Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy?

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is defined by germline mutations in the E-cadherin gene, CDH-1. The first family in which CDH-1 mutations were identified was a large Maori kindred, where lifetime penetrance is 70%. Prophylactic gastrectomy is an unacceptable option for many mutation carriers. The results of annual chromoendoscopic surveillance using the methylene blue/congo red technique in 33 mutation carriers over a five year period are described. PATIENTS AND METHODS: Thirty three confirmed CDH-1 mutation carriers (18 males, 15 females), median age 32 years (range 14-69), were enrolled in 1999-2003. Medical records, endoscopy, and pathology were reviewed retrospectively. RESULTS: Over five years, 99 surveillance endoscopies were performed, of which 93 were chromo-dye enhanced. Sixty nine chromoendoscopies were normal. In 24 procedures, 1-6 pale areas/stomach (size 2-10 mm) were detected post chromo-dye application (totalling 56 pale lesions). One biopsy was taken from each pale lesion: 23 lesions (41%) showed signet ring cell carcinoma (10 patients), 10 lesions (18%) gastritis (four patients), and 23 (41%) normal mucosa (10 patients). No chromo-dyes were used in six procedures with macroscopic lesions (two HDGC, four ulceration). Total gastrectomies from patients with carcinoma were macroscopically normal but pathological mapping showed multiple microscopic foci of early signet ring cell carcinoma. Correlation of chromoendoscopic and gastrectomy findings showed that congo red/methylene blue detected carcinoma foci 4-10 mm in size but not foci <4 mm. CONCLUSIONS: The use of chromoendoscopy following normal white light gastroscopy facilitated detection of early gastric carcinoma foci not visible with white light gastroscopy. If these findings are validated in other HDGC kindred, chromogastroscopy represents an improved surveillance technique that can be safely considered alongside prophylactic gastrectomy.     

The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome

Hereditary diffuse gastric cancer(HDGC) syndrome is an inherited cancer risk syndrome associated with path-ogenic germline CDH1 variants. Given the high risk for developing diffuse gastric cancer, CDH1 carriers are recommended to undergo prophylactic total gastrectomy for cancer risk reduction. Current guidelines recommend upper endoscopy in CDH1 carriers prior to surgery and then annually for individuals deferring prophylactic total gastrectomy.Management of individuals from HDGC families without CDH1 pathogenic variants remains less clear, and management of families with CDH1 pathogenic variants in the absence of a family history of gastric cancer is particularly problematic at present. Despite adherence to surveillance protocols, endoscopic detection of cancer foci in HDGC is suboptimal and imperfect for facilitating decision-making. Alternative endoscopic modalities, such as chromoendoscopy,endoscopic ultrasound, and other non-white light methods have been utilized,but are of limited utility to further improve cancer detection and risk stratification in HDGC. Herein, we review what is known and what remains unclear about endoscopic surveillance for HDGC, among individuals with and without germline CDH1 pathogenic variants. Ultimately, the use of endoscopy in the management of HDGC remains a challenging arena, but one in which further research to improve surveillance is crucial.     

Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone

BACKGROUND AND AIMS: Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). While two recent series of prophylactic gastrectomy described microscopic foci of signet ring cell carcinoma in sample sections from 10 macroscopically normal stomachs, whole stomach phenotype has not been mapped. We aimed to describe the size and distribution of foci in relation to mucosal zones and anatomical location. METHODS: Six patients (from three HDGC kindred) were referred for total gastrectomy via three different referral pathways. Following fixation, five stomachs were completely blocked and one extensively sampled. Histopathology was mapped to a mucosal photograph of each stomach, enabling precise localisation of carcinoma foci, benign pathology, and mucosal zones. RESULTS: There were 4-318 microscopic foci of intramucosal signet ring cell adenocarcinoma in the six macroscopically normal stomachs (foci size 0.1-10 mm in diameter). The distal third of the stomach contained 48% of total foci (range 29-75%). The body-antral transitional zone occupied 7.7% of mucosal area (range 3.6-11.8) but had 37% of foci (range 10%-75%). The largest foci were found in the transitional zone and foci density was five times greater in the transitional zone than in body or antral type mucosa. CONCLUSIONS: In germline CDH-1 mutation carriers, multiple microscopic foci of intramucosal signet ring cell carcinoma show a predilection for the distal stomach and the body-antral transitional zone. Targeting the transitional zone would maximise the likelihood of finding foci in macroscopically normal gastrectomies, and particular attention should be paid to this area during endoscopy.     

Hereditary diffuse gastric cancer

Some diffuse type gastric cancers are of hereditary origin. Their histological characteristics are poor cell differentiation and the presence of signet-ring cells. The cause is a mutation of the CDH1 gene which is responsible for abnormal E-cadherin. The transmission mode is autosomal dominant. Because of serious prognosis of symptomatic hereditary diffuse gastric cancer (HDGC), the high penetrance of the gene (67% in men and 83% in women) and the young age of onset of these tumors (before the age of 40), a prophylactic gastrectomy is recommended to the mutation carriers. The search for the genetic mutation should be recommended to families corresponding to clinical criteria such as the number of affected family members, degree of relationship and age of onset of these tumors.     

E-cadherin mutations and hereditary gastric cancer: prevention by resection?

BACKGROUND: A small percentage of gastric cancers (1-3%) arise as a result of clearly identified inherited gastric cancer predisposition syndromes. Recently, linkage analysis has implicated E-cadherin (CDH1) mutations in a subset of dominantly inherited gastric cancers termed hereditary diffuse gastric cancer (HDGC). Heterozygotes with the CDH1 mutation have a 70-80% chance of developing gastric cancer and once patients have invasive, symptomatic disease there is a high associated morbidity and mortality. As a result prophylactic gastrectomy has been advocated for affected family members identified by genetic screening. There are many issues to be considered in order to determine whether prophylactic gastrectomy is the optimal management strategy for these patients. METHODS: A MEDLINE literature search was performed and combined with our own experience in order to identify relevant background information on hereditary gastric cancer. In particular we extracted information about prophylactic gastrectomy in HDGC patients. RESULTS: Once the decision has been undertaken to perform genetic testing, the therapeutic options are either endoscopic screening with the aim of identifying an early, curable lesion or prophylactic surgery. Two groups have published their data on prophylactically resected stomachs in asymptomatic patients from affected families. In these series all of the post-gastrectomy specimens had microscopic evidence of diffuse gastric cancer confined within the mucosal layer. These early cancers had not been identified by endoscopic surveillance. Technical issues surrounding the age at which to operate, the best operation to reduce the risk of post-operative complications and the risk of other cancers developing in other organs in these patients are still controversial. Long-term follow-up studies in specialist centres are required to resolve these issues. CONCLUSIONS: From the limited experience so far the estimated risk reduction of gastric cancer by gastrectomy is significant.     

Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families.

BACKGROUND & AIMS: Germline mutations in CDH1 are known to cause hereditary diffuse gastric cancer (HDGC). Breast and colorectal cancer have also been reported in CDH1-associated HDGC. The purpose of this study was to estimate the cumulative risk of gastric and breast cancer in CDH1 mutation carriers. METHODS: Family data were collected by member groups of the International Gastric Cancer Linkage Consortium. Eligible families had at least 3 cases of diffuse gastric cancer, and at least 1 affected member had tested positive for a mutation in CDH1. Eleven families met these criteria. We used the pedigree information to estimate penetrance using the MENDEL program. The conditional likelihood of the pedigree was maximized given the phenotype of the pedigree and genotype of the index case at ascertainment. We parameterized the model in terms of log relative risks for mutation carriers compared with risks in the general population of the United Kingdom. Noncarriers of the gene were assumed to develop the disease at population incidence rates. RESULTS: The estimated cumulative risk of gastric cancer by age 80 years was 67% for men (95% confidence interval [95% CI], 39-99) and 83% for women (95% CI, 58-99). For women, the cumulative risk of breast cancer was 39% (95% CI, 12-84). The combined risk of gastric cancer and breast cancer in women was 90% by age 80 years. CONCLUSIONS: These penetrance estimates should be useful for genetic counseling in multiple-case families. However, they may not apply to individuals with a minimal family history, in whom the risks may be lower.     

Hereditary gastric cancer. Genetics and clinical management

Recently, germline mutations in the E-cadherin/CDH1 gene have been identified in families with an autosomal-dominant inherited predisposition to gastric cancer of the diffuse type. Criteria to define familial gastric cancer syndromes have been proposed and include review of the histopathology and pedigree analysis of any family with an aggregation of gastric cancer cases. Of families with two or more cases of diffuse gastric cancer in first- or second-degree relatives < 50 years of age or three or more cases at any age, up to half may be attributable to inherited germline mutations in the E-cadherin/CDH1 gene. Cumulative lifetime risk of developing gastric cancer in CDH1 mutation carriers is 70%, women from these families also have increased risk for developing lobular breast cancer. Prophylactic gastrectomies have been performed in several unaffected CDH1 mutation carriers; despite normal endoscopic examinations and negative gastric biopsy specimens, pathologic foci of early gastric cancer were found in all surgical specimens. Based on these results, guidelines for genetic testing, counseling and management of individuals with hereditary diffuse gastric cancer have been proposed. Raised awareness among the physician community regarding this syndrome may allow for increased detection and prevention of gastric and breast cancers in these high-risk individuals.     

Familial gastric cancer - clinical management

The clinical management of familial gastric cancer is the same as that for sporadic gastric cancer at the current time. As the causative mutations for these cases are identified this should lead to the development of specific treatments which target the molecular abnormality. The only germline mutations identified so far occur within the E-cadherin gene (CDHI) and they account for approximately 30% of familial gastric cancer cases. When index patients fulfilling the clinical criteria for hereditary diffuse gastric cancer syndrome have a CDHI mutation identified then genetic testing of asymptomatic relatives should be considered. The clinical sequelae of testing positive for such a mutation are profound and therefore it is essential that counselling is given prior to genetic testing. The management options are surveillance endoscopy and prophylactic gastrectomy. In this chapter the practicalities of genetic testing are discussed as well as the pros and cons of the two management options. It is essential that experience of these rare families is pooled so that surveillance and treatment can be optimised in the future.     

Prophylactic surgery in Lynch syndrome

Lynch syndrome (LS) is caused by a germline mutations in DNA mismatch repair genes and is a dominantly inherited syndrome, responsible for 2–5% of all colorectal cancer (CRC) cases. Mutation carriers have a 60–85% risk of developing CRC. With the increasing use of genetic predisposition testing, patients and health care providers must decide on cancer risk-reduction strategies. The cancers observed in families with LS are diagnosed at an unusually early age and may be multiple. The decision about which surgery is suitable should be made on the basis of patient factors and preferences, with special emphasis on age, comorbidity, sphincteric function, and the ability of the patient to cope with intensive surveillance. Colectomy decreases the risk of second CRC significantly. The estimated lifetime risk for endometrial adenocarcinoma is 40–60% in women with LS, and the mean age at diagnosis is around 50 years. This risk equals or exceeds the risk of CRC. The optimal management of the elevated risk for cancer in carriers of mutations for hereditary nonpolyposis colorectal cancer is unclear. Patients who are gene mutation carriers should receive counseling about colectomy, and if women, prophylactic hysterectomy and bilateral oophorectomy.     

Hereditary diffuse gastric cancer: strategies to reduce tumoral risk

The main goal at a High-Risk Gastrointestinal Cancer Clinic is to identify individuals at increased risk of developing tumors for diagnosis them in presymptomatic stages, when they are potentially curable. We report an asymptomatic patient belonging to a family with hereditary diffuse gastric cancer syndrome with a novel pathogenic mutation in the E-cadherin gene. In the absence of any proven diagnostic tool in surveillance tumor of this syndrome, the recommendation accepted today for an asymptomatic individual with known mutation is to perform prophylactic surgery. This patient underwent total laparoscopic gastrectomy. A microscopic focus of tumor was detected in the surgical specimen. Strategies to reduce the tumor risk in the hereditary diffuse gastric cancer syndrome are limited, but it is necessary to recognize them in order to treat these patients accordingly to the available evidence.     

Prophylactic total gastrectomy in the management of hereditary tumor syndromes

Purpose

Germline mutations in several genes confer a relevant lifetime risk of gastric cancer. In this context, an increasing involvement of a surgeon can be seen, mainly with the question of performing a prophylactic operation.

Methods

Patients with hereditary tumor syndromes predisposing for gastric cancer who received care leading to prophylactic total gastrectomy in our Center for Hereditary Tumor Syndromes were analyzed. For each patient, the multidisciplinary decision-making process, the perioperative course, and the histopathologic findings were assessed. Short-term morbidity was evaluated based on the medical reports.

Results

The analysis includes nine patients (six female, three male) with a median age of 41.6 (range 23–60) years. Indication for prophylactic total gastrectomy was based on family history and genetic analysis (eight patients with a germline mutation of the CDH1 gene and one patient with a SMAD4 mutation). Removal of the entire gastric mucosa was documented intraoperatively by fresh frozen section examination. Extended (DII) lymphadenectomy was performed in four patients. Histopathologic examination of gastrectomy specimens revealed six patients (6/9, 67 %) with multifocal signet ring cell carcinomas. In our series, prophylactic total gastrectomy was a safe procedure without mortality and low morbidity.

Conclusions

Patients with hereditary syndromes predisposing for gastric cancer should be evaluated for this curative procedure in a specialized center. Further research is necessary, and the implementation of nationwide registers including patients with prophylactic gastrointestinal operations due to hereditary tumor syndrome is advisable.

     

Combined molecular and clinical approach for decision making for surgery in HNPCC patients: a report on three cases in two families

Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with highly penetrant germline mutations in mismatch repair genes. Due to a high lifetime risk in gene carriers for synchronous and for metachronous colorectal cancer and endometrial cancer in women, prophylactic and extended surgery are considered as options for gene carriers. A 54-year-old patient with a history of metachronous rectal cancer and a family history fulfilling the Amsterdam criteria presented with carcinoma of the cecum and highly dysplastic adenomas of the splenic flexure and descending colon. As a result of these findings, medical history and molecular diagnosis, the decision was made to perform colectomy and prophylactic hysterectomy with oophorectomy; histological examination of the specimen showed three synchronous colon carcinomas. The 31-year-old son carrying the pathogenic mutation refused to be included in the HNPCC surveillance program. One year later he presented with symptoms of bowel obstruction, and a carcinoma of the descending colon was diagnosed. Intraoperatively, in addition to the colon cancer, a small bowel cancer and peritoneal carcinomatosis were found. In another family fulfilling the Amsterdam criteria without known germline mutation a woman presented with synchronous cancer of the ascending colon and the lower rectum at the age of 49 years. Proctocolectomy and prophylactic hysterectomy were performed, which revealed an additional colon cancer and endometrial cancer. We discuss approaches for individual decision making for surgery in HNPCC patients. Is a subtotal colectomy indicated in the case of first colon cancer in HNPCC patients, or if the first tumor occurs in the lower rectum, should a proctocolectomy or a restorative proctocolectomy be considered? The aim of prospective clinical studies should be to assess acceptability, survival rates, mortality, and the quality of life in HNPCC patients who have undergone surveillance and standard oncological resections versus extended or prophylactic surgery.     

Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance

BACKGROUND & AIMS: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers. METHODS: Mutation analysis was performed in 20 families with a germline mutation in MSH6. We compared the cancer risks between MSH6 and MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors. RESULTS: A total of 146 MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in MSH6 than in MLH1 or MSH2 mutation carriers (P = 0.002). In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in MSH6 mutation carriers, but the difference was not significant (P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in MSH6. CONCLUSIONS: We recommend starting colonoscopic surveillance in female MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for MSH6 mutation analysis.     

26例残胃癌临床诊治分析

目的探讨残胃癌的早期诊断方法和外科治疗,观察不同手术方式对预后的影响。方法对26例残胃癌的临床病理资料进行回顾性分析,比较胃镜和钡餐对残胃癌的诊断价值。结果胃镜对残胃癌的诊断率为80.8%,钡餐为50.0%。手术切除的20例中根治性残胃切除13例均生存≥3年;姑息性切除7例,术后生存2年5例,1.5年2例。行胃空肠吻合4例中3例于6个月内死亡,1例生存10个月。2例腹腔内广泛转移者仅行肿块活检术。结论胃镜对残胃癌的诊断价值优于钡餐。早期诊断并行根治性残胃切除患者预后较好。     

Prevalence of pre-malignant and malignant lesions in prophylactic mastectomy specimens of BRCA1 mutation carriers: comparison with a control group

PURPOSE: BRCA1 mutation carriers are at high risk for breast cancer (BC). The risk management strategy may include radiological investigations for early detection or prophylactic mastectomy (PM). For a mutation carrier, PM may be more significant than surveillance alone when pre-malignant and malignant changes occur increasingly in mastectomy specimens, given normal findings on radiological investigations. In the present study we retrospectively investigated the differences between histological findings in PM specimens of BRCA1 carriers and those of a control group. METHODS: Twenty-four healthy and 28 affected carriers in the presence of normal preoperative radiological findings were included in the study. To compare the frequency of pre-malignant and malignant lesions in PM specimens, a control group matched for age and disease status was included. T-tests for independent samples and Wilcoxon's signed-rank test were used for comparison of groups. RESULTS: The entire study group differed significantly from the control group (42.3 vs. 5.8%; P < 0.001) in terms of the occurrence of pre-malignant and malignant lesions. Both, the sub-group comparison of healthy mutation carriers as well as diseased carriers with their controls, showed a significant difference in terms of the occurrence of pre-malignant and malignant changes (45.8 vs. 0%; P = 0.002; 39.3 vs. 10.7%; P = 0.03). In PM specimens of mutation carriers, carcinomas were identified in 5.8% (3/52) and pre-malignant changes in 36.5% (19/52). CONCLUSIONS: BRCA1 mutation carriers should be informed of the fact that pre-malignant and even malignant changes are frequently found in PM specimens despite normal radiological findings.     

Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities

The ground‐breaking discovery of genotype–phenotype relationships in hereditary medullary thyroid cancer has greatly facilitated early prophylactic thyroidectomy. Its timing depends not solely on a positive gene test but, more importantly, on the type of the REarranged during Transfection (RET) mutation and its underlying mode of RET receptor tyrosine kinase activation. In the past decade, the therapeutic corridor opened by molecular information has been defined down to a remarkable level of detail. Based on mutational risk profiles, preemptive thyroidectomy is recommended at 6 months of age for carriers of highest‐risk mutations, before the age of 5 years for carriers of high‐risk mutations, and before the age of 5 or 10 years for carriers of least‐high‐risk mutations. Additional lymph node dissection may not be needed in the absence of increased preoperative basal calcitonin levels. Better comprehension of RET function should enable the design of targeted therapies for RET carriers beyond surgical cure in whom the DNA‐based ‘window of opportunity’ has been missed.     

Hereditary colorectal cancer: clinical consequences of predictive molecular testing

The continuing increase in knowledge about the genetic basis of carcinogenesis has led to diverse efforts to exploit this knowledge clinically, primarily in the form of predictive genetic testing. In conjunction with family history, gene tests are intended to improve individual cancer risk assessment. The objectives of predictive molecular testing are to identify the disease-causing germline mutation in an index person who has already developed the disease and to distinguish asymptomatic mutation carriers from non-mutation carriers within a given cancer-prone family. At present, genetic testing for colorectal cancer risk, primarily in form of DNA sequencing, is applied in familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). In these inherited colorectal tumor syndromes determining the genetic status may result in an individually tailored surveillance program and prophylactic treatment. The implications of genetic testing for the clinical management of disease, both of mutation and non-mutation carriers, in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families are discussed. Accepted: 9 September 1999     

E-cadherin mutation-associated diffuse gastric adenocarcinoma: penetrance and non-penetrance

According to the published medical literature to date, prophylactic gastrectomy undertaken in the context of carriage of a germline truncating E-cadherin mutation and an appropriate positive family history will lead to the discovery of occult foci of adenocarcinoma in all gastrectomy specimens. We describe the first published case of a patient whose prophylactic gastrectomy in this setting failed to reveal any dysplastic or malignant foci. Furthermore the patient's nephew, who was found to carry an identical E-cadherin mutation on family screening and also underwent prophylactic gastrectomy, was shown to have multi-focal diffuse adenocarcinoma after analysis of the gastrectomy specimen. Both patients were also found to have penetrant genetic haemochromatosis. Within this case, we discuss the clinical manifestations and penetrance of germline E-cadherin mutations and the difficult decisions facing both clinicians and families with this mutation. We also speculate on how these patients' undiagnosed genetic haemochromatosis may have influenced the pathology encountered.     

Cancer risks in LKB1 germline mutation carriers

BACKGROUND AND AIMS: Germline mutations in the LKB1 gene are known to cause Peutz-Jeghers syndrome, which is an autosomal dominant disorder characterised by hamartomatous polyposis and mucocutaneous pigmentation. This syndrome is associated with an increased risk of malignancies in different organs but there is a lack of data on cancer range and risk in LKB1 germline mutation carriers. PATIENTS AND METHODS: The cumulative incidence of cancer in 149 Peutz-Jeghers syndrome patients with germline mutation(s) in LKB1 was estimated using Kaplan-Meier time to cancer onset analyses and compared between relevant subgroups with log rank tests. RESULTS: Thirty two cancers were found in LKB1 mutation carriers. Overall cancer risks at ages 30, 40, 50, 60, and 70 years were 6%, 18%, 31%, 41%, and 67%, respectively. There were similar overall cancer risks between male and female carriers. However, there were overall cancer risk differences for exon 6 mutation carriers versus non-exon 6 mutation carriers (log rank p=0.022 overall, 0.56 in males, 0.0000084 in females). Most (22/32) of the cancers occurred in the gastrointestinal tract, and the overall gastrointestinal cancer risks at ages 40, 50, 60, and 70 years were 12%, 24%, 34%, and 63%, respectively. In females, the risks for developing gynaecologic cancer at ages 40 and 50 years were 13% and 18%, respectively. CONCLUSIONS: Mutations in exon 6 of LKB1 are associated with a higher cancer risk than mutations within other regions of the gene. Moreover, this study provides age related cumulative risks of developing cancer in LKB1 mutation carriers that should be useful for developing a tailor made cancer surveillance protocol for Peutz-Jeghers syndrome patients.     

Surveillance for Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer is caused by germline mutations in DNA mismatch repair genes. Mutation carriers have a 60 to 85 percent risk of developing colorectal cancer. In the Netherlands hereditary nonpolyposis colorectal cancer families are monitored in an intensive surveillance program. The aim of this study was to examine the stage of the screening-detected tumors in relation to the surveillance interval and to assess the risk of developing colorectal cancer while on the program. METHODS: The Dutch hereditary nonpolyposis colorectal cancer family registry was used. A total of 114 families had a mismatch repair gene defect and/or met the clinical criteria for hereditary nonpolyposis colorectal cancer. The interval between surveillance and colorectal cancer was investigated in initially healthy family members who underwent at least one surveillance examination without showing evidence for colorectal cancer (surveillance group) and in family members who previously underwent partial or subtotal colectomy for colorectal cancer. The risk of colorectal cancer was calculated for proven mutation carriers (surveillance group) and for putative carriers after partial or subtotal colectomy. RESULTS: A total of 35 cancers were detected while on the program. With intervals between colorectal cancer and the preceding surveillance examination of two years or less, tumors were at Dukes Stage A (n = 4), B (n = 11), and C (1). With intervals of more than two years, tumors were at Dukes Stage A (n = 3), B (n = 10), and C (n = 6). The 10-year cumulative risk of developing colorectal cancer was 10.5 (95 percent confidence interval, 3.8–17.2) percent in proven mutation carriers, 15.7 (95 percent confidence interval, 4.1–27.3) percent after partial colectomy, and 3.4 percent after subtotal colectomy. CONCLUSION: There is a substantial risk of developing colorectal cancer while on the program. However, all tumors but one of subjects who underwent a surveillance examination two years or less before detection were at a local stage. We recommend surveillance for hereditary nonpolyposis colorectal cancer with an interval of two years or less.