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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

The incidence rate of familial adenomatous polyposis

Based on the Danish Polyposis Register epidemiological calculations on familial adenomatous polyposis (FAP) were carried out. The mean annual incidence was 1.85x10^-6 during the years 1971–1992, and the prevalence increasing to about 32x10^-6 at the end of 1992. FAP patients constituted a decreased percentage of all Danish patients with colorectal cancer (0.07% in 1980–1992). The completeness of registration was 97% in 1983–1992. The results are similar to Finnish estimates based on the same direct method of calculation, and as both series are based on almost complete national polyposis registration in well-registered populations we regard our results to be close to the true incidence rate.

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Résumé En se basant sur le registre danois des polyposes, des calculs épidémiologiques ont été réalisés sur la polypose familiale multiple. L'incidence annuelle moyenne est de 1.85x10^-6 au cours des années 1971 à 1992 et la prévalence augmente à environ 32x10^-6 à la fin de 1992. Les patients porterus d'une polypose familiale constituent un pourcentage en diminution de tous les patients porteurs d'un cancer colo-rectal (0.07% entre 1980 et 1992). L'exactitude du registre était de 97% entre 1983 et 1992. Les résultats sont similaries aux estimations finlandaises basées sur une même méthode de calcul; et étant donné que les deux séries témoignent d'un enregistrement pratiquement complet des polyposes à l'échelon national dans une population correctement enregistrée, nos résultats semblent refléter l'incidence réelle de l'affection. and increasing bias due to the significant improval of the prognosis of familial adenomatous polyposis during the last decades. Moreover, most studies are not based on epidemiologically valid patient series without selection bias. Recent calculations of the incidence rate with a direct method have been published on the basis of the national Danish and Finnish polyposis series, showing an annual incidence rate of 1.3–1.6x10^-6 in the early 1980's [5, 6].The aim of the present study was to reevaluate the occurrence of the disease about 25 years after the establishment of the Danish Polyposis Register by presenting estimates on the incidence rate, the point prevalence rate, and the completeness of registration.

     

About a case of familial adenomatous polyposis

The authors present a case of FAP, familial adenomatous polyposis. This condition comprises 3 different syndromes characterized by the development of numerous polyps in the colon. Other different expressions of the same genetic anomaly are: familial adenomatous polyposis coli, Gardner's syndrome and Turcot's syndrome. The main risk for these pathologies consists in the frequent cancer outcome, which usually occurs between the 4th and the 5th decade of life and, however, after about 12 years from the first diagnosis. The patient came to the authors' observation in the surgery room of the department of geriatrics, in the university of Catania, where patients from South Italy and Sicily are treated. He had a severe anemic condition and poor general health. At the time of the diagnosis the patient, 56 years old, was subjected to endoscopic investigations which showed extensive polyposis of the entire colon and of the stomach, later on typified as 'Familial polyposis'. He was then subjected to total colectomy and gastric polypectomy. Besides, the patient and his direct family members (4 children and 2 sisters) were also genetically screened. The results proved that the patient and 3 of his children presented a genetic mutation located in connection with one of the two alleles of the APC gene. The potentially cancerous evolution makes it necessary to perform a genetic screening of all direct relatives of patients affected by FAP in order to both uncover the genetic anomaly responsible for this pathology and to prevent cancer, which is the natural outcome of this disease.     

Familial colorectal cancer and familial adenomatous polyposis

Familial adenomatous polyposis (FAP) affects around 1 in 10,000 individuals; the gene for this condition was recently shown to be located on chromosome 5, and it is only a matter of time before its precise location and function are determined, making prephenotypic, and even prenatal, diagnosis more generally available and reliable. In the mean time, care of FAP families will continue to depend on careful registration of family information, prophylactic bowel surgery and surveillance for other potentially serious manifestations of the disease. Upper gastrointestinal malignancies and desmoid tumours have overtaken colorectal cancer as the leading causes of death in some centres. Other dominantly-inherited colorectal cancer syndromes produce less striking phenotypes, but affect far more individuals than FAP. It appears that there are two patterns of hereditary non-polyposis colorectal cancer (HNPCC) syndromes, one involving cases of bowel cancer alone, the other associated with breast and gynaecological cancers; these may prove to be variable expressions of a common gene abnormality. More effort is required by clinicians managing cases of colorectal cancer to identify affected families in order to offer surveillance and appropriate treatment in the hope that such measures may prevent cancer in family members.