不同分子学筛查方法在Lynch综合征相关子宫内膜癌患者中的对比分析#br#

Objective?Compare the accuracy of immunohistochemical staining (IHC), microsatellite instability detection (MSI), and the combined detection of the two in the screening of Lynch Syndrome-related endometrial cancer (LS-EC), and analyze the advantages and disadvantages of actual clinical applications, to identify a routine and reasonable screening strategy. This study also reveals the incidence of LS-EC and the mutations of different mismatch repair (MMR) genes in the Chinese population in this region. Methods?IHC MMR protein detection and MSI detection were performed on the pathological tissues of diagnosed EC patients from the Second Hospital of Jilin University from November 2019 to November 2020, and the preoperative venous blood was subjected to next-generation sequencing (NGS) of Lynch syndrome-related mutations. Results?After NGS testing, 8 cases of LS were confirmed, with an incidence rate of 7.90%. 28 cases had lack of expression of MMR protein, 7 cases were diagnosed as LS, 1 case was missed diagnosis; 13 cases had high microsatellite instability (MSI-H), 3 cases were diagnosed as LS, 5 cases were missed; the combined detection of the two tests can screen out all LS patients. Conclusion?IHC combined with MSI screening is highly sensitive but not cost-effective. IHC alone is recommended as the first clinical screening method.     

Screening and diagnosis of endometrial cancer in Lynch syndrome

Lynch syndrome (LS) is an autosomal dominant inherited cancer predisposition syndrome caused by a mismatch of DNA repair (MMR system). Lifetime risk of developing endometrial and ovarian cancer in LS is higher than in the general population and gynecologic screening appears interesting. Screening is based on several tests: pelvic ultrasound, endometrial biopsy and hysteroscopy for endometrial cancer, pelvic ultrasound and CA125 for ovarian cancer. Those tests appear efficient for the diagnosis of gynecologic cancers in LS. Nevertheless, screening tests have not proved clinical benefit until now, and potential problems of compliance, risk of false negative cases, and interval cancer associated with screening do justify offering prophylactic surgery to patients. Women with LS should be informed of the potential benefits and risks of screening and the importance of evaluation in case of gynecologic symptoms or abnormal bleeding. Chemoprevention by progestin-containing oral contraceptives and the treatment of premalignant lesion are available options for reducing the risk of endometrial cancer in LS population.     

Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome

Objective

Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years.

Methods

We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1–2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation.

Results

Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected.

Conclusions

Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1–2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer.     

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for lynch syndrome

Objective

Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer.

Methods

The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6 or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing.

Results

In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome, and 42% was seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome; 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel and limited insurance coverage.

Conclusions

There are several barriers to genetic counseling and testing follow-up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome.     

The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome

Objective

Based on previous studies, standard gynecological screening consisting of annual transvaginal ultrasonography (TVU) was added with endometrial sampling in women with Lynch syndrome (LS). The aim of this study was to evaluate the additional value of endometrial sampling in detecting (pre)malignancies of the endometrial tissue in women with LS or first-degree relatives.

Methods

All women above 30 years of age with LS or first-degree relatives at 50% risk of LS are offered annual gynecological screening in our family cancer clinic. Endometrial screening results from January 2003-December 2007 (period I: standard screening by transvaginal sonography and serum CA125) were compared with screening results from January 2008-June 2012 (period II: standard screening added with endometrial sampling).

Results

Seventy five women (300 patient years) were screened annually. There were 266 screening visits, 117 in period I and 149 in period II. In period I, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II, two premalignancies were found. None of the lesions would have been missed without standard endometrial sampling. No interval endometrial cancers were detected in this study.

Conclusion

In this study, annual endometrial screening seems an effective screening tool in the detection of premalignancies and early endometrial cancer in women with LS. Adding standard endometrial sampling to annual TVU has no additional value in the early detection of (pre)malignant endometrial lesions in women with LS in this study.     

Prevalence of occult gynecologic malignancy at the time of risk reducing and nonprophylactic surgery in patients with Lynch syndrome

Objective

The primary aim of this study was to determine the prevalence of occult gynecologic malignancy at the time of risk reducing surgery in patients with Lynch Syndrome. A secondary aim was to determine the prevalence of occult gynecologic malignancy at the time of surgery for non-prophylactic indications in patients with Lynch Syndrome.

Methods

A retrospective review of an Inherited Colorectal Cancer Registry found 76 patients with Lynch syndrome (defined by a germline mutation in a DNA mismatch repair gene) or hereditary nonpolyposis colorectal cancer (HNPCC) (defined by Amsterdam criteria) who had undergone hysterectomy and/or salpingo-oophorectomy for a prophylactic or non-prophylactic indication. Indications for surgery and the prevalence of cancer at the time of each operation were reviewed.

Results

24 of 76 patients underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy for Lynch syndrome or HNPCC. In 9 of these patients, a benign indication for surgery was also noted. 4 of 24 patients (17%, 95% CI = 5–38%) were noted to have cancer on final pathology. 20 of 76 patients (26%) undergoing operative management for any indication were noted to have occult malignancy on final pathology.

Conclusions

Patients should be counseled about the risks of finding gynecologic cancer at the time of prophylactic or non-prophylactic surgery for Lynch syndrome and HNPCC, and the potential need for additional surgery.     

Current and future approaches to screening for endometrial cancer

Due largely to the rise in obesity and prolonged life expectancy, endometrial cancer (EC) rates have increased by 56% since the early 90s. Women at high risk (Lynch Syndrome) have a 12–47% lifetime risk of developing EC and professional societies recommend annual surveillance using transvaginal ultrasound (TVS) and endometrial biopsy (outpatients hysteroscopy) from the age of 30–35 years with hysterectomy from the age of 40 years. In women at low risk, screening is not currently advocated. The emerging data from Genome Wide Association studies (GWAS) in combination with epidemiological data may refine risk stratification in the future. In addition to screening, preventative approaches such as intrauterine progesterone may help reduce disease burden in those identified at ‘higher risk’.     

Knowledge of Lynch syndrome among obstetrician/gynecologists and general surgeons

Objective

To determine comfort and knowledge among obstetrician/gynecologists and general surgeons regarding recommendations for cancer screening for women with Lynch syndrome.

Methods

A questionnaire on Lynch syndrome was administered to all obstetrician/gynecologists and general surgeons at a hospital in New York, USA.

Results

Fifty obstetrician/gynecologists and 62 general surgeons completed the survey (67% response rate). Physicians were more comfortable counseling on colon cancer than endometrial cancer screening (51% vs 28%; P < 0.001). Obstetrician/gynecologists were more comfortable than general surgeons counseling patients on endometrial cancer screening (36% vs 21%; P = 0.090) but less comfortable counseling patients on colon cancer screening (36% vs 63%; P = 0.008). There was no significant difference between the specialties in the number of knowledge-based questions answered correctly. Furthermore, there was no correlation between a physician’s perceived knowledge and number of correct answers.

Conclusion

Most physicians did not report being comfortable counseling about recommendations for endometrial cancer screening. While obstetrician/gynecologists reported greater comfort than general surgeons, we found no significant difference in disease knowledge between the groups. Because appropriate cancer screening can improve the outcomes of patients with Lynch syndrome, physicians must be knowledgeable and comfortable with screening recommendations for both endometrial and colon cancer, regardless of clinical specialty.     

子宫内膜癌中错配修复(MMR)蛋白表达缺失筛查Lynch综合征及其临床病理特点

目的:通过分析比较子宫内膜癌患者的错配修复(MMR)蛋白表达缺失的情况,研究其与临床标准诊断之间的关系,以及MMR蛋白表达缺失者的临床病理特征。方法:收集北京大学第一医院2011年12月至2015年7月收治的313例子宫内膜癌患者的临床资料,免疫组化法分析子宫内膜癌组织中MMR蛋白(MLH1/MSH2/MSH6/PMS2)表达情况。结果:临床诊断或可疑的Lynch综合征22例(7.0%),存在MMR表达缺失者49例(15.7%)。临床诊断或可疑Lynch的患者中,存在MMR表达缺失者的比例明显升高(P=0.011),其中主要是MSH6表达缺失存在差异(P=0.004)。MSH2表达缺失和MSH6表达缺失的患者中合并高血压的比例更低(P=0.002,P=0.045)、淋巴结转移的比例更高(P=0.025,P=0.020)、肿瘤分化差(P=0.030,P=0.010);MSH6表达缺失的患者,相对年龄更小(P=0.021)。结论:免疫组化检测MMR蛋白表达缺失在诊断或可疑Lynch综合征患者中的比例更高,可用于辅助进行Lynch综合征的筛查及诊断。MMR蛋白表达缺失与患者低龄、存在淋巴结转移、肿瘤分化不良等临床病理特征相关。     

Risk factors for HPV infection among American Indian and White women in the Northern Plains

Introduction

Immunohistochemistry (IHC) for the presence or absence of DNA mismatch repair (MMR) proteins in tumor samples is a quick and relatively inexpensive method to screen for Lynch syndrome (LS). At our institution we have found that > 20% of patients lack expression of MMR proteins and > 10% would be expected to benefit from genetic counseling (GC). However, compliance with referral to GC is poor. Therefore, we set out to analyze the reasons for noncompliance, hypothesizing that it could be due to a perception of a low risk for developing other cancers.

Methods

All patients with endometrial cancer between 2007 and 2009 were identified. Patients with absence of MMR protein expression who would be expected to benefit from GC were identified. These patients were sent a questionnaire assessing the utilization of GC services as well as their perception of LS and Lynch-associated cancers.

Results

Forty-seven patients out of 384 were identified who would have been expected to benefit from GC. Of the responders, 20 patients (77%) reported that they were referred by their physician for GC, of which 9 saw a genetic counselor, 8 had genetic testing, and 3 mutations were detected. The primary reason for not seeing a genetic counselor was no insurance coverage/cost of the visit followed by anxiety for the results. Nine patients stated that the patient/family did not want to know information regarding cancer risk. As compared to the general population 35% thought their risk of having LS was higher, 12% thought it was the same, 15% lower, and 38% was unsure. Forty-six percent of patients thought the risk of colon cancer was higher than background risk, and 26% thought it was the same.

Conclusion

Most patients underestimate their risk of LS associated heritable cancer. Physicians should pay more attention to family history and IHC in order to refer patients appropriately. In addition, more verbal and written information may enable patients to accurately assess their cancer risk. This could further improve compliance with genetic counseling and detection of Lynch syndrome.     

Guillain-Barre syndrome occurring after adjuvant chemo-radiotherapy for endometrial cancer

BACKGROUND: The association between Guillain-Barre syndrome (GBS) and malignancy is uncommon and has not been previously reported in gynecological cancers. CASE: Our case documents this syndrome occurring in a patient shortly after completion of adjuvant chemo-radiotherapy for endometrial carcinoma. We review the current literature and discuss potential pathogenic mechanisms of this likely paraneoplastic association. CONCLUSION: GBS in cancer patients is a potentially life-threatening condition and should be differentiated from simple chemotherapy toxicity, particularly as effective treatment is available.     

子宫内膜癌与代谢综合征的关系

目的 探讨子宫内膜癌与代谢综合征的关系.方法 对浙江省肿瘤医院妇瘤科2005年1月-2009年3月收治的123例原发性子宫内膜癌患者(病例组)和同期90例健康体检妇女(对照组)的临床资料进行回顾性分析,临床资料包括一般情况[年龄、绝经与否、体质指数(BMI)]及代谢综合征相关指标[腰隔、甘油三酯(TG)、高密度脂蛋白(HDL)、血压及空腹血糖],分别采用t检验和χ~2检验及logistic回归模型进行单因素及多因素分析,并对病例组内合并代谢综合征患者的病理情况进行分析.结果 (1)单因素分析结果显示,病例组与对照组比较,年龄相似[分别为(54.3±0.6)和(54.2±0.9)岁,P>0.05];绝经比例(分别为67.5%、48.9%)、BMI过大(≥25 kg/m~2)比例(分别为45.5%、23.3%)均升高,分别比较,差异均有统计学意义(P<0.05,P<0.01).病例组与对照组比较,合并代谢综合征比例(分别为43.9%和18.9%)、腰围过大(>80 cm)比例(分别为50.4%、27.8%)、高TG(>1.7 mmol/L)比例(分别为40.7%、21.1%)、血压异常[≥130/85 mm Hg(1 mm Hg=0.133 kPa)]比例(分别为40.7%、25.6%)、血糖异常(空腹血糖≥5.6 mmol/L)比例(分别为53.7%、21.1%)及低HDL(<1.30 mmol/L)比例(分别为63.4%、32.2%)均升高,分别比较,差异均有统计学意义(P<0.05).(2)病例组内是否合并代谢综合征患者的病理类型、手术病理分期、病理分级比较,差异均无统计学意义(P>0.05).(3)logistic多因素分析提示,中心性肥胖、高TG、低HDL、空腹血糖异常是子宫内膜癌合并代谢综合征的独立危险因素(P<0.05).结论 子宫内膜癌与代谢综合征关系密切,代谢综合征可能成为筛查和防治子宫内膜癌的新视点.     

Disseminating universal genetic testing to a diverse,indigent patient population at a county hospital gynecologic oncology clinic

Objective

The universal genetic testing initiative (UGTI) is a quality improvement effort to increase rates of guideline-based genetic counseling (GC) and genetic testing (GT) of patients with potentially hereditary cancers. The UGTI was disseminated to a county hospital gynecologic oncology clinic that serves a diverse, indigent patient population.

The results of gynecologic surveillance in families with hereditary nonpolyposis colorectal cancer

Objective

We aimed to estimate the incidence rate of endometrial cancer (EC) and to evaluate the results of EC-surveillance in hereditary nonpolyposis colorectal cancer (HNPCC) families.

Methods

All at-risk women recommended for EC-surveillance by the HNPCC-register—2959 women (19,334 women years)—were included. Data on EC-surveillance were available for 871 women (6894 women years), who had performed 1945 surveillance visits. The average surveillance period was 7.9 (range 0.1−21.7) years and 46% of the women had had less than 3 years between their visits.

Results

During 19,334 women years, 60 women with gynecological malignancies or premalignancies were diagnosed. Thirty-nine women had EC. Of these, 31 were from families with identified MMR gene mutations with the median age at diagnosis of 54 (39–83) years (Incidence Rate, IR = 0.63 per 100 women years) and four women from each Amsterdam (AMS)-positive and AMS-like families (median age 64 (55–73) years, IR = 0.06 and 0.05 per 100 women years, respectively, p < .0001).Among the 871 surveilled women, 13 EC were found: 7/13 cases were diagnosed by surveillance examination—two as prevalent cancers, diagnosed at the first visit—and 6/13 based on symptoms. In addition, five complex atypical hyperplasias and four ovarian cancers (OCs) were diagnosed. All these women were MMR mutation carriers.

Conclusion

Based on 19,334 women years of EC-surveillance, our analysis provides a thorough estimation of the EC risk in women with an MMR mutation, or suspected of having Lynch syndrome. We conclude that EC surveillance should only be targeted at MMR-mutation carriers.     

林奇综合征相关卵巢癌新进展

林奇综合征（Lynch syndrome,LS）是一种常染色体显性肿瘤综合征,是由DNA错配修复（MMR）基因中的一个胚系突变使细胞具有高微卫星不稳定表型（MSI-H）的超突变或缺乏MMR蛋白表达从而引起肿瘤的发生。突变携带者具有罹患结直肠癌、子宫内膜癌和卵巢癌等一系列恶性肿瘤的高风险。虽然LS中最常见的是结直肠癌,但约有60％的LS首发癌为妇科恶性肿瘤（如子宫内膜癌、卵巢癌等）,且其被诊断年龄较早、组织病理学大多为子宫内膜样或非浆液性类型、总体存活率良好。因此及时发现LS相关卵巢癌（LSAOC）这一亚类,对于预防LS患者其他肿瘤的发生,提高LS患者的生存率具有重要意义。目前关于LS的发病机制、组织病理学等方面不断有新的探索,现就LSAOC的早期诊断、组织病理学、筛查及降低风险方案的最新进展进行综述。     

Recurrence patterns and surveillance for patients with early stage endometrial cancer

Introduction

To evaluate the recurrence patterns and the clinical and economic role of surveillance with vaginal cytology in women with low risk endometrial cancer.

Methods

Patients undergoing primary surgery with final pathology consistent with a grade 1 endometrial cancer confined to the endometrium (FIGO 1988 stage IA) between 9/1997–12/2007 were retrospectively identified. Follow-up data for at least 2 years was also collected, including diagnosis of a recurrence, symptomatology at that time, and method of detection. Costs for vaginal cytology were estimated using Medicare charge-to-cost ratios adjusted to 2010 costs.

Results

One hundred fifty-four patients met study inclusion criteria. The mean age was 54.4 years and the mean follow-up was 46.9 months. Four recurrences were detected, occurring 16–73 months after the initial diagnosis. During a scheduled visit, one patient was found to have an asymptomatic vaginal cuff recurrence, detected on physical examination. The remaining three cases were diagnosed at an unscheduled visit after the presence of symptoms (vaginal bleeding, abdominal pain, shortness of breath) prompted further evaluation. In all, cytology detected no cases of recurrence and the estimated cost associated with cytology alone for all patients over the study time frame was approximately $7,760 per year.

Conclusions

Patients with grade 1 endometrial cancer confined to the endometrium have a low risk of recurrence (2.6%) and were detected on clinical findings alone. Emphasis should be placed on counseling patients on symptoms of recurrence and performing a thorough physical examination. The elimination of vaginal cytology for this select group of patients may be appropriate and result in a significant reduction in health care costs.     

Clinical tools and counseling considerations for breast cancer risk assessment and evaluation for hereditary cancer risk

Breast cancer is a complex and heterogeneous disease. Unfortunately, it is the most common malignancy diagnosed in women in the USA, with 281,550 new cases of invasive breast cancer and 49,290 new cases of noninvasive breast cancer are diagnosed per year. In England, it is currently estimated that approximately 1 in 7 (14%) women will be diagnosed with breast cancer in their lifetime. In the UK in 2017, 54,700 women and 390 men were diagnosed with breast cancer. The risk of breast cancer is influenced by many factors, including but not limited to age, family history, reproductive history, hormonal exposure, proliferative breast lesions, physical activity, alcohol use, tobacco use, breast density, and environmental exposures. Breast cancer risk assessment is a critical part of public health. By identifying women at high risk for breast cancer, personalized recommendations can be deployed with regards to modes of screening, the age to initiate breast screening, and the frequency for completing such screens. In addition, breast cancer risk assessment can assist in determining a woman's eligibility for interventions to reduce risk, either through the use of chemoprevention medications or through surgical means with risk-reducing bilateral mastectomy.This chapter summarizes breast cancer risk assessment models and discusses interventions to reduce breast cancer risk to aid in reducing morbidity and mortality from breast cancer.     

Low serum selenium concentration in patients with cervical or endometrial cancer

Serum concentrations of selenium were determined in 37 patients with cervical and 64 patients with endometrial cancer. The patients had lower (P less than 0.001) serum concentrations of selenium than the age-, weight- and place of residence-matched paired control women. There was no difference in the selenium concentration between various age groups or different clinical stages of cervical or endometrial cancer. A low serum concentration of selenium might be a contributing factor in uterine carcinogenesis.     

Risk factors for early and late postoperative complications of patients with endometrial cancer

OBJECTIVE: We have routinely performed staging with pelvic and/or paraaortic lymphadenectomy in patients with endometrial cancer having moderate to high risk for lymph node metastasis. The aim of this study was to investigate the risk factors for the occurrence of early and late postoperative complications in patients managed primarily by surgery in our institution. STUDY DESIGN: Two-hundred and fifty-nine consecutive cases of endometrial cancer were enrolled in the study. Past history, body mass index, type of surgery, intraoperative findings, and follow-up information were collected from patient charts. Of these, 200, 127, and 30 patients underwent systematic pelvic lymphadenectomy, systematic paraaortic lymphadenectomy, and radical hysterectomy, respectively. The median numbers of dissected pelvic and paraaortic lymph nodes were 32 and 14, respectively. RESULTS: None of the complications resulted in death. Of the study population, 36 early complications and 34 late complications occurred. Overall 65 patients (25.1%) had at least one complication. Multivariate analysis revealed that a longer operative time and paraaortic lymphadenectomy were independent predictors for the occurrence of early and late postoperative complications, respectively. CONCLUSIONS: Since the therapeutic value of lymphadenectomy is still under evaluation, the indications for systematic pelvic and paraaortic lymphadenectomy should be carefully considered.