Recommendations to improve identification of hereditary and familial colorectal cancer in Europe.

Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.

Screening for urinary tract cancer with urine cytology in Lynch syndrome and familial colorectal cancer.

AIM: The aim of this study was to evaluate if Urine Cytology (UC) is an appropriate screening procedure for detecting urinary tract neoplasia at an early stage in persons at risk in Hereditary Non-Polyposis Colorectal Cancer families. METHOD: In the National Danish HNPCC-register persons at risk were identified in three categories of HNPCC-families (1) families harbouring a disease causing mutation in a Mismatch repair gene (MMR), (2) families fulfilling the Amsterdam I or II criteria and (3) families suspected of HNPCC. In total 3,411 persons were identified and traced in Patobank-the National Danish Pathology database. All UC and UTC (Urinary Tract Tumours) were listed and evaluated. RESULTS: 977 persons had a total of 1,868 screening procedures performed. Two of these procedures (0.1%) lead to diagnosis of an asymptomatic urothelial tumour. In ten times as many procedures (22 persons) UC lead to a false positive screening diagnosis. During the study period fourteen persons (1.4%) developed a UTC and five of these were interval tumours. The sensitivity of UC in diagnosing asymptomatic UTC in HNPCC patients was 29%. Twelve of the tumours were found in persons from families with a proven MMR-mutation and eleven out of these were MSH2 mutations (92%, 95% cl 62-100%). DISCUSSION: UC is not a proper method of screening for UTC in HNPCC. However, the study can not reveal if screening for UTC in special families ought to be recommended. Consequently, further studies needs to be performed in order to evaluate an appropriate screening programme.

[Recurrence and survival after conventional low anterior resection for rectal cancer]. / Recidiv og overlevelse efter konventionel lav anterior resektion for cancer recti.

INTRODUCTION: The aim of the study was to evaluate the incidence of recurrence of local cancer, distant metastases and survival after conventional low anterior resection for cure in patients with rectal carcinoma, on the basis of the poor prognosis after colorectal cancer in Denmark. MATERIAL AND METHODS: Consecutive patients operated on in the nine Danish departments of surgical gastroenterology in 1992-1993. Retrospective collection of data on recurrence of local cancer, distant metastases, and over-all survival at the end of 1996. RESULTS: Of 268 patients, 77 (29%) developed recurrent local cancer and/or distant metastases. Forty-eight (18%) had local recurrence with a cumulative 5-year rate of 39%. Distant metastases were seen in 54 (20%). The local recurrence rate increased with increasing Dukes' tumour stage and was higher after operation by a non-specialist (30%) than by a consultant, another specialist, or a surgeon under training and supervised by a consultant (15-17%) (p = 0.04). Multiple regression showed that the recurrence rate was independent of tumour localisation, blood loss, transfusion, anastomotic leakage, and status of the surgeon. The cumulative crude 5-year survival was 50% and independent of the status of the surgeon. DISCUSSION: Our relatively high local recurrence rate and the results in the literature after total mesorectal excision (TME) indicate that the conventional technique should be replaced by TME, which has become the recommended method in recent years. Furthermore, we propose a changed strategy in the treatment of rectal cancer. The patients should be treated in fewer departments with established teams of rectal cancer specialists taking part in all operations for rectal cancer.

[Registration of hereditary non-polyposis colorectal cancer]. / Registrering af hereditaer non-polypøs kolorektal cancer.

Hereditary non-polyposis colorectal cancer is a dominant inherited disease, with development of colorectal cancer (CRC) and other cancers too. About 3% of all CRC-cases belong to an HNPCC-family. Mutations responsible for the disease has been identified in five genes, all of them involved in DNA mismatch repair. Since the establishment of the Danish HNPCC Register 345 families have been referred, and 101 of these families had HNPCC. Median age of onset for CRC was 50 years: Approximately 60% of the tumors were situated on the right side, 9% had synchronous tumors and the risk of metachronous tumours was 40% in 20 years. Tumours were localised in 64% of the cases, and the 5-year crude survival rate was better in HNPCC compared to sporadic CRC. The number of CRC diagnosed as Dukes A in HNPCC has risen since 1990, and the survival after CRC in HNPCC has increased. The disease specific mutation is identified in 21 families, from which 152 persons at risk have had a molecular genetic diagnose, and 83 could afterwards evade screening protocols. Few years after the establishment of the HNPCC-registry, it is indicated that information, registration and screening lead to an earlier diagnosis and a better prognosis after CRC.

Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. International Collaborative Group on HNPCC.

BACKGROUND: Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients. METHODS: A questionnaire was mailed to the members of International Collaborative Group on HNPCC (ICG-HNPCC) requesting clinicopathologic data in their registries on HNPCC patients with small bowel carcinoma. Survival was estimated utilizing the Kaplan-Meier method. RESULTS: Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors. There were 46 adenocarcinomas and 3 carcinoid tumors. The median age at diagnosis of the index small bowel tumor was 49 years. Mismatch repair gene mutations were present in 15 of 42 patients (36%). There were nine hMLH1 and six hMSH2 mutations. The small bowel was the first site of carcinoma in 24 patients (57%). The median survival for the 42 patients was 47 months (range, 0-447 months). The overall 5- and 10-year survival rates were 44% and 33%, respectively. CONCLUSIONS: Small bowel tumors can be the presenting neoplasms in HNPCC patients. Similar to colorectal carcinoma in HNPCC, small bowel adenocarcinomas in HNPCC patients occur at an earlier age and appear to have a better prognosis than those occurring in the general population.

Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by mutations in one of at least four different DNA mismatch repair genes, hMLH1, hMSH2, hPMS1, and hPMS2. Phenotypically, HNPCC is characterized by the early onset of colorectal cancers and various extracolonic cancers. Depending on the presence or absence of extracolonic tumors, HNPCG-has been divided into two syndromes (Lynch syndrome I and Lynch syndrome II), but, so far, no correlation to distinct genotypes has been demonstrated. In this study, we present a frequent hMLH1 intron 14 founder mutation that is associated with a highly reduced frequency of extracolonic tumors. The mutation disrupts the splice donor site and silences the mutated allele. Tumors exhibited microsatellite instability, and loss of the wild-type hMLH1 allele was prevalent. We propose that the mutation results in a milder phenotype, because the mutated hMLH1 protein is prevented from exerting a dominant negative effect on the concerted action of the mismatch repair system.

Hereditary non-polyposis colorectal cancer: clinical features and survival. Results from the Danish HNPCC register.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome characterized by the development of colorectal cancer (CRC) and other carcinomas. Our aim was to evaluate tumour parameters and survival in HNPCC. METHODS: One hundred and eight Danish HNPCC patients were compared with 870 patients with sporadic colorectal cancer. RESULTS: The median age at CRC diagnosis was 41 years in the HNPCC group. HNPCC patients had significantly more carcinomas located to the right colon (68% against 49% in controls), more synchromous tumours (7% versus 1%), more metachronous CRC after 10 years (29% versus 5%), more localized carcinomas (62% versus 39%), and significantly higher crude cumulative 5-year survival (56% versus 30%). CONCLUSIONS: CRC in HNPCC behaves differently compared to sporadic cases concerning age of onset, frequency of multiple lesions, and location. The metastatic tendency is less than in sporadic CRC and the survival is better.

Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis are not only at high risk of developing adenomas in the colorectum but a substantial number of patients also develop polyps in the duodenum. Because treatment of duodenal polyps is extremely difficult and it is unknown how many patients ultimately develop duodenal cancer, the value of surveillance of the upper digestive tract is uncertain. AIMS: (1) To assess the cumulative risk of duodenal cancer in a large series of polyposis patients. (2) To develop a decision model to establish whether surveillance would lead to increased life expectancy. METHODS: Risk analysis was performed in 155 Dutch polyposis families including 601 polyposis patients, and 142 Danish families including 376 patients. Observation time was from birth until date of last contact, death, diagnosis of duodenal cancer, or closing date of the study. RESULTS: Seven Dutch and five Danish patients developed duodenal cancer. The lifetime risk of developing this cancer by the age of 70 was 4% (95% confidence interval 1-7%) in the Dutch series and 3% (95% confidence interval 0-6%) in the Danish series. Decision analysis showed that surveillance led to an increase in life expectancy by seven months. CONCLUSIONS: Surveillance of the upper digestive tract led to a moderate gain in life expectancy. Future studies should evaluate whether this increase in life expectancy outweighs the morbidity of endoscopic examination and proximal pancreaticoduodenectomy.

Rectal cancer risk in hereditary nonpolyposis colorectal cancer after abdominal colectomy. International Collaborative Group on HNPCC.

OBJECTIVE: The authors analyzed the incidence of rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) after an abdominal colectomy. SUMMARY BACKGROUND DATA: The treatment of choice for a newly diagnosed patient with HNPCC with colon cancer is an abdominal colectomy. The incidence of rectal cancer after abdominal colectomy in HNPCC is not known. MATERIALS AND METHODS: A questionnaire was mailed to all International Collaborative Group on HNPCC members to identify patients in whom rectal cancer developed after total, subtotal or completion colectomy. Statistics were performed using the log-rank test, Kaplan-Meier method, and Cox's proportional hazards model. RESULTS: Rectal cancer developed in 8 (11%) of 71 patients a median of 158 months (range, 38-282 months) from their primary procedure. Of these eight patients, adenomas in the rectal mucosa developed in five at risk either before (4) or synchronous (1) with the diagnosis of rectal cancer. At the time of diagnosis of rectal cancer, six of eight patients were being observed. Age at first procedure and whether the patient was under surveillance were the only significant variables (p < 0.05) in the multivariate analysis in terms of rectal cancer risk. The risk of developing rectal cancer was estimated to be 3% every 3 years after abdominal colectomy for the first 12 years. CONCLUSIONS: The risk of rectal cancer in patients with HNPCC after an abdominal colectomy is approximately 12% at 12 years. Age at first surgical procedure and surveillance correlated with rectal cancer risk. Aggressive endoscopic surveillance of the rectum should be performed after abdominal colectomy.

[Anastomotic leakage after low anterior resection for rectal cancer]. / Anastomoselaekage efter lav anterior resektion for cancer recti.

A series of 377 consecutive patients were operated upon with low anterior resection for rectal cancer in the nine Danish departments of surgical gastroenterology during 1992-1993. A retrospective analysis was carried out to calculate the frequency of anastomotic leakage and to evaluate factors of potential influence on the development of leakage according to the literature. Sixty-three patients (17%) developed leakage, which was followed by an increased mortality within the first three postoperative months. Only two variables significantly influenced the leakage rate: male gender was associated with a higher leakage rate (p = 0.02), whereas departments with a low number of rectal cancer surgeons had a low rate of anastomotic leakage (p = 0.02). In conclusion, the rather high frequency of anastomotic leakage calls for further clinical and pathogenetic research in this field. Until then, we recommend the routine use of a peroperative leakage test and selective use of prophylactic ostomy in cases of unsatisfactory anastomosis. Furthermore, it is recommended that low anterior resection for rectal cancer is limited to few surgeons in each department in order to ensure a uniform quality and hopefully also thereby reduce the rate of anastomotic leakage.

[Surgery for ulcerative colitis. Treatment with proctocolectomy, stapled ileum-J-pouch, stapled pouch-anal anastomosis and temporary ileostomy]. / Operation for colitis ulcerosa. Behandling med proktokolektomi, staplet ileum-J-pouch, staplet pouch-anal anastomose og midlertidig ileostomi.

Thirty-two patients with ulcerative colitis, median age 29 (range 14-49), were submitted to restorative proctocolectomy. Twenty-five patients had a three-stage procedure and seven had a two-stage procedure. A stapled J-pouch was formed, and a pouch-anal anastomosis was created by the double stapling technique. A temporary end ileostomy was closed through peristomal incision after three months. There were no pouch failures and no cases of pouch-anal anastomosis leakage. In one patient secondary mucosectomy and neo-anastomosis became necessary due to severe inflammation of remnant rectal mucosa. Five patients were operated for small bowel obstruction, and two had to have a dilatation of a slight stricture of the pouch-anal anastomosis. In two patients the final diagnosis was verified or probable Crohns disease, of whom one developed recurrence of a previous rectovaginal fistula. Twenty-seven patients have had the ileostomy closed for more than one month, 25 of these (93%) were fully continent three months after ileostomy closure and later on. After one year the patients had median five (range 3-9) bowel movements per day. It is concluded that restorative proctocolectomy with a stapled J-pouch-anal anastomosis and a temporary end ileostomy for ulcerative colitis carries few complications and provides a good functional result.

Ophthalmoscopy for congenital hypertrophy of the retinal pigment epithelium (CHRPE) in patients with sporadic colorectal carcinoma.

In order to investigate the frequency of congenital hypertrophy of the retinal pigment epithelium (CHRPE) in sporadic colorectal cancer, ophthalmoscopy was carried out in 34 patients with colorectal carcinoma without known familial disposition. CHRPE is one of the most frequent extracolonic manifestations in familial adenomatous polyposis. None of the patients showed any sign of CHRPE. It is concluded that although genetic factors are presumably of importance in the development of sporadic colorectal cancer, CHRPE cannot be used as a marker for future risk of colorectal carcinoma except in polyposis families.

Closure of rectal stump after colectomy for acute colitis.

In a retrospective study complications, mortality and morbidity following acute colectomy for severe colitis with intra-abdominal closure of the rectal stump were reviewed in 147 consecutive patients (71 women and 76 men, median age of 40 years, range 18-95 years). Five patients (3%) died within 30 days postoperatively; none of the deaths were related to the rectal stump. Three patients (2%) had a pelvic abscess due to leakage of the rectal closure, all were treated successfully with percutaneous drainage, guided by ultrasonography. No difficulties in locating the rectal stump or performing intended subsequent surgery were reported. The overall complications and mortality rate in this study are low and comparable to the best results reported from centers using the mucous fistula. Closure of the rectal stump is a safe procedure, and has the advantage of not leaving the patient with a second stoma.

The establishment of an HNPCC register.

Guidelines for the establishment of an HNPCC-register are presented. The aims of a register are discussed. Steps in identification of families and persons at risk are suggested, and possible sources of family and pedigree data are mentioned. The role of a register in surveillance, information of family members and medical colleagues, research and international collaboration are discussed.

Mandibular osteomas in sporadic colorectal carcinoma. A genetic marker.

Pantomography of the mandible was performed in 98 patients with sporadic colorectal adenocarcinoma. Twenty-eight patients (29%) had osteomas versus 5% in a control group (P < 0.001). Mandibular osteomas are found in most patients with the premalignant dominant syndrome familial adenomatous polyposis. Sporadic colorectal cancer examinations of married couples have shown that diet has only a moderate influence on the development of colorectal cancer, whereas pedigree studies indicate a genetic component. On this basis we conclude that mandibular osteomas are probably genetic markers of the development of sporadic colorectal carcinoma.

[Hereditary non-polyposis colorectal cancer]. / Hereditaer non-polyposis kolorektal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) probably constitutes 5% of all the cases of sporadic colorectal cancer. At present, the diagnosis can only be established on the basis of a family history which should fulfill the "Amsterdam criteria": 1) Colorectal cancer in at least three family members, 2) One family member must be a close relative of the other two, and 3) The diagnosis must have been established prior to the age of 50 years in at least one relative. Other forms of cancer also occur in the HNPCC syndrome, particularly endometrial cancer. The syndrome has a dominant inheritance and, therefore, all close relatives should be submitted to control examinations for the most important forms of cancer associated with the syndrome.

Twelve hour overnight oesophageal pH monitoring in patients with reflux symptoms.

Results of continuous 12 hour overnight pH monitoring (duration of pH less than 4) were reviewed in 112 patients with heartburn or regurgitation, or both, and in 56 normal subjects. Patients had more reflux than normal subjects. Medically controlled patients (n = 51) had less acid reflux than patients who subsequently underwent reflux surgery (n = 61), but there was a considerable overlap between those two groups. Surgery was followed by a reduction in acid reflux to a value similar to that in normal subjects. Patients in whom surgery was deemed to have failed had more reflux after the operation than those in whom it was successful, but no difference could be found in the preoperative reflux values of these two subgroups. Monitoring pH is not of value in selecting candidates for surgery since the results are not a good predictor of outcome, but it is useful in the objective evaluation of surgical results.

[Proctoscopic versus histologic diagnosis of rectal polyps]. / Rektoskopisk versus histologisk diagnose af rektalpolypper.

On the basis of the endoscopic appearance, 71 rectal polyps were assessed as adenomata or non-neoplastic polyps, after which the endoscopic diagnosis was compared with the results of histological examination. The diagnosis based on macroscopic examination of the polyps proved correct in only 62% of the cases. It is concluded that the diagnosis of adenoma cannot be established solely on the proctoscopic appearance of a polyp and, as adenomata are premalignant, removal of all polyps found at proctoscopy is recommended.