Frequency of duodenal adenomas in patients with familial adenomatous polyposis

OBJECTIVE: To estimate the prevalence of polyps in the stomach and duodenum in patients with familial adenomatous polyposis (FAP), and to examine the relationship between age and severity of duodenal adenomatosis. DESIGN: Retrospective. METHOD: Using the FAP-registry of the Netherlands Foundation for the Detection of Hereditary Tumours, data were obtained from patients who had undergone a gastroduodenoscopy before 1 July 1999. The endoscopic and histological findings were used to classify the duodenal adenomas according to the Spigelman classification. RESULTS: 224 patients had undergone at least one gastroduodenoscopy: 117 men and 107 women with a mean age at the time of the first endoscopy of 37 years (range: 13-78). Fundic gland polyposis was detected in 79 patients (35%), stomach adenomas in 6 patients (3%) and duodenal adenomas in 92 patients (41%). A total of 21 patients (9%) had severe duodenal adenomatosis (Spigelman III or IV). Duodenal adenomatosis was often more severe if the patient was older. Ten patients were known to have duodenal cancer; the mean age at diagnosis was 50.3 years (range: 39-67). CONCLUSION: Nearly 10% of the patients with FAP had developed severe duodenal adenomatosis. The severity of duodenal adenomatosis was related to the patient's age.     

Rectal polyposis as a guide to duodenal polyposis in familial adenomatous polyposis.

Almost all patients with familial adenomatous polyposis (FAP) develop duodenal polyps, the severity of which is graded stage 1 (minor) to stage V (cancer). Regular endoscopy is recommended for all patients with FAP. To test whether the development of severe duodenal polyposis could be predicted in another way, rectal and duodenal polyp severity were compared in 91 patients with FAP. The fulguration ratio (number of rectal fulgurations divided by number of years since colectomy) supplied the rectal polyp severity index. Patients with stage V duodenal polyposis had significantly higher fulguration ratios (median 0.38) than did patients with stage 1 disease (median 0; P = 0.009). However, the wide scatter of results means that rectal polyp severity cannot be used as a guide to duodenal polyp severity in individual patients. The coexistence of populations with severe duodenal and rectal polyposis suggests that environmental factors are important in phenotypic expression in FAP.     

Duodeno-gastric reflux and gastric adenomas: a scintigraphic study in patients with familial adenomatous polyposis.

To test whether the presence of gastric adenomas (dysplasia) was associated with gastric reflux of duodenal contents, six patients with familial adenomatous polyposis (FAP) who had gastric adenomas and nine matched FAP patients without gastric adenomas underwent scintigraphic duodeno-gastric reflux scanning. Reflux was graded 0-6, where 0 = no reflux, 1 = intermittent reflux into antrum only, 2 = prolonged reflux into antrum only, 3 = intermittent reflux into body, 4 = prolonged reflux into body, 5 = intermittent reflux into body and fundus, and 6 = prolonged reflux into body and fundus. FAP patients with gastric adenomas had more severe reflux (median 6, range 4-6) than did controls (median 3, range 0-6; P = 0.009, Mann-Whitney U test). These results are consistent with a role for bile in the development of gastric adenomatous polyps and suggest that bile is involved in the dysplasia-carcinoma sequence.     

Digestive polyposis. Retrospective study of 20 cases

BACKGROUND: Three main polyposis syndromes are transmitted as an autosomal dominant disorder: familial adenomatous polyposis (FAP), juvenile polyposis syndrome (JPS) and Peutz-Jeghers syndrome. AIM: Evaluate this management of digestive polyposis. METHODS: Our study included 20 patients which were collected in th departements of pathology surgery and garstroenterology of MT Maarmouri's Hospital, Nabeul city. RESULTS: We reported 15 cases of adenomatous polyposis with 2 family groups. We identified a family group of JPS with 3 members and 2 cases of Peutz-Jeghers syndrome. We found 11 cases of colonic adenocarcinoma out of the 15 patients affected by adenomatous polyposes. FAP is a generalized disorder involving the entire colorectum segment with numerous extra-colonic manifestations. The risk to develop colonic cancer is 100%. JPS is characterised by the development of numerous gastrointestinal juvenile polyps and occurs usually before 20 years old, the progression to cancer is rarely observed. CONCLUSION: Peutz-Jeghers syndrome consists in hamartomatous polyps associated to a characteristic mucosal pigmentation. The patients are usually young adults and have an increased incidence of cancer in extradigestive sites.     

Genetics of colorectal cancer. I. Non-polyposis and polyposis forms of hereditary colorectal cancer]

About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.     

Serum nutrients and habitual dietary intake in colectomized FAP patients in Norway

Background  Patients with familial adenomatous polyposis (FAP) are colectomized in young age in order to avoid development of colorectal cancer. Because colectomy radically changes gastrointestinal physiology, and food avoidance may be present, colectomized patients may be at risk for nutritional deficiency. Aim of the study  to evaluate: (1) serum biochemical levels as compared to reference; (2) dietary intake as compared to the recommendations. Methods  Blood samples, interviews and food frequency questionnaire were collected from 38 colectomized FAP patients with duodenal adenomas (mean age 40 years, range: 24–70). They were recruited from the Norwegian database on FAP. Results  Serum albumin was significantly higher (P ≤ 0.0001), and Mg (P = 0.02), ferritin (P ≤ 0.001), and cholesterol (P = 0.03) significantly lower, than reference levels. Compared to recommendations, a low intake was seen for folate and fiber (<50%), iron, thiamin, riboflavin (<25%), and omega-3 fatty acids (8%). Sugar intake exceeded the recommendation, mainly due to a high intake of soft drinks. Food avoidance was reported by 53%. Conclusions  We would suggest that the nutrient intake among FAP patients should at least meet the recommendations for healthy subjects. Their risk of metachronous cancers should also cause special attention to dietary factors that may prevent nutritional deficiency and carcinogenesis. Disclaimers: None of the authors had any disclaimers.     

Prevention of colorectal cancer: acetylsalicyclic acid and cyclo-oxygenase-2 inhibitors are only partially effective

Acetylsalicylic acid was recently shown to inhibit the development of colorectal adenomas in subjects with a moderately increased risk for colorectal cancer. The mechanisms by which acetylsalicylic acid and other NSAIDs, including COX-2 inhibitors, exert this effect include: inhibition of COX-2, induction of apoptosis and induction of the P21 protein that controls the development of crypt cells. For the majority of the population, a healthy lifestyle and healthy eating habits are the best means of preventing colorectal cancer. In addition, population-wide screening should be encouraged. For people with an increased risk of colorectal cancer, acetylsalicylic acid only has a partial effect and therefore endoscopic surveillance is still indicated. Sulindac or celecoxib may be useful for patients with familial adenomatous polyposis and in particular for inhibiting the development of rectal adenomas after subtotal colectomy with ileorectal anastomosis. However, in these cases endoscopic surveillance is also still necessary.     

Risk and surveillance of individuals with heritable factors for colorectal cancer. WHO Collaborating Centre for the Prevention of Colorectal Cancer.

Heritable and genetic factors pertinent to colon cancer can be divided into three categories: inherited syndromes, genetic epidemiology, and molecular genetics. Familial adenomatous polyposis (FAP) and Gardner syndrome (GS) are rare dominantly inherited syndromes characterized by hundreds to thousands of colonic adenomatous polyps. Colon cancer occurs at a young age in both diseases unless the colon is removed. Peutz-Jeghers syndrome and familial juvenile polyposis are inherited hamartomatous polyposis conditions with a less dramatic, but definite, increased risk for colon cancer. These four polyposis syndromes together account for less than 1% of cases of colon malignancy. Hereditary nonpolyposis colorectal cancer is a dominantly inherited form of colon cancer characterized by an early age of onset and a predilection for proximal colonic tumours. Multiple primary malignancies are frequently observed and one or several adenomatous polyps are often present in affected individuals; 4-6% of colon cancer cases occur in relationship to this syndrome. Genetic epidemiological studies have consistently shown that first-degree relatives of persons with colon cancer have a twofold to threefold increased risk of having colon malignancy. More recent studies have found a similar risk among relatives of those with adenomatous polyps. Studies of colon cancer and adenomatous polyps in pedigrees have further demonstrated that this familial clustering probably occurs on the basis of partially penetrant inherited susceptibilities. These inherited susceptibilities probably interact with environmental factors to give rise to polyp growth and finally colon cancer. Molecular studies have begun to elucidate the genetic mechanisms of colon cancer at the DNA level. The germinal mutation of FAP and GS has been localized to the long arm of chromosome 5. Tissue samples from "random" adenomatous polyps and colon cancers have shown frequent and specific acquired DNA sequence deletions on chromosomes 5, 17, and 18. Mutations and over-expression of the ras oncogene likewise have been observed in such tissues. The chromosome 5 defect in polyp and cancer tissues is probably at the same locus as the germinal mutation of FAP. There is evidence that this locus normally regulates expression of the c-myc oncogene, which in turn probably has a regulatory function in DNA replication. The chromosome 17 deletion is a mutation of the gene for the transformation-associated protein, p53. Appropriate screening starting at a relatively young age is necessary to prevent cancer in the inherited syndromes. Screening is also indicated in close relatives of those with nonsyndromic or common colon cancer in view of the moderately increased risk for colon cancer in this group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chemoprevention of colorectal cancer

Although colorectal cancer is one of the most preventable forms of cancer, it remains the second leading cause of cancer death worldwide. Primary prevention involves the identification and elimination of factors, which cause or promote colorectal cancer. The goal of screening is to prevent colorectal cancer mortality through the detection and treatment of premalignant adenomas and curable-stage cancer. Most colorectal cancers are believed to arise from adenomatous polyps. Early identification and removal of adenomas can prevent the development of colorectal cancer. Chemoprevention is the use of specific chemical compounds to prevent, inhibit, or reverse carcinogenesis. Several chemoprevention options have been investigated and confirmed as effective. Aspirin and other nonsteroidal anti-inflammatory drugs are the most widely studied agents, their use has been consistently associated with reduction in the risk of mortality and the incidence of colorectal adenomas and cancers. The selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been demonstrated to decrease the number and the size of polyps in patients with familial adenomatous polyposis syndrome. Because the gastrointestinal toxicity of coxibs is lower, it might be safer than aspirin or other non-selective nonsteroidal anti-inflammatory drugs for long-term use. This review aims to summarize the recent theoretical and practical advances in the chemoprevention of colorectal cancer.     

Current concepts in the genetics of hereditary and sporadic colorectal cancer and the role of genetics in patient management. Hereditary colorectal cancers

Colorectal cancer (CRC) is the second leading cause of mortality of malignant diseases in Hungary and according to the incidence and prevalence of CRC Hungary is second among European countries. Hence, it is of outstanding interest to know the current concepts on pathogenesis and genetical background of CRC, as well as incorporate this knowledge in the everyday practice. In the first part of the review authors address the genetic background of hereditary colorectal cancer syndromes. In fact, a positive family history may be found in 20-30% and genetically defined trait (e.g. familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and Peutz-Jeghers-syndrome (PJS)) is responsible for 3-5% of all colon cancers. Germline mutations of tumor suppressor gene, APC (5q21) are found in 70-90% of the cases. Until now more than 300 mutations were identified. Though a typical mutation was not found, the location of the mutation is associated to the clinical phenotype and prognosis. Of note, beside APC mutations, biallelic mutations of the MYH gene may be found in a subset of individuals with FAP. The diagnosis of HNPCC is based on family history and the presence of Amsterdam I-Il or Bethesda criteria. The genetic background and clinical phenotype of the syndrome is heterogeneous. Mutations of different mismatch repair genes (mainly hMLH1 or hMSH2) may be identified in most cases. Genetic testing is advised in first degree relatives of FAP patients, if genetic testing is not available colonoscopic surveillance should be done starting at the age of 10-12 years. Due to the high number of mutation genetic testing is difficult in HNPCC families and colonoscopic screening should be advised to affected families.     

From gene to disease; the APC gene and familial adenomatous polyposis coli

Familial adenomatous polyposis coli is an autosomal dominant hereditary form of colorectal cancer associated with mutations in the adenomatous polyposis coli (APC) gene on chromosome 5. The APC protein is thought to mediate the stability of beta-catenin in the WNT signaling transduction pathway ('wingless-type mouse mammary tumor virus integration site family member') in normal colonic epithelial cells, thereby indirectly regulating the expression of WNT target genes such as the c-myc-oncogene. APC gene mutations cause the development of multiple adenomatous polyps in the colorectum, which strongly predisposes gene carriers to colorectal cancer. Extracolonic manifestations, including gastric and duodenal polyps, osteomas, desmoids, epidermoid cysts, and retinal lesions, are commonly observed in patients with familial adenomatous polyposis. Detection of mutations in the APC gene allows genetic counselling and reliable identification of at-risk individuals.     

Pancreas-preserving total duodenectomy due to familial adenomatous polyposis in 4 patients

In 4 patients with familial adenomatous polyposis (FAP) and multiple severe dysplastic adenomas in the duodenum (a 42-year-old woman and 3 men aged 44, 53 and 33 years, respectively), pancreas-preserving total duodenectomy (PPTD) was carried out. In 2 of the patients, serious early post-operative complications arose (leakage and haemorrhage of the gastrojejunostomy, respectively), and 1 patient developed a late complication (attacks of pancreatitis). During the 1-5-year follow-up period, small villous adenomas were seen in the jejunum (neoduodenum) of 1 of the patients. PPTD is a technically possible procedure which allows targeted treatment to be carried out if duodenum polyps are found upon endoscopic examination.     

Genetics of colorectal cancer. II. Hereditary background of sporadic and familial colorectal cancer]

About 15% of patients with colorectal cancer have a positive family history: 5% have hereditary colorectal cancer (hereditary non-polyposis colorectal carcinoma (HNPCC), familial adenomatous polyposis (FAP) or some other hereditary syndrome), while in 10% no clear hereditary pattern can be recognized ('familial colorectal cancer'). In sporadic and in familial intestinal cancer, a demonstrable hereditary predisposition may undoubtedly exist. HNPCC is often characterized by microsatellite instability, i.e. an increased number of short DNA sequences in the DNA indicating a disorder in DNA repair and a mutation in a DNA 'mismatch repair' (MMR) gene. Indicative of hereditary bowel cancer on the basis of such an MMR gene mutation are: (a) presence of bowel cancer in > or = 3 relatives, (b) early age at the time of the diagnosis of 'bowel cancer', (c) multiple primary bowel tumours, (d) uterine cancer in the family and (e) bowel and uterine cancer in a woman. Recent data demand a new subdivision of hereditary bowel cancer, based upon both the clinical picture and the results of DNA-tests. The genetic alterations in colonic adenomas and carcinomas are known to a large extent. In future these insights may be important in clinical practice, such as a more individual determination of the patient's prognosis and accordingly, of the treatment and follow-up.     

Can resistant starch and/or aspirin prevent the development of colonic neoplasia? The Concerted Action Polyp Prevention (CAPP) 1 Study

Loss of function of the adenomatous polyposis coli (APC) tumour suppressor gene through truncating mutations or other means is an early event in most colo-rectal cancer (CRC). The APC gene encodes a large multifunctional protein that plays key roles in several cellular processes, including the wnt signalling pathway where an intact APC protein is essential for down regulation of beta-catenin. The APC protein also plays a role in regulation of cell proliferation, differentiation, apoptosis, cell-cell adhesion, cell migration and chromosomal stability during mitosis. Acquisition of a non-functional APC gene can occur by inheritance (in the disease familial adenomatous polyposis (FAP)) or by a sporadic event in a somatic cell. Whilst there is strong epidemiological evidence that variation in diet is a major determinant of variation in CRC incidence, conventional adenoma recurrence trials in sporadic cases of the disease have been relatively unsuccessful in identifying potentially protective food components. Since the genetic basis of CRC in FAP and in sporadic CRC is similar, intervention trials in FAP gene carriers provide an attractive strategy for investigation of potential chemo-preventive agents, since smaller numbers of subjects and shorter time frames are needed. The Concerted Action Polyp Prevention (CAPP) 1 Study is using a 2 x 2 factorial design to test the efficacy of resistant starch (30 g raw potato starch-Hylon VII (1:1, w/w)/d) and aspirin (600 mg/d) in suppressing colo-rectal adenoma formation in young subjects with FAP. Biopsies of macroscopically-normal rectal mucosa are also being collected for assay of putative biomarkers of CRC risk.     

Cost-minimization analysis of genetic testing versus clinical screening of at-risk relatives for familial adenomatous polyposis

OBJECTIVE: Familial adenomatous polyposis (FAP) is a well-known hereditary colorectal cancer-predisposing syndrome. Genetic testing for colorectal cancer risk is now part of standard medical practice, but very little is known about the economic impact of this technology. The aim of this study was to assess, from a healthcare system perspective, the direct costs of two strategies for screening at-risk relatives of FAP patients: clinical screening versus genetic testing for FAP. METHODS: A systematic review of the literature was carried out. Additional information was gathered from experts in research and clinical laboratories and in hospital departments. A decision tree was constructed to compare per-person and per-family costs of the two strategies for screening at-risk relatives of FAP patients. Sensitivity analysis was performed to assess the stability of the model across the full range of plausible values for all key parameters. RESULTS: According to the decision analysis, with FAP screening starting at puberty, the average screening costs are $3,181 and $2,259 (Canadian dollars), respectively, for the clinical screening and the genetic testing strategies. Genetic screening is cost saving up to a first screening age of 36. Sensitivity analysis shows that the results of the baseline analysis hold across a variety of assumptions concerning the parameter values. CONCLUSIONS: The genetic testing strategy is cost saving relative to the clinical screening alternative. Apart from its lower costs, it is associated with many other benefits. Accordingly, under predefined conditions, predictive genetic testing seems to be the optimal screening strategy for FAP.     

家族性腺瘤性息肉病的家系调查研究

目的探讨家族性腺瘤性息肉病的临床特点及家系调查登记的意义。方法对10个家系的患者及高危亲属进行登记、随访、结肠镜检查。结果普查Ⅰ、Ⅱ级亲属共45例，发现患者26例，其中新突变者3例，有症状者19例，已癌变者3例，5例有视网膜色素上皮细胞先天性肥大（CHRPE）。结论家族性腺瘤性息肉病的早期临床表现无特异性，开展患者登记家系调查是早期发现患者的主要途径。     

A decision model and cost-effectiveness analysis of colorectal cancer screening and surveillance guidelines for average-risk adults

OBJECTIVES: Guidelines for colorectal cancer screening and surveillance in people at average risk and at increased risk have recently been published by the American Gastroenterological Association. The guidelines for the population at average risk were evaluated using cost-effectiveness analyses. METHODS: Since colorectal cancers primarily arise from precancerous adenomas, a state transition model of disease progression from adenomatous polyps was developed. Rather than assuming that polyps turn to cancer after a fixed interval (dwell time), such transitions were modeled to occur as an exponential function of the age of the polyps. Screening strategies included periodic fecal occult blood test, flexible sigmoidoscopy, double-contrast barium enema, and colonoscopy. Screening costs in 1994 dollars were estimated using Medicare and private claims data, and clinical parameters were based upon published studies. RESULTS: Cost per life-year saved was $12,636 for flexible sigmoidoscopy every 5 years and $14,394 for annual fecal occult blood testing. The assumption made for polyp dwell time critically affected the attractiveness of alternative screening strategies. CONCLUSIONS: Sigmoidoscopy every 5 years and annual fecal blood testing were the two most cost-effective strategies, but with low compliance, occult blood testing was less cost-effective. Lowering colonoscopy costs greatly improved the cost-effectiveness of colonoscopy every 10 years.     

Fruits,vegetables, and adenomatous polyps: the Minnesota Cancer Prevention Research Unit case-control study

Although high vegetable intakes have been associated with a lower risk of colorectal cancer, this relation is less well established for the precursor lesions, adenomatous polyps. With a case-control design involving adenomatous polyp cases (n = 564), colonoscopy-negative controls who were polyp free at colonoscopy (n = 682), and community controls (n = 535), this 1991-1994 Minnesota Cancer Prevention Research Unit study investigated the relation between fruit and vegetable consumption and first incident adenomatous polyps. Dietary intake was assessed using a food frequency questionnaire. For women, adenoma risk was approximately halved in the highest versus lowest quintile of juice consumption (cases vs. colonoscopy-negative controls: odds ratio (OR) = 0.50, 95% confidence interval (CI): 0.27, 0.92; cases vs. community controls: OR = 0.56, 95% CI: 0.30, 1.06). The association was stronger for adenomas with moderate or severe dysplasia compared with mild dysplasia. Juice was not associated with adenoma risk in men. The results for fruits, vegetables, total fruits and vegetables, green leafy vegetables, and several botanically and phytochemically defined subgroups generally were not statistically significant. Because elevated vegetable consumption has been associated with a lower risk of colorectal cancer, vegetables may have a stronger role in preventing the progression of adenomas to carcinomas rather than in preventing the initial appearance of adenomas.     

Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice

The multiple intestinal neoplasia (Apc(Min/+)) mouse possesses a germline mutation at codon 850 of the adenomatous polyposis coli (Apc) gene resulting in the formation of a nonfunctional truncated gene product. Following a somatic mutation of the remaining wild-type allele, mice spontaneously develop approximately 40-50 tumors throughout the intestinal tract. This mouse model has been used to study intestinal tumorigenesis because this mutation is analogous to the inherited APC mutation in humans with familial adenomatous polyposis (FAP). These individuals characteristically develop numerous adenomas throughout their intestinal tracts. Only a few studies have evaluated the effects of dietary fatty acids on tumorigenesis in this animal model with varying results, and none have linked these effects to alterations in arachidonic acid (AA) metabolism. This study was designed to evaluate the antitumorigenic effect of dietary (n-3) polyunsaturated fatty acids (PUFA) in the Apc(Min/+) mouse model and to determine whether these effects are related to inhibition of AA metabolism. Male Apc(Min/+)mice were fed diets supplemented with eicosapentaenoic acid (EPA), AA or a combination of AA + EPA. Mean tumor number in the EPA group was 68% lower (P<0.05) compared with the control group, whereas AA supplementation did not significantly alter tumor load. The reduction in tumor load coincided with significant reductions in intestinal AA content and levels of prostaglandins. However, supplementing AA to the EPA diet (AA + EPA) abolished the antitumorigenic effect of EPA, increased tissue AA content fourfold and prostaglandin production two- to fourfold. These results indicate that AA is involved in tumorigenesis and suggest that EPA's ability to reduce tumor load in Apc(Min/+) mice is related to reductions in tissue AA content or its metabolism.     

Cyclooxygenase(COX)-2-inhibition in the prevention and treatment of colorectal carcinoma

Epidemiological studies have found that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of colorectal cancer (CRC). Cyclooxygenase (COX)-2 expression is present in colorectal cancer and overexpression is associated with metastases and poorer prognosis in multivariate analysis. NSAID treatment results in a reduction of the incidence of colorectal adenoma in patients with familial adenomatous polyposis, in patients with a history of colorectal adenomas and in patients with a history of CRC. Pre-clinical research shows that COX-2 expression is associated with cell proliferation, angiogenesis, apoptosis inhibition and local immune-down modulation. An anticarcinogenic effect has been shown specifically in selective COX-2 inhibitors in animal models. Selective COX-2 inhibitors have fewer adverse effects than the non-selective NSAIDs and are promising chemopreventative and chemotherapeutical agents. The effects of selective COX-2 inhibition in the prevention of and treatment for colorectal carcinoma will be investigated in clinical randomized multicentre trials.