Presymptomatic diagnosis of familial adenomatous polyposis coli

Familial adenomatous polyposis (FAP), an autosomal dominant inherited disease, confers a high risk of colon cancer, and recently the gene responsible for FAP, termed adenomatous polyposis coli (APC) gene, was identified and fully characterized. PURPOSE: For the presymptomatic diagnosis of FAP, we have performed linkage studies using two polymorphic systems close to or at the APC locus; cytosine-adenine dinucleotide repeat length polymorphism and restriction endonuclease RsaI site polymorphism. METHODS and RESULTS: Based on the two polymorphic systems, we have determined the haplotype at the APC locus in 23 individuals of two Korean families with FAP. From these haplotypes of individuals, we could make the diagnosis, whether affected or unaffected, in 74 percent of 31 at-risk persons. To decrease the chance of misdiagnosis caused by recombinant events, the use of haplotypes was better than using one polymorphic system. In addition to polymorphic analysis, we have also searched germline mutations of the APC gene in eight individuals (26 percent of all 31 at risk persons) of another two FAP families which could not be diagnosed definitely by linkage analysis. A 5 base-pairs deletion at codon 1309 was detected in one of the families, and a 5 base-pairs deletion at codon 1185 was also identified in another family by using a ribonuclease protection assay followed by DNA sequencing. From these results, we could diagnose FAP with 100 percent accuracy. CONCLUSION: Linkage studies by the Rsa I site polymorphism and cytosine-adenine repeat length polymorphism as well as the polymerase chain reaction-based sequencing method provide accurate and efficient tools for presymptomatic diagnosis of FAP in their families.Supported in part by a grant from the Seoul National University Hospital Research Fund (04-93-007) and a grant from Korea Science and Engineering Foundation (KOSEF-SRC-56-CRC-8).Read at the meeting of The American Society of Colon and Rectal Surgeons, Chicago, Illinois, May 2 to 7, 1993.     

Role of molecular diagnostic testing in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families

PURPOSE: Genetic tests are available for familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. The goal of this review was to develop an algorithm for application of molecular diagnostic techniques to the management of hereditary colorectal carcinoma and to familiarize the clinician with the vocabulary of molecular genetic testing for hereditary colorectal carcinoma. METHODS: Studies examining the clinical use of genetic testing for hereditary colorectal carcinoma syndromes are evaluated. Recent advances in molecular genetic technology are reviewed, and clinical management as practiced here and elsewhere is outlined. RESULTS: This review is a guide to the most reliable molecular diagnostic techniques. Three key questions are answered: who, when, and how to test. CONCLUSIONS: When integrated with existing testing protocols for colorectal carcinoma and when applied with appropriate caveats, particularly regarding interpretation of negative results, genetic testing can result in improved management of patients and families.     

Chemoprevention in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) predictably leads to adenomas and eventual adenocarcinomas in the lower gastrointestinal tract and less frequently, the upper gastrointestinal tract. Chemopreventive strategies have been studied in FAP patients to delay the development of adenomas in the upper and lower gastrointestinal tract, as well as to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery with colectomy and ileorectal anastamosis (IRA). The nonsteroidal anti-inflammatory drug (NSAID) sulindac and selective cyclooxygenase-2 (COX-2) inhibitor celecoxib reduce polyposis of the retained rectum after colectomy with IRA. Reports of cardiovascular risks of some NSAIDs and selective COX-2 inhibitors have led to promising studies of lower doses in combination with ursodeoxycholic acid, statin, and difluoromethylornithine. Curcumin and eicosapentaenoic acid show efficacy in small clinical trials of FAP chemoprevention. This article will review the concept of chemoprevention and the current clinical literature in FAP chemoprevention.     

Diagnosis of familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a hereditary disease with autosomal dominant transmission, it is a practically 100% precancerosis. For detection of further patients in the family careful examination of the patient and all subjects at risk, i.e. above all grade 1 relatives, is decisive. The presented paper summarizes the author's own experience with the follow up and examination of a group of 96 patients from 42 families. The group of patients has been assembled gradually since 1967. The basis of the examination is preparation of a pedigree, somatic examination, endoscopic examination of the large intestine and the oral portion of the digestive tract. Examination of the ocular fundus is valuable as it evaluates the presence of congenital hypertrophy of the retinal pigmented epithelium (CHRPE). A positive finding in relatives permits conclusions on the presence of FAP. Most evidence is provided by molecular genetic examination at the DNA level which makes presymptomatic diagnosis of FAP possible.     

Management of familial adenomatous polyposis

The management of FAP involves treatment of affected individuals and their families. Such an approach is best coordinated by registrars working in dedicated registries, in close collaboration with nurses, physicians, surgeons, clinical geneticists and others who become involved in the care of these patients. The large bowel of patients with FAP should be removed (totally or subtotally) by the third decade of life. Screening of other areas at risk is recommended to document the natural history of extracolonic manifestations and to allow study of the effects of intervention. Despite these other, sometimes life-threatening manifestations, a near to normal life span is possible in the majority of patients with FAP. The aims of management of the individual and of the family are to ensure that their quality of life is optimal, that support is provided in times of emotional need, that anxiety is minimized and that relatives are adequately screened and treated.     

Iatrogenic pancreatitis in familial adenomatous polyposis

The first case of a patient with familial adenomatous polyposis (FAP) who developed pancreatitis after routine screening and biopsy of the ampulla of Vater is described.     

Risk estimation in familial adenomatous polyposis using DNA probes linked to the familial adenomatous polyposis gene.

The familial adenomatous polyposis gene has recently been assigned to the long arm of chromosome five through linkage to several 5q DNA probes. These probes can now be used to trace inheritance of the disease gene in affected families. In this study, DNA samples from 152 members of 10 Australian familial adenomatous polyposis families have been examined for restriction fragment length polymorphisms detected by DNA probes C11P11, ECB27, and YN5.48. Linkage analysis confirmed linkage between the familial adenomatous polyposis gene and each probe with a maximum combined LOD score of 2.82 for C11P11, 2.90 for ECB27 and 5.49 for YN5.48 all at a recombination fraction of zero. Risk estimates were determined for the 51 at risk individuals in these families based on their restriction fragment length polymorphism data alone or in addition by including the effect of age dependent penetrance. Thirty two of those at risk (63%) could be assigned specific high (greater than or equal to 95%) or low (less than or equal to 5%) risks of developing familial adenomatous polyposis on the basis of their probe results. When the effect of age dependent penetrance was included, 26 (51%) fell at the extremes of risk (greater than or equal to 99% or less than or equal to 1%). Such estimates provide a sound basis for planning sigmoidoscopic screening of at risk family members and will thus facilitate surveillance in familial adenomatous polyposis families.     

Duodenal adenomatosis in familial adenomatous polyposis

In order to evaluate the prevalence of duodenal adenomas in familial adenomatous polyposis (FAP) and the risk of carcinoma development, a multicenter study was initiated in Denmark, Finland, Holland, Norway and Sweden, which have national polyposis registers with an almost complete registration. Patients aged 20 years or more are being examined with biennial gastroduodenoscopy during 1990–2000. Multiple duodenal biopsies are examined by one pathologist from each country, and the endoscopic and histological criteria of Spigelman have been adopted. At the end of August 1992, 312 patients with a median age of 37 years (range 20–86) had completed their first endoscopy. The duodenum was examined in 310 patients, of whom 199 (64%) had duodenal adenomas. Twenty-two patients (11% of all patients with duodenal adenomas) had no endoscopically visible polyps. One patient had an asymptomatic adenocarcinoma. The Spigelman stage worsened significantly (P<0.05) with time from the diagnosis of FAP, which may suggest an increasing risk of carcinoma by time.

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Résumé Afin d'évaluer la prévalence des adénomes duodénaux chez des sujets porteurs d'une polypose adénomateuse familiale, et établir le risque d'un développement d'un cancer, une étude multicentrique a été débutée an Danemark, Finlande, Hollande, Norvége et Suède, pays qui possèdent un registre national des polyposes avec un enregistrement le plus souvent complet. Les patients âgés de 20 ans ou plus seront examinés tous les deux ans par une gastro-duodénoscopie de 1990 à 2000. De multiples biopsies duodénales sont examinées par un seul pathologue par pays et les critères endoscopiques et histologiques de Spigelman ont été retenus. A la fin du mois d'août 1992, 312 patients dont l'âge moyen est de 37 ans (20 à 86) ont complété leur première endoscopie. Le duodénum a été examiné chez 310 patients dont 199 (64%) étaient porteurs d'adénomes duodénaux. Vingt-deux patients (11% de tous les patients porteurs d'adénomes duodénaux) étaient porteurs de polypes visibles à l'endoscopie. Un patient était porteur d'un adéno-carcinome asymptomatique. Le stade de Spigelman se péjorait de manière significative (P<0.05) avec le temps qui s'écoule depuis le diagnostic de la FAP, ce qui peut suggérer un risque accru de cancers avec la durée d'évolution.

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The DAF Project Group includes the present authors and A. Mellon Mogensen, F. Moesgaard, L. B. Svendsen, J. Søndergaard and L. Karlsen (Denmark), J.-P. Mecklin and A. Kahri (Finland), G. Griffioen, F. Nagengast and G.J.A. Offerhaus (Holland), A. Bakka, S. Norheim Andersen (Norway), C. Rubio (Sweden)     

Spontaneous mutation in familial adenomatous polyposis

A retrospective review of the familial adenomatous polyposis registry at the Cleveland Clinic Foundation revealed an incidence of spontaneous mutation in familial adenomatous polyposis (FAP) of 22 percent of family kindreds. These patients were reviewed retrospectively and compared with the total FAP population followed at The Cleveland Clinic Foundation with respect to the onset of disease, the incidence of carcinoma in the resected colon, and incidence of extracolonic manifestations. Review of the characteristics and presentations of these patients suggested that these individuals may harbor a more severe form of FAP. This may be due, in part, to the delay in diagnosis and, therefore, a higher rate of development of colorectal carcinoma and possibly duodenal adenomas. There is also a demonstrable higher rate of extracolonic manifestations of FAP present in this subset of patients. When selecting the initial type of prophylactic colonic resection the surgeon should bear in mind the increased incidence of extracolonic manifestations of the disease in this group of patients and their potential for complications.Read at the meeting of the American Society of Colon and Rectal Surgeons, Anaheim, California, June 12 to 17, 1988.     

Duodenal adenomatosis in familial adenomatous polyposis

BACKGROUND: The prevalence of duodenal carcinoma is much higher in familial adenomatous polyposis (FAP) than in the background population, and duodenal adenomatosis is found in most polyposis patients. AIMS: To describe the long term natural history of duodenal adenomatosis in FAP and evaluate if cancer prophylactic surveillance of the duodenum is indicated. METHODS: A prospective five nation study was carried out in the Nordic countries and the Netherlands. PATIENTS: A total of 368 patients were examined by gastroduodenoscopy at two year intervals during the period 1990-2001. RESULTS: At the first endoscopy, 238 (65%) patients had duodenal adenomas at a median age of 38 years. Median follow up was 7.6 years. The cumulative incidence of adenomatosis at age 70 years was 90% (95% confidence interval (CI) 79-100%), and of Spigelman stage IV 52% (95% CI 28-76%). The probability of an advanced Spigelman score increased during the study period (p<0.0001) due to an increasing number and size of adenomas. Two patients had asymptomatic duodenal carcinoma at their first endoscopy while four developed carcinoma during the study at a median age of 52 years (range 26-58). The cumulative incidence rate of cancer was 4.5% at age 57 years (95% CI 0.1-8.9%) and the risk was higher in patients with Spigelman stage IV at their first endoscopy than in those with stages 0-III (p<0.01). CONCLUSIONS: The natural course of duodenal adenomatosis has now been described in detail. The high incidence and increasing severity of duodenal adenomatosis with age justifies prophylactic examination, and a programme is presented for upper gastrointestinal endoscopic surveillance.     

Colorectal cancer in familial adenomatous polyposis

PURPOSE: This study was performed to determine the relationship among surgical treatment, colorectal cancer, and outcome in patients with familial adenomatous polyposis (FAP). METHODS: Records of 115 patients with FAP who underwent surgery at The Mount Sinai Medical Center between 1947 and 1994 were retrospectively reviewed. Patients without cancer were compared with those with colorectal cancer at initial surgery and with patients who developed rectal cancer following colectomy. RESULTS: Thirty-one patients (27 percent) had colorectal cancer at the time of initial surgery (colon=24; rectal=7). Another 11 patients (26 percent) developed rectal cancer after colectomy with ileorectal anastomosis (IRA). Mean age of patients with colorectal cancer at initial surgery was significantly higher than those without cancer (P <0.01). Patients who developed rectal cancer after IRA were significantly older than patients with colorectal cancer at initial surgery (P <0.01). All patients with rectal cancer after IRA had advanced disease with either nodal or distant metastases at the time of diagnosis. CONCLUSIONS: Colorectal cancer remains a major problem in the treatment of patients with FAP. Nearly one-fourth of these patients have colorectal cancer at initial operation, and one-fourth of patients with IRA develop rectal cancer after a mean follow-up of 13 years. Patients with rectal cancer following IRA are more likely to have advanced tumors than patients with colorectal cancer at initial operation. The high incidence and late stage of rectal cancer detected while under surveillance after IRA supports excision of the entire colorectal mucosa as the treatment of choice for most patients with FAP.     

Brain tumors in familial adenomatous polyposis

Familial adenomatous polyposis was always believed to be a colonic disease of genetic determination with a high risk of development of cancer of the large bowel. Over the years the list of extracolonic manifestations of this disease, both benign and malignant, has amplified. Brain tumors and, in particular, medulloblastoma have not become recognized as major malignant extracolonic manifestations of familial adenomatous polyposis. They are of particular significance because, unlike most of the other manifestations, they occur prior to or early in the development of the colonic manifestations of this disease. This report documents the investigation of 168 kindreds in The Cleveland Clinic Familial Adenomatous Polyposis Registry in a search for those at-risk individuals who developed brain tumors.     

The pancreas in familial adenomatous polyposis

Familial adenomatous polyposis is an archetypal disease illustrating the genetic basis of human cancer. The adenomatous polyposis coli gene functions as a tumor suppressor with hundreds of known mutations that result in a defective adenomatous polyposis coli protein. In addition to the certain fate of colon cancer without colectomy, patients with familial adenomatous polyposis are also at increased risk for other types of neoplasms, including those which affect the pancreas. This review focuses on periampullary and ampullary tumors, benign and malignant pancreatic neoplasms that are associated with familial adenomatous polyposis and Gardner syndrome and pancreatitis in these patients. An individualized surveillance regimen is suggested which for certain patients could include endoscopic ultrasound.     

Non-penetrance and late appearance of polyps in families with familial adenomatous polyposis.

One case of non-penetrance of the familial adenomatous polyposis (FAP) gene at 59 years of age and late onset of polyps on endoscopy and biopsy in this and two other families is described. Screening protocols should include dental screening as well as indirect ophthalmoscopy and endoscopy to detect minimal manifestations of the gene. In the absence of a specific DNA predictive test, bowel screening should continue well beyond 30 years of age.     

Occurrence of desmoid tumours in familial adenomatous polyposis and results of treatment

Desmoids are of major concern in patients with familial adenomatous polyposis (FAP) besides the cancer risk. We estimated the risk for desmoid tumours and the results of their treatment in the Finnish Polyposis Registry. The analysis included 202 FAP patients, of whom 169 had undergone colectomy. Desmoids were observed in 29 cases: 15 in the mesentery, 10 in the abdominal wall and 4 in other sites. There were 12 male and 17 female patients with a mean age of 28.2 years (range 7 months to 59 years). The cumulative life-time risk was 21%; 1.5, 3.0, 8.9, 16 and 18% at ages of 10, 20, 30, 40 and 50 years, respectively. The risk of postcolectomy desmoids was 17% after ileorectal anastomosis and 12% after proctocolectomy. There were no deaths due to desmoids. One abdominal scar desmoid disappeared spontaneously and all the other abdominal wall desmoids could be excised without complications, but recurrence occurred in five (45%) cases. Excision was possible in only nine mesenteric desmoids (56%); in these cases recurrence was less common (two cases, 22%) but two others had lifethreatening compli-cations (bleeding, short bowel). We conclude that the desmoid problem concerns more than 20% of all FAP patients in long-term. Despite high recurrence rates and surgical hazards surgery remains a useful option for most desmoid tumours in FAP patients considering that other treatments are often ineffective or hazardous as well.

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Résumé. Outre le risque de cancer, les tumeurs desmo?des constituent un problème majeur chez les patients porteurs d'une polypose adénomateuse familiale (FAP). Nous avons évalué le risque de tumeurs desmo?des et le résultat de leur traitement sur la base du registre finlandais des polyposes. L'analyse inclut 202 patients porteurs d'une polypose familiale dont 69 ont subi une colectomie. Des tumeurs desmo?des ont été observées dans 29 cas: 15 fois dans le mésentère, 10 fois au niveau de la paroi abdominale et 4 fois dans d'autres sites. Il s'agit de 12 patients de sexe masculin et 10 de sexe féminin avec une moyenne d'age de 28.2 ans (7 à 59 ans). Le risque cumulatif est de 21%; 1.5, 3.0, 8.9, 16 et 18% à respectivement 10, 20, 30, 40 et 50 ans. Le risque d'une tumeur desmo?de après colectomie est de 17% en cas d'anastomose iléo-rectale et de 12% aprés procto-colectomie. Aucun décès ne résulte de la lésion desmo?de. Une cicatrice abdominale desmo?de a disparu spontanément et toutes les autres tumeurs desmo?des de la paroi abdominale ont pu être excisées sans complications mais avec une récidive dans 5 cas (45%). Une excision n'a été possible que chez 9 patients porteurs de tumeurs desmo?des mésentériques (56%); le risque de récidive dans ces cas était moindre (2 cas, 22%) mais 2 complications entra?nant des risques vitaux se sont produites (hémorragie, intestin court). Nous concluons de cette étude que le risque d'une tumeur desmo?de concerne plus de 20% de tous les patients porteurs de polypose adénomateuse familiale à long terme. Malgré un taux de récidive élevé et malgré les risques chirurgicaux, le traitement chirurgical demeure l'option de choix pour le traitement des traitements desmo?des survenant chez des patients porteurs de polypose familiale étant donné que tous les autres traitements sont hasardeux et également inefficaces.

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Accepted: 29 March 1996     

The value of screening and central registration of families with familial adenomatous polyposis

In 1984 a national registry of families with familial adenomatous polyposis was set up in The Netherlands to promote screening in those families. Eighty-two families had been registered by the end of 1988. Analysis of the pedigrees showed that 204 family members at risk had not yet been screened. The diagnosis of familial adenomatous polyposis was histologically confirmed in 230 patients. These patients were subdivided into two groups. Group A comprised patients with familial adenomatous polyposis referred because they were symptomatic, and Group B relatives of these patients who were found by screening to have familial adenomatous polyposis. The authors compared these groups with respect to the occurrence of colorectal carcinoma. Fifty-four patients were found to have a colorectal carcinoma at the time of diagnosis of familial adenomatous polyposis,i.e.,49 of the 104 patients in Group A (47 percent) and five of the 126 patients in Group B (4 percent). The average age at diagnosis of the 104 patients in Group A was 35 years (range, 13 to 66 years) and that of the 126 patients in Group B was 24 years (range, 8 to 59 years). By the age of 40 years, 90 percent of the patients in group B had been diagnosed. Late onset of familial adenomatous polyposis was found in four families. Endoscopy and/or radiography of the upper digestive tract were (was) performed in 44 of the 230 patients. Nineteen patients (43 percent) were found to have polyps in the stomach or duodenum, or both. In our series, only one patient died from cancer of the upper digestive tract (ampullary carcinoma). These results show conclusively that screening leads to the early detection of familial adenomatous polyposis. The value of a national registry is proved by the finding of many at-risk family members who had not previously been screened. Screening should start between the ages of 10 and 12 and should continue up to the age of 50. In the rare cases of families with an apparently late onset of familial adenomatous polyposis, screening should be continued up to age 60. More studies are needed to determine the natural history of polyps in the upper digestive tract.