Gynecologic screening in hereditary nonpolyposis colorectal cancer

OBJECTIVE: In hereditary nonpolyposis colorectal cancer (HNPCC), women with a mismatch repair (MMR) gene mutation have a cumulative lifetime risk of 25-50% for endometrial cancer and 8-12% for ovarian cancer. Therefore, female members of HNPCC families are offered an annual gynecologic and transvaginal ultrasound (TVU) examination and serum level CA 125 analysis. The aim of the present study was to evaluate our 10-year experience with this screening program. METHODS: Women who are MMR gene mutation carriers or who fulfil the Amsterdam criteria were identified from our HNPCC database. Information concerning the screening program was retrospectively collected from patient files. RESULTS: Forty-one women, 35 premenopausal and 6 postmenopausal, were enrolled in the program with a median follow-up of 5 years (range 5 months-11 years). In 197 patient years at risk, 17 of 179 TVUs gave reason for endometrial sampling. Three premalignant lesions, with complex atypical hyperplasia, were discovered. One interval endometrial cancer was detected as a result of clinical symptoms. No abnormal CA 125 levels were measured and no ovarian cancers were detected. CONCLUSIONS: These results demonstrate that gynecologic screening allows the detection of premalignant lesions of the endometrium but also illustrate that recognition and reporting of clinical symptoms by the women themselves is of utmost importance.     

Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40-60% lifetime risk for colon cancer, a 40-60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their "sentinel cancer." METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the "sentinel cancer," preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome.     

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.     

The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer

OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS:. Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage.     

The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer

OBJECTIVE: Ovarian cancer has one of the highest fractions of hereditary cases. The hereditary breast and ovarian cancer syndrome, primarily due to mutations in BRCA1 and BRCA2, is the main cause of heredity, but also the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome confers an increased risk of ovarian cancer. In order to clarify the contribution of HNPCC to the development of ovarian cancer, we collected data on family history of cancer and characterized MMR function in a consecutive series of 128 tumors unselected for age at diagnosis and previously characterized for BRCA gene mutations. METHODS: Expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry using tissue microarray sections. Tumors with reduced staining or loss of staining were also analyzed for microsatellite instability (MSI). RESULTS: Loss of MMR protein expression was identified in 3 ovarian cancers, all of which had a MSI-high phenotype. DNA sequence analysis revealed disease-causing germline mutations (deletions of exons 4-6 in MLH1 and a 1-nucleotide deletion in exon 5 of MSH6) in two patients diagnosed at ages 40 and 49 years, both of whom had family histories suggestive of HNPCC. The genetic defect in the third case, which was a 47-year old woman without knowledge about her family history with loss of MLH1/PMS2 expression in the tumor tissue, remains elusive. A family history suggestive of HNPCC was identified in an additional case, but this tumor showed normal, retained MMR protein expression and a microsatellite stable phenotype. CONCLUSIONS: About 2% of ovarian cancer is caused by germline mutations in the MMR-genes, a minor proportion as compared to the contribution of the BRCA-genes (11% in the present series). However, identification of HNPCC patients is important since it allows inclusion of high-risk individuals into control programs aimed at preventing the more frequent colorectal and endometrial cancers. Tumors within the HNPCC-spectrum should therefore be included when recording a family history of cancer among patients diagnosed with ovarian cancer.     

Occult endometrial cancer and decision making for prophylactic hysterectomy in hereditary nonpolyposis colorectal cancer patients

BACKGROUND AND OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent form of hereditary colorectal cancer. In addition to the high lifetime risk for colorectal cancer in mutation carriers, there is also a remarkably increased risk for endometrial cancer (EC). METHODS: In this retrospective study, clinical and molecular approach to the individual decision making as to whether or not to perform a prophylactic hysterectomy in a subset of HNPCC patients is discussed. 147 female patients meeting at least one criterion of the Bethesda guidelines were included in this analysis between 1995 and 2003. After clinical and genetic counseling, patients gave informed written consent and microsatellite analysis, immunohistochemistry and sequencing of the mismatch repair genes MLH1, MSH2 and MSH6 was performed. RESULTS: 11 of the analyzed patients had a personal history of EC and had undergone previous hysterectomy at ages 26 to 62 years. Prophylactic hysterectomy with oophorectomy was considered in postmenopausal women meeting the Amsterdam criteria and/or carrying a disease causing mismatch repair gene mutation who were operated on because of diagnosed colorectal cancer in our center for hereditary cancer. This procedure was performed in 4 patients. None of them had shown any symptoms of a gynecologic malignancy. Preoperative gynecological examination showed no evidence for EC or ovarian cancer in these patients. Postoperative histological examination showed EC stage T1b N0 M0 in 2 patients. CONCLUSIONS: Since the efficiency of gynecological surveillance is uncertain, prophylactic hysterectomy could be an option for a subset of HNPCC patients and mutation carriers.     

Two cases of endometrial cancer meeting new clinical criteria for hereditary nonpolyposis colorectal cancer

BACKGROUND: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC) that includes extracolonic cancers were recently proposed. We present 2 endometrial cancer patients who met the new criteria of 161 endometrial cancer patients. CASE REPORTS: Case 1: A 55-year-old female was operated on for synchronous double primary cancers of the endometrium and rectum. She had also undergone an operation for metachronous ascending colon cancer at the age of 44. She had five relatives with a history of colorectal cancer. The rectal cancer tissue revealed no microsatellite instability (MSI). Case 2: A 48-year-old female underwent a radical operation for synchronous double primary cancers of the endometrium and ovaries. She had three relatives with a history of colorectal cancer. The endometrial cancer tissue showed high MSI. CONCLUSIONS: The frequency of endometrial cancer patients meeting the new HNPCC criteria was 1.2% (2/161). These are the first case reports selected from consecutive endometrial cancer patients.     

遗传性非息肉性结直肠癌综合征相关性子宫内膜癌的临床病理特征

目的 探讨遗传性非息肉性结直肠癌综合征(HNPCC)相关性子宫内膜癌的临床病理特征.方法 采用回顾性分析方法,将1981年1月至2006年6月间天津医科大学总医院421例住院的子宫内膜癌患者根据有无恶性肿瘤家族史分为3组:A组:散发性子宫内膜癌,331例;B组:非特异肿瘤聚集性子宫内膜癌,63例;C组:HNPCC相关性子宫内膜癌,27例.比较3组临床病理特征的差异.结果 HNPCC相关性子宫内膜癌占全部子宫内膜癌患者的6.4%(27/421);平均发病年龄为49.7岁,明显早于A组的56.3岁及B组的55.2岁,C组分别与A组、B组比较,差异均有统计学意义(P=0.004、0.035).C组患者合并其他部位原发肿瘤的发生率为33.3%(9/27),较A组及B组的5.1%(17/331)及14.3%(9/63)显著升高;C组分别与A组、B组比较,差异均有统计学意义(P值分别为＜0.01、0.038).3组患者绝经状态及病理类型无显著差异(P均＞0.05).C组及B组病理分级G1患者分别为70.4%(19/27)、61.3%(38/62),明显高于A组的45.5%(141/310);C组及B组分别与A组比较,差异均有统计学意义(JP值分别为0.013、0.023).C组患者的预后明显好于A组,病死率低于A组,两组比较,差异有统计学意义(x2=5.337,P=0.021).C组患者的5年和10年生存率均为96%,B组分别为88%、85%,A组分别为80%、70%.结论 HNPCC相关性较散发性子宫内膜癌平均发病年龄早,易合并其他部位原发肿瘤,以高分化癌多见,预后较好.     

Gynecologic cancer clues to Lynch syndrome II diagnosis: a family report.

Lynch syndrome II was diagnosed when two sisters manifested early-onset synchronous carcinomas of the ovary and endometrium and a third sister was found to have Duke's A carcinoma of the cecum. A detailed cancer family history indicated paternal transmission of the deleterious genotype. The pattern of carcinoma of the colorectum and extracolonic sites throughout the extended family was then found to be consonant with this hereditary cancer-prone disorder. Lynch syndrome II may be exceedingly difficult to diagnose due to an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Its recognition is therefore dependent on a detailed cancer family history (all anatomic sites), coupled with knowledge of the pattern of the cancer spectrum, distribution, and natural history, as manifested in this hereditary disorder. We describe the decision logic that was involved in the diagnosis of Lynch syndrome II in this family and indicate the important role of the gynecologists in this process.     

Gynecological tumors revealing hereditary nonpolyposis colorectal cancer: analysis of a large Lebanese pedigree

The objective of this study was to evaluate the aggregation of colorectal cancer (CRC) and hereditary nonpolyposis colorectal cancer (HNPCC)-related extracolonic cancers in an extended Lebanese family with HNPCC. This was a pedigree analysis and a prospective follow-up over an 8-year period. The causative germ line mutation was detected using denaturing high-performance liquid chromatography, polymerase chain reaction (PCR) of short fluorescent fragments, and direct DNA sequencing of purified PCR products. The penetrance of CRC is high and accounts for approximately two thirds of risk carriers with an early age of onset (21 years). The extracolonic cancer spectrum includes ovary, endometrium, small bowel, skin, and brain, with an age of onset as early as 30 years. The causative mismatch repair gene mutation is an MSH2 point mutation involving the splice donor site of intron 3 (G-->A). Scrutinized in genomic DNA from 35 consented members, it was found in 18 of them and cosegregates with the cancer phenotype in the family. Early-onset ovarian and endometrial carcinomas may reveal HNPCC families in the Middle Eastern region, with MSH2 germ line mutation. We propose a biannual screening program, starting around the age of 20-25 years, pending additional data on this topic.     

Hereditary nonpolyposis colorectal cancer with gynecologic malignancies: report of two families in Taiwan.

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is characterized by germline and somatic mutations of DNA mismatch repair genes with dominant inheritance of site-specific colorectal cancer or colorectal cancer plus cancers of extracolonic sites. We describe two Taiwanese HNPCC families with members who had predominantly gynecologic malignancies. In one family, the 53-year-old proband was found to have five synchronous and metachronous tumors of the genitourinary system, which included endometrial adenocarcinoma, cervical squamous cell carcinoma, ureteral and bladder transitional cell carcinoma, and ovarian teratoma. Fourteen of her first- and second-degree relatives were victims of genitourinary and gastrointestinal malignancies. The other family was characterized by four sisters who developed endometrial adenocarcinomas at young ages (36-42 yr). Their father died of both stomach cancer and colon cancer at age 47. The diagnosis of HNPCC was confirmed in this family by genetic analysis. A heterozygous germline mutation (G5 to G6 frame-shift at 183-187) of the hMSH2 (human MutS homolog 2) gene was identified in white blood cells of all the affected family members. The frequent presentation of genitourinary cancers in HNPCC highlights the importance of family-history taking in patients with gynecologic cancers and a genetic diagnosis of HNPCC.     

The detection of microsatellite instability in blind endometrial samples—a potential novel screening tool for endometrial cancer in women from hereditary nonpolyposis colorectal cancer families?

Microsatellite instability (MSI) is the phenotypic molecular characteristic of the majority of tumors associated with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC). Women in this group have an increased risk of endometrial cancer (EC). This study aimed to determine whether MSI could be demonstrated in blind endometrial samples from women with EC, HNPCC kindreds undergoing screening for EC, and women with normal endometrium. Twenty-four women with EC, 20 women from HNPCC kindreds, and 20 women undergoing gynecological surgery for benign indications underwent blind sampling. MSI analysis was performed by conventional polymerase chain reaction using fluorescent-labeled primers and automated analysis. Twelve microsatellites were studied with MSI defined as evident when novel alleles were seen in endometrial biopsy samples compared to genomic DNA. Of the 24 EC samples obtained, sufficient DNA for analysis was extracted in 17 cases. Three cases had evidence of MSI in at least 7/12 loci. None of the endometrium from the two other study groups revealed evidence of MSI. This is the first demonstration of MSI in blind endometrial biopsies. The ability to demonstrate MSI in heterogeneous endometrial samples suggests potential for the development of a novel EC screening tool for women in HNPCC kindreds.     

Microsatellite instability and hMLH1 and hMSH2 gene expression in Taiwanese hereditary nonpolyposis colorectal cancer.

BACKGROUND AND PURPOSE: The mutation rate of hMSH2 and hMLH1 (20%) in Taiwanese hereditary nonpolyposis colorectal cancer (HNPCC) is lower than that reported in other countries. This study aimed to examine the microsatellite instability (MSI) status and gene expression pattern of Taiwanese HNPCC in an effort to establish correlation between these data and results of prior genetic screening. METHODS: The "Bethesda markers" were used for the MSI analysis. Tumor and neighboring tissues were obtained from 10-mm sections of neutral formalin-fixed, paraffin-embedded, hematoxylin and eosin-stained specimens with a PixCell laser-capture microdissector. Four-mm sections were used for the immunohistochemical analysis by avidin-biotin complex method and final coloring with diaminobenzidine. A pathologist performed scoring of the pathological specimens twice, using a double-blinded methodology. Thirteen tissue blocks from 8 HNPCC families (Amsterdam's criteria) were included in this study. RESULTS: Although the majority of the HNPCC tissues displayed a MSI-high phenotype (10/13, 76.9%), lack of expression of MSH2 and MLH1 was infrequent. Furthermore, only 1 germ-line mutation was detected in the peripheral blood leukocytes of the patients whose tumors had lost protein expression of MSH2 or MLH1. CONCLUSIONS: Our results indicate that the pathogenesis of Taiwanese HNPCC is different from that in other countries. Rather than immunohistochemical analysis, MSI status, and genetic screening, clinical history remains a reliable method for diagnosis of HNPCC in Taiwanese the population.     

Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance

OBJECTIVES: The lifetime risk of endometrial and ovarian cancers in hereditary nonpolyposis colorectal cancer (HNPCC) is up to 60 and 12%, respectively, in addition to the high risk of colorectal cancer. International guidelines recommend surveillance of those at risk with colonoscopy every 1--2 years from age 20--25 years and annual gynecologic surveillance from 25--35 years for women. We reviewed our own experience to see whether these recommendations were appropriate. METHODS: Pedigrees of 120 HNPCC families registered with the Familial Bowel Cancer Service at The Royal Melbourne Hospital were reviewed. Ninety families met our criteria for HNPCC and were included in the study. Pedigrees were analyzed to identify early-age onset colorectal and gynecologic cancers and to calculate cumulative incidence of both cancer types for at-risk women (HNPCC-affected and first-degree female relatives of affected family members) for comparison with the general population. RESULTS: Colorectal cancer occurred in 434 individuals, endometrial cancer in 43, and ovarian cancer in 24. Gynecologic and colorectal cancers were diagnosed at similar ages (mean 49.3 versus 51.8 years; P = 0.25), with 5 (7.1%) gynecologic cancers diagnosed by 35 years. Cumulative incidences of gynecologic and colorectal cancers to ages 25, 30, 35, and 40 years were substantially higher among at-risk women than in the general population. CONCLUSIONS: Consideration should be given to offering gynecologic cancer surveillance from the age of 25 years, as for colorectal cancer. However, this approach should be individualized as it has yet to be demonstrated that surveillance reduces the mortality of gynecologic cancer in HNPCC.