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.     

Outcomes of screening endometrial cancer patients for Lynch syndrome by patient-administered checklist

Objective

The aims of this study were to implement a patient-administered checklist designed to identify endometrial cancer patients at elevated risk for Lynch syndrome; measure subsequent genetic counseling and testing; and identify differences between those who attended genetic counseling and those who did not.

Methods

We developed a 4-item yes/no checklist of personal and family history risk factors for Lynch syndrome-associated endometrial cancer and recommended referral for genetic counseling for patients meeting any of the criteria. Retrospective chart review was performed to determine subsequent genetic counseling and testing outcomes over a 15 month period.

Results

6/387 (1.6%) of endometrial cancer patients tested positive for a Lynch syndrome mutation. 4/24 (17%) of endometrial cancer patients who met referral criteria and attended genetic counseling tested positive. 38/70 (55%) of patients who met referral criteria were not seen for genetic counseling. Patients who were diagnosed with endometrial cancer at younger ages, who had primary surgery at our institution, or who met more than one referral criteria were more likely to be seen for genetic counseling.

Conclusions

Endometrial cancer patients who met referral criteria and attended genetic counseling comprised a population enriched for Lynch syndrome. This approach allowed Lynch syndrome evaluation resources to be targeted to a population of patients that is high risk and interested in the information. The referral rate of at-risk patients needs to be improved, and allocating resources towards this goal could increase the identification of Lynch syndrome while avoiding some of the pitfalls of universal screening.     

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’.     

Mismatch repair protein deficiency in endometriosis: Precursor of endometriosis-associated ovarian cancer in women with lynch syndrome

ObjectiveWe aimed to elucidate the pathogenesis of ovarian cancer through the loss of mismatch repair (MMR) proteins in women with Lynch syndrome (LS) in this report.Case reportTwo women with LS underwent surgery for synchronous endometrial cancer and ovarian cancer. In both cases, immunohistochemical examination showed concomitant MMR protein deficiency in endometrial cancer, ovarian cancer, and contiguous ovarian endometriosis. In Case 1, the macroscopically normal ovary included multiple endometrioses with MSH2 and MSH6 expression, and FIGO grade 1 endometrioid carcinoma and contiguous endometriosis without MSH2 and MSH6 expression. In Case 2, all endometriotic cells contiguous with carcinoma in the lumen of the ovarian cyst showed loss of the expression of MSH2 and MSH6.ConclusionOvarian endometriosis with MMR protein deficiency may progress to endometriosis-associated ovarian cancer in women with LS. Diagnosing endometriosis in women with LS during surveillance is important.     

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.     

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.     

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.     

林奇综合征相关子宫内膜癌研究进展

林奇综合征（lynch syndrome,LS）是一种常染色体显性遗传病,既往称为遗传性非息肉病性结直肠癌（hereditary nonpolyposis colorectal cancer,HNPCC）,是由DNA错配修复（mismatch repair,MMR）基因MLH1、MSH2、MSH6和PMS2的胚系突变引起。LS患者有多种癌变倾向、发病低龄化及家族易感性,可同时或异时发生结直肠癌、子宫内膜癌（endometrial cancer,EC）、卵巢癌、胃癌和乳腺癌等,女性患者中EC与之最为密切,目前我国对于LS相关EC（LS-EC）认识尚不足,并未形成完整的诊疗标准或指南。为提高对LS-EC的认识,综述LS-EC的分子机制、临床病理特征、筛查及诊断、临床治疗手段、预防等。     

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.     

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。     

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.     

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.     

Clinicopathologic significance of DNA mismatch repair protein status in endometrial cancer

ObjectiveThe prognostic implications of DNA mismatch repair protein (MMRP) have not been determined in endometrial cancer. Therefore, in this study, we aimed to evaluate the clinicopathologic characteristics of DNA MMRP deficiency in endometrial cancer.Materials and methodsWe examined the MMRP status of 206 patients with endometrial carcinomas, using immunohistochemistry, and analyzed their clinicopathologic factors and survival outcomes stratified by MMRP status using the Kaplan–Meier method and Cox regression analysis.ResultsForty-three cases were deficient for at least one MMRP (20.9%). Loss of MLH1 was the most common (13.1%), followed by MSH6 (7.8%). MMRP deficiency was significantly associated with lympho-vascular space invasion, deep myometrial invasion, and adjuvant treatment (P = 0.032, 0.041, and 0.047, respectively). MMRP-deficient patients had a better overall survival (OS), particularly at advanced cancer stages (III/IV) (100% vs. 73.7%, P = 0.170) or if they had received adjuvant treatment (100% vs. 86.7%, P = 0.087).ConclusionAlthough MMRP deficiency was associated with unfavorable prognostic risk factors in endometrial cancer, we found a trend in favor of OS in MMRP-deficient patients. More studies are needed to confirm its prognostic implication.     

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。     

Expression of DNA repair proteins in endometrial cancer predicts disease outcome

Objective

The consequences of defective homologous recombination and other DNA repair pathways are important in disease outcomes of numerous tumor types. The objective of this study was to explore BRCA1, PARP, FANCD2, PTEN, H2AX, and ATM protein expression in endometrial cancer (EC).

Methods

PARP1, γH2AX, ATM, FANCD2, PTEN, BRCA1, and p53 proteins were evaluated in EC tissue microarray (TMA) and their expressions were correlated with clinical and pathological parameters in 357 patients.

Results

In type I EC, PARP1⁺, ATM⁺, and FANCD2⁺ were associated with high tumor grade (p 0.031, p 0.0045, p 0.0062 respectively); γH2AX⁺ and FANCD2⁺ with advanced tumor stage (p 0.0004, p 0.0085 respectively); γH2AX⁺, FANCD2⁺ and p53⁺ with the presence of lympho-vascular invasion (p 0.0004, p 0.0042, p 0.0098 respectively); and γH2AX⁺ and ATM⁺ with tumor recurrence (p 0.0203, p 0.0465) respectively. In type II EC, only PARP1⁺ was associated with tumor stage (p 0.0499). EC patients with p53⁺ or FANCD2⁺ were more likely to recur with 5 year recurrence free survival (RFS) probability of 71.4% in comparison to 85.5% for the other patients and they were more likely to have shorter 5 year overall survival (OS) of 66.46% in comparison to 78.5% of those other patients Finally, patients with ATM⁺ and p53⁺ or FANCD2⁺ were more likely to recur with 5 year RFS probability of 68% versus 80.3% for the other patients.

Conclusion

DNA repair proteins seemed to play an important role in EC, and their expressions can forecast for poor outcomes.     

A self-administered family history questionnaire improves identification of women who warrant referral to genetic counseling for hereditary cancer risk

Objectives

This study was undertaken to assess a self-administered family history questionnaire in order to better identify women within a gynecologic oncology practice for referral to genetic counseling services.

Methods

Returning patients at an outpatient gynecologic oncology clinic completed a self-administered family health history questionnaire and a detailed telephone interview. A genetic counselor separately assessed blinded information garnered from the questionnaire, structured genetic interview, and electronic medical records to determine whether these data warranted referral to genetic counseling based on established criteria. The structured genetic interview was considered the gold standard to which the questionnaire and medical record information were compared.

Results

Of the 45 total participants in the study, 26 (58%) were identified from the structured genetic interview as meeting criteria for referral to genetic counseling. The questionnaire identified 21 (81%) of these 26 referrals, while the medical record identified 13 (50%) of these 26 referrals. This led to a 62% increase in referral capture by the questionnaire. The median time to complete the questionnaire was 17 min (range 5-57 min). Thirty-four participants (75.6%) had more family members with cancer identified on the questionnaire compared to the electronic medical record. The questionnaire identified fewer family members with cancer in the five cases that were missed for appropriate referral.

Conclusions

Current standard clinical practices are insufficient at identifying patients in need of referral to genetic counseling. A self-administered questionnaire improves recognition of candidates for genetic counseling in a gynecologic oncology practice.     

The development and evaluation of a community based model for cervical cancer screening based on self-sampling

Objective

To develop and implement a community based model for cervical cancer prevention that allows the communities to manage the screening and the healthcare system to focus resources on evaluation and management of the positives.

Methods

Using self-sampling and the concepts founded in Community Based Participatory Research (CBPR), we progressively developed a model to efficiently reach the women, especially rural communities; and collect the volume of samples needed to support high throughput centralized low cost per case processing.

Results

8382 eligible women, ages 35 to 59, in 130 rural communities participated. The screening was organized by the local government administration and conducted by the community leaders (CLs). The model used was progressively designed through detailed assessment of key elements at 6 decision points in 26 workshops that were used to train the CLs and the local promoters. The communities were able to accurately conduct the screening; in the final model a local medical worker conducted a 50-minute workshop featuring instructional posters and structured role-play. A manual and a workshop DVD were created for distribution to and implementation by local governments. The average callback rate was 84.3%, without involvement of the local doctors in the management of the positives.

Conclusion

An efficient community based model capable of massive screening events was developed. We believe that the callback rate will be further improved when local doctors are trained in the management of the positives. Many elements impact coverage and further research is needed to define the influence of the identified key variables.