furthermore, the authors calculated the fraction of cases of endometrial carcinoma and atypical hyperplasia that were identified correctly as well as the fraction of women in whom these diseases were diagnosed false positively. RESULTS: The detection rate for endometrial carcinoma was higher in postmenopausal women compared with premenopausal women. In both postmenopausal and premenopausal women, the Pipelle was the best device, with detection rates of 99. 6% and 91%, respectively. For the detection of atypical hyperplasia, there was only one study that reported explicitly on postmenopausal women, thereby hampering the possibility of subgroup analysis. Again, the Pipelle was the most sensitive technique with a sensitivity of 81%. The specificity of all devices was > 98%. CONCLUSIONS: Endometrial biopsy with the Pipelle is superior to other endometrial techniques in the detection of endometrial carcinoma and atypical hyperplasia. The accuracy of the Pipelle is higher in postmenopausal women compared with premenopausal women.     

MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer

The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (I) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (II) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who underwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostaining for MLH1 and MSH2 was performed on paraffin-embedded sections. In group III, tumor DNA was examined for microsatellite instability (MSI) and MLH1, MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLH1 mutation carriers, MLH1 protein loss was also observed in concurrent endometrial hyperplasia. In group II, no protein loss was detected in normal endometrial tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 protein loss was observed. In group III, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometrial hyperplasia protein loss was also observed in the hyperplasia. MSI analysis in group III revealed 26 MSI-low and 12 MSI-high tumors. Mutation analysis in 28/38 patients showed only 1 missense MSH6 and no MLH1 or MSH2 germline mutations. In group III, loss of MLH1/MSH2 protein expression was not related to the presence of MSI or MLH1/MSH2 germline mutations. In conclusion, MLH1 or MSH2 protein loss in HNPCC-related endometrial neoplasia is strongly related to corresponding germline mutations. This relation was not clearly present in young sporadic endometrial cancer patients. Immunohistochemical pre-screening of the MLH1 and MSH2 proteins in endometrial hyperplasia or cancer can thus be helpful in HNPCC families. Frequent loss of MLH1 or MSH2 protein in endometrial hyperplasia indicates that this loss is an early event in endometrial carcinogenesis.     

Mutational analysis of <Emphasis Type="BoldItalic">hMsh6</Emphasis> in Israeli HNPCC and HNPCC-like Families

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9±13.2 years (range16–73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6±3.26 years, range 38–45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3±11.7 years (range 30–69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel. We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.     

PTEN及p27在子宫内膜腺癌中的表达及临床意义

目的　研究 PTEN及 p2 7蛋白在子宫内膜腺癌中的表达及临床意义。方法　应用免疫组化法检测 11例正常增生期内膜、4 4例子宫内膜增生症及 5 2例子宫内膜腺癌 PTEN及 p2 7蛋白表达。结果　 PTEN及 p2 7蛋白在正常增生期内膜、子宫内膜简单型 /复杂型增生过长 (无不典型增生 )、子宫内膜不典型增生过长及子宫内膜腺癌中表达率分别为 10 0 .0 %、91.4 %、6 6 .7%、6 7.3%和 90 .9%、88.6 %、6 6 .7%、5 9.6 %。子宫内膜腺癌 PTEN及 p2 7蛋白表达率明显低于正常增生期内膜和简单型 /复杂型增生过长 ( P<0 .0 1) ,与不典型增生过长相比差异无显著性( P>0 .0 5 )。 PTEN及 p2 7蛋白表达随组织分化越差呈递减趋势 ,PTEN表达与子宫内膜腺癌差分化相关 ( P<0 .0 5 ) ,与其它临床病理因素无关。在子宫内膜腺癌中 PTEN及 p2 7蛋白表达有相关性 ( P=0 .0 19)。结论　 PTEN及 p2 7在子宫内膜腺癌发生、发展中起重要作用 ,并可能是子宫内膜腺癌发生中的早期事件 ,检测 PTEN及 p2 7蛋白表达有助于子宫内膜腺癌的早期诊断及预后判断     

Anastrozole versus tamoxifen treatment in postmenopausal women with endocrine-responsive breast cancer and tamoxifen-induced endometrial pathology.

PURPOSE: To investigate the effect of switching from adjuvant tamoxifen to anastrozole (Arimidex) treatment in postmenopausal women with endocrine-responsive breast cancer and histologically proven tamoxifen-induced benign endometrial pathology. EXPERIMENTAL DESIGN: Two hundred twenty-six postmenopausal women who had received adjuvant tamoxifen 20 mg/d (> or =12 months, < or =48 months) and developed abnormal vaginal bleeding and/or an asymptomatic endometrial thickness >10 mm [measured by transvaginal ultrasound (TVUS)] were subjected to hysteroscopy and dilation and curettage (D&C). Thereafter, 171 patients were randomized in a phase III study to continue tamoxifen treatment (n = 88) or switch to anastrozole 1 mg/d (n = 83). Patients were monitored for < or =42 months using TVUS at 6-monthly intervals. RESULTS: At study entry, there were no significant differences in vaginal bleeding, endometrial thickness, and histologic findings between the two treatment groups. Throughout the treatment period, there was no significant difference in recurrent vaginal bleeding between groups [anastrozole, 4 of 83 (4.8%); tamoxifen, 9 of 88 (10.2%); P = 0.18]. Six months after randomization, the mean endometrial thickness for patients who switched to anastrozole was significantly reduced compared with those who continued tamoxifen treatment (P < 0.0001). Significantly fewer anastrozole patients required a repeat hysteroscopy and D&C compared with those on tamoxifen [4 of 83 (4.8%) and 29 of 88 (33.0%), respectively; P < 0.0001]. Repeat hysteroscopy and D&C revealed endometrial atrophy in all 4 cases in the anastrozole group and 14 polyps, 8 hyperplasias, and 7 atrophies in the tamoxifen group. CONCLUSIONS: Switching from tamoxifen to anastrozole treatment significantly reduced the need for a second hysteroscopy and D&C due to recurrent vaginal bleeding or thickening of the endometrium in postmenopausal breast cancer patients with tamoxifen-induced endometrial abnormalities.     

APC promoter hypermethylation is an early event in endometrial tumorigenesis

The aim of the current study was to investigate the role of promoter methylation of adenomatous polyposis coli (APC) and epithelial cadherin (E‐cadherin) genes in endometrial tumorigenesis. The methylation status of both genes was investigated in 43 cases of normal endometrium, 21 simple hyperplasia, 17 atypical hyperplasia, and 86 endometrial carcinoma (EC). Additionally, the methylation pattern of both genes was analyzed in 24 primary ECs and their corresponding metastases. DNA methylation of the APC gene increased from atypical hyperplasia (23.5%) to endometrial carcinoma, reaching its highest level of 77.4% in early stage cancer (FIGO I and II) and decreasing stepwise to 24.2% in advanced stage carcinomas (FIGO III and IV). No methylation of APC was found in normal endometrium or simple hyperplasia. Methylation of E‐cadherin was found only in EC (22.1%). The mean age of the patients with aberrant APC methylation was 68.8 years and was significantly higher compared to the mean age (60.9 years) of the patients without methylation of APC promoter (P = 0.02). APC promoter methylation significantly correlated with decreased protein expression of APC (P = 0.039), with increased expression of the Ki‐67 proliferative marker (P = 0.006) and decreased metastatic potential (P = 0.002). There was no correlation between APC and E‐cadherin methylation patterns and the other clinicopathologic features, nor with patient outcome. Our results suggest that hypermethylation of APC promoter region is an early event in endometrial tumorigenesis. (Cancer Sci 2009)     

Associations of pregnancy-related factors and birth characteristics with risk of endometrial cancer: A Nordic population-based case–control study

Many pregnancy-related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy-related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy-related factors, pregnancy complications and birth characteristics. Utilizing population-based register data from four Nordic countries, we conducted a nested case–control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy-related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39–2.55]; gestational hypertension 1.47 [1.33–1.63]; preeclampsia 1.43 [1.30–1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59–0.69]) and shorter time since last birth (<10 vs. ≥30 years: 0.34 [0.29–0.40]) were associated with reduced endometrial cancer risk, with consistent associations across most subtypes. Our findings support the role for both hormonal exposures and cell clearance as well as immunologic/inflammatory etiologies for endometrial cancer. This research supports studying endometrial hyperplasia, a precursor condition of endometrial cancer, in the context of pregnancy-related exposures, as this may provide insight into the mechanisms by which pregnancy affects subsequent cancer risk.     

Gynecologic Cancers in Lynch Syndrome/HNPCC

Recent studies have estimated that the lifetime risk of endometrial cancer in women with Lynch syndrome/hereditary non-polyposis colorectal cancer syndrome (Lynch/HNPCC) is 40–60%. This risk equals or exceeds their risk for colon cancer. While much research has been done to define the natural history and molecular features of Lynch/HNPCC associated colon cancer, there has been considerably less research defining Lynch/HNPCC associated endometrial cancer. This article will review current information regarding the clinico-pathologic features of Lynch/HNPCC associated endometrial cancer. In addition, current consensus guidelines for endometrial cancer screening and prevention for women with Lynch/HNPCC will be discussed. Given the increased risk of multiple cancers, changing the name of this syndrome from hereditary non-polyposis colorectal cancer syndrome to Lynch Syndrome may benefit both patients and clinicians. Clinicians caring for women with Lynch/HNPCC may stress colon cancer screening and prevention without reviewing endometrial cancer risks and symptoms or screening and prevention options. Perhaps more importantly, women with Lynch/HNPCC may focus on colon cancer risks and lack understanding of endometrial cancer risks. With increasing evidence that women with Lynch/HNPCC have significant risks for both colon and endometrial cancers, we believe a multi-disciplinary approach to the management of these individuals is crucial.     

CHEK2 mutations and HNPCC‐related colorectal cancer

Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non‐polyposis‐colorectal cancer (HNPCC) and HNPCC‐related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC‐related families in Poland, we genotyped 463 probands from HNPCC and HNPCC‐related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC‐related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC‐related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR = 1.9; p = 0.1) and for the 346 cases who do not fulfill the criteria (OR = 1.6; p = 0.03). One hundred forty‐five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR‐positive families). A positive association between the CHEK2 I157T mutation and HNPCC‐related cancer was observed only for MMR‐negative cases (OR = 2.1; p = 0.0004), but not for MMR‐positive cases (OR = 0.8; p = 0.9). The association with I157T was particularly strong for MMR‐negative cases with familial colorectal cancer (2 or more first‐degree relatives affected) (OR = 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR‐negative, HNPCC/HNPCC‐related families in Poland.     

Risk of endometrial cancer for women diagnosed with HNPCC‐related colorectal carcinoma

The risk of endometrial cancer (EC) subsequent to a diagnosis of colorectal cancer in women with a germline mutation in a mismatch repair gene [Lynch syndrome or hereditary non‐polyposis colon cancer (HNPCC)] is unknown. We estimated the risk of EC following a diagnosis of colorectal carcinoma (CRC) for women with Lynch syndrome. A retrospective cohort study was performed on women diagnosed with CRC with a germline mutation in a mismatch repair (MMR) gene (Lynch syndrome cases), and women with microsatellite stable (MSS) CRC who were not known to carry a germline mutation (non‐Lynch cases), identified from the Colon Cancer Family Registry. The incidence of EC following CRC was estimated and compared for women with and without Lynch syndrome, using adjusted hazards ratios calculated for time at risk among each group. A total of 112 women with Lynch syndrome and a previous diagnosis of CRC were compared with 908 women without Lynch and with a MSS CRC diagnosis. The estimated 10‐year cumulative risk of EC subsequent to CRC was 23.4% [95% confidence interval (CI): 15–36%] for Lynch syndrome women compared with 1.6% (95% CI: 0.7–3.8%) for non‐Lynch women. After adjusting for ascertainment, age at diagnosis and diagnosis of other cancers, risk of subsequent diagnosis with EC was elevated sixfold in women with Lynch syndrome compared with non‐Lynch women (HR 6.2; 95% CI 2.2–17.3; p = 0.001). Approximately one quarter of women diagnosed with Lynch syndrome‐associated CRC developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women.     

Risk factor analysis of coexisting endometrial carcinoma in patients with endometrial hyperplasia: a retrospective observational study of Taiwanese Gynecologic Oncology Group

Objective

To evaluate the clinical outcome and parameters related to coexisting endometrial carcinoma in women with tissue-diagnosed endometrial hyperplasia.

Methods

Between January 1991 and December 2009, three hundred and eighty-six patients with the presumptive diagnosis of endometrial hyperplasia were retrieved. Among these, one hundred and twenty-five patients were identified as having coexisting endometrial carcinoma in hysterectomy specimens. The three hundred and eighty-six patients were divided into two groups: the hyperplasia-benign group (261 cases) and the hyperplasia-malignant group (125 cases). Several clinical parameters including age, menopausal status, history of abnormal uterine bleeding, obstetrical history, medical history of diabetes and hypertension, BMI, and preoperative pathologic results were investigated.

Results

Age ≥53 (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.26 to 4.57), menopausal status (OR, 2.07; 95% CI, 1.14 to 3.76), diabetes history (OR, 7.33; 95% CI, 2.79 to 19.26), abnormal uterine bleeding (OR, 3.99; 95% CI, 1.22 to 13.02), atypical endometrial hyperplasia (OR, 7.38; 95% CI, 4.03 to 13.49), and body mass index ≥27 (OR, 3.24; 95% CI, 1.76 to 5.97) were independent risk factors for prediction of endometrial hyperplasia coexisting with endometrial carcinoma. The diagnostic efficacy of atypical endometrial hyperplasia to predict the endometrial hyperplasia coexisting with endometrial carcinoma was better than or similar to those of other independent factors and combinations of these factors.

Conclusion

Coexisting malignancy should be considered when examining endometrial hyperplasia patients with the related risk factors, especially atypical endometrial hyperplasia.     

Does a family history of cancer increase the risk for postmenopausal endometrial carcinoma? A prospective cohort study and a nested case-control family study of older women.

BACKGROUND: As part of the hereditary nonpolyposis colon carcinoma (HNPCC) constellation of neoplasia caused by defects in mismatch repair genes, some endometrial carcinomas are known to have a genetic contribution to etiology. However, most endometrial carcinomas occur in postmenopausal women, presumably without the HNPCC defect. Consequently, the genetic contribution to these cases is unclear. The objective of this study was to determine whether family history of cancer is a risk factor for endometrial carcinoma in older women. METHODS: The authors analyzed incident endometrial carcinoma data, as well as data on family history of various cancers in first-degree relatives, from a cohort of 24,848 postmenopausal Iowa women ages 55-69 years who were cancer free at baseline in 1986. Because a positive family history is dependent on many factors, including the age of the patient, the number of relatives, and the distribution of other risk factors in relatives, the authors also conducted a nested case-control study on family members of 95 patients with endometrial carcinoma diagnosed during 1988-1989 and 91 cancer free controls who were chosen randomly from subjects matched for age (+/-1 year). RESULTS: During 10 years of follow-up of the cohort, 322 incident endometrial carcinoma cases occurred. Women who reported a positive family history of cancer overall or at any specific site (e.g., the endometrium, colon, or breast) were not at increased risk for endometrial carcinoma. Adjustment for potential confounders, such as age, obesity, parity, oral contraceptive use, and estrogen replacement therapy, did not alter these results. Analysis of the family members of the cases and controls produced little evidence to suggest that this lack of association between family history and endometrial carcinoma could be explained by unequal distribution of known risk factors among relatives. Case family members were slightly older than control family members, but no significant differences were found in body mass index (kg/m2), age at menarche, age at menopause, or number of pregnancies. Relation to a case or control was not associated with increased risk of endometrial, ovarian, breast, or colon carcinoma for family members. Controlling for a variety of potential confounders did not alter the results. CONCLUSIONS: No evidence was found that genetics contribute to the risk of postmenopausal endometrial carcinoma for women with no personal cancer history.