Iliac mucosa changes in late periods after total colectomy in patients with syndromes of gastro-intestinal polyposis

We studied follow-up iliac mucosa biopsies from 11 patients with juvenile polyposis and 4 patients with familial adenomatous polyposis who had undergone total colectomy with mucosal proctoectomy with creation of straight ileoanal anastomosis. The biopsies that have been taken from the posterior wall of the terminal ileum show incomplete and focal neocolonic transformation of iliac mucosa. Nevertheless, in most cases iliac mucosa preserved its architectural and histochemical characteristics. Chronic inflammation in iliac mucosa is not typical for patients with polyposis.     

Adenocarcinoma in Ileal Pouch after Proctocolectomy for Familial Adenomatous Polyposis: Report of A Case

Restorative proctocolectomy with ileal pouch-anal anastomosis is one of the surgical treatments of choice for patients with familial adenomatous polyposis. Although the risk of cancer developing in an ileal pouch is not yet clear, a few cases of adenocarcinoma arising in an ileal pouch have been reported. We report a case of adenocarcinoma in ileal pouch after proctocolectomy with ileal pouch-anal anastomosis. A 56-yr-old woman was diagnosed as having familial adenomatous polyposis. Total colectomy with ileorectal anastomosis was performed. Six years later, she underwent completion-proctectomy with ileal J pouch-anal anastomosis including anorectal mucosectomy for rectal cancer. After 7 yr, she presented with anal spotting. Endoscopic biopsies revealed adenocarcinoma at the ileal pouch. Resection of the ileal pouch and permanent ileostomy were performed. The risk of cancer in an ileal pouch and its prevention with regular surveillance must be emphasized.     

Molecular genetic analysis of exons 1 to 6 of the APC gene in non-polyposis familial colorectal cancer

Familial adenomatous polyposis coli is caused by constitutional mutations in the APC gene. The hallmark of familial adenomatous polyposis coli is the presence of numerous (>100) colorectal polyps, but mutations in the 5' end of the APC gene have been associated with familial colorectal cancer without florid polyposis. Although familial adenomatous polyposis coli accounts for only a minority of familial colorectal cancer cases, we hypothesised that APC mutations which were not associated with florid polyposis might make a significant contribution to nonpolyposis familial colorectal cancer. To investigate this possibility, we analysed 40 unrelated patients with familial colorectal cancer without classical familial adenomatous polyposis coli for mutations in exons 1 to 6 (codons 1 to 243) of the APC gene. No mutations were detected, but a C→T polymorphism at nucleotide 333 (Arg→Trp at codon 99) was identified. No 5' APC mutations were detected in two patients with desmoid tumours and a family history of colorectal cancer and polyps. We conclude that mutations in exons 1 to 6 of the APC gene are infrequent in patients with familial colorectal cancer who do not have many colorectal polyps.     

Human gut mucosal mast cells: ultrastructural observations and anatomic variation in mast cell-nerve associations in vivo.

One hundred and seventeen coded intestinal biopsy specimens were examined by electron microscopy. All surgical biopsies were obtained from uninvolved sites of patients with two inflammatory bowel diseases (ulcerative colitis or Crohn's disease) and from patients with preneoplastic and neoplastic diseases (adenocarcinoma, rectal polyp, familial polyposis). Biopsy sites included normal ileum, colon, and rectum as well as conventional ileostomies and continent pouches constructed from the ileum. The data reported here describe the ultrastructural anatomy of human gastrointestinal tract mucosal mast cells in vivo and their anatomic associations with enteric nerves.     

Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists

Two main colorectal polyposis syndromes have been described, familial adenomatous polyposis and MUTYH-associated polyposis syndromes. Some polyposis remains unexplained: 20% of adenomatous polyposis and serrated polyposis. The aim of this study was to evaluate in a cohort of patients with unexplained polyposis whether a genetic defect could be detected. Individuals presenting polyposis with more than 40 adenomas or more than 20 serrated polyps (hyperplastic, sessile serrated and mixed), without causative mutation identified, were included. Complementary explorations on APC or MUTYH were performed: search for APC mosaicism, splicing-affecting mutations, large genomic rearrangement of MUTYH. Four genes of Wnt pathway (AXIN2, PPP2R1B, WIF1, SFRP1) and two genes of transforming growth factor-β (TGF-β) pathway (SMAD4, BMPR1A) were screened for germline mutation. Twenty-five patients had an unexplained adenomatous polyposis (familial or sporadic). Five pathogenic mutations were found: four in APC gene (with one case of mosaicism) and one in BMPR1A gene. The exploration of APC mosaicism was better performed from adenoma DNA with high-resolution melting. The screening of the candidate genes did not find any causative mutation. Thirteen individuals had an unexplained serrated polyposis and a frameshift on SMAD4 gene was identified. All mutations were identified in familial cases of polyposis. After new pathological examination, both BMPR1A and SMAD4 cases were found to be associated with a juvenile polyposis while the polyposis was initially described as adenomatous or undetermined. In 17% (6/38) of the patients the causative mutation of the polyposis was identified. Genetic causes were heterogeneous. Sporadic polyposis patients must be considered as potential APC mosaicism. The histological classification of polyposis is strongly important in direct genetic exploration.     

Ornithine decarboxylase as a biologic marker in familial colonic polyposis

We investigated whether the activity of ornithine decarboxylase might serve as a diagnostic test for detecting the presence of the genotype for familial polyposis. This rate-limiting enzyme in the polyamine biosynthetic pathway is essential for intestinal mucosal proliferation. In colonic mucosa from 16 normal controls, ornithine decarboxylase activity was less than 2.5 nmol per milligram per hour. In contrast, it was higher than 2.5 nmol per milligram per hour in the normal-appearing areas of colonic mucosa from 11 of 13 patients with familial polyposis and in all polyps biopsied from these same subjects (P less than 0.05 for specimens from both sites, as compared with controls). Mucosa from dysplastic polyps showed higher mean ornithine decarboxylase activity than mucosa from polyps that were not dysplastic (P less than 0.05). In colonic mucosa from clinically unaffected, first-degree relatives of patients with familial polyposis, there was a bimodal distribution of ornithine decarboxylase activity, with one peak at the mean for normal controls and the other near the mean for normal-appearing mucosa from affected patients. Our study suggests that ornithine decarboxylase activity in colonic mucosa may reflect the abnormal proliferative state in familial polyposis and identify clinically normal family members who carry the genotype.     

腹腔镜全结肠切除治疗家族性腺瘤性息肉病9例报道

目的探讨腹腔镜在全结肠切除治疗家族性腺瘤性息肉病（FAP）的应用价值。方法9例家族性腺瘤性息肉病患者应用腹腔镜实施全结肠切除术,对手术及术后恢复情况进行总结分析。结果9例FAP患者手术均获成功,无中转开腹手术病例,手术时间230～310min,术中失血量80～210mL,肛门排气时间为术后2～3d,住院时间为12～14d,随访6～36个月,术后恢复良好。结论腹腔镜全结肠切除治疗家族性腺瘤性息肉病,手术创伤小,术中出血少,切口小美观,术后恢复快,效果良好。     

Colonic aberrant crypts in children with familial adenomatous polyposis

Aberrant crypt foci of the colonic mucosa have been reported in adults. The alteration may be defined macroscopically or histologically and may or may not be combined with adenomatous changes. Aberrant crypt foci have been regarded as precancerous lesions and are more common in patients with familial adenomatous polyposis. The present report describes the presence of many histologically recognizable aberrant crypt foci without adenomatous changes in the colonic mucosa of 3 children with familial adenomatous polyposis. The openings of the aberrant crypt foci contained inspissated granulofilamentous mucus. Additionally, this report documents the presence of a peculiar serrated appearance of the mucosae surface outline of the nonadenomatous areas. This appears to result from elongation of the crypts and dilated openings/micropapillary arrangement of the uppermost part of the walls of the crypts, with a thin intervening stroma. Neither of these findings has been reported previously to occur in children. They may represent the earliest histologically identifiable changes ever recorded in the colon of patients with familial adenomatous polyposis.     

Biliary neoplasia in Gardner's syndrome

Familial adenomatous polyposis coli is now known to encompass a more complicated spectrum of anomalies than was initially suspected. The term Gardner's syndrome, broadened from its original definition, currently includes all cases of familial polyposis coli with extracolonic neoplasms. Small-bowel adenomata occur in approximately 12% of these patients, and sporadic instances of biliary neoplasia have also been reported. We describe multifocal adenomatous change with severe dysplasia of the gallbladder in a young woman known to have familial adenomatous polyposis coli. Review of this and other such cases in the literature leads us to conclude that neoplasms of the biliary tree constitute a new component of Gardner's syndrome.     

Lipomatosis coli,a mimicker of familial polyposis

Multiple intestinal lipomas (lipomatous polyposis) are quite rare, and they can be quite challenging to diagnose because this condition may be clinically confused with familial adenomatous polyposis with a suggestive family history. Herein, we present a case of lipomatous polyposis that was presented with abdominal pain and, in colonoscopy, had more than 100 polyps. The patient was admitted for surgery with diagnosis of familial polyposis. Resected colon specimen had multiple polyps ranging from 0.1 to 1.5 cm. Microscopically, the polyps were composed of mature adipose tissue with normal overlying mucosa. There were also increased fat cells in the submucosa of the colon adjacent to the polyps. Lipomatous polyposis rarely occurs and can be confused with familial polyposis. Polypectomy is a simple and cost-effective procedure to help in diagnosis and prevent a major surgery.     

Abnormal distribution of c-myc oncogene product in familial adenomatous polyposis.

Monoclonal antibodies raised by synthetic peptide immunisation were used to determine the distribution of the protein product of the c-myc gene by immunocytochemical staining of archival wax embedded material from patients with familial adenomatous polyposis. Polyps from 18 cases of familial adenomatous polyposis, 10 of whom had developed malignant change, and 30 normal control colonic biopsy specimens were examined. A consistent staining pattern was observed in normal mucosa; nuclear staining in the basal proliferative zone; mixed nuclear and cytoplasmic staining in the maturation zone; and cytoplasmic localisation in the surface mature zone. In contrast, the polyps and carcinomata showed a mixed pattern of cytoplasmic and nuclear localisation in the basal proliferative zone with nuclear persistence throughout the crypts to the surface mature zone. This abnormal distribution of the c-myc oncogene product may have a role in the evolution of polyps and their subsequent malignant transformation into familial adenomatous polyposis.     

Simple,rapid, and accurate determination of deletion mutations by automated dna sequencing of heteroduplex fragments of the adenomatous polyposis coli (APC) gene generated by PCR amplification

Germline mutations in patients with familial adenomatous polyposis were analyzed by polymerase chain reaction (PCR) amplification of the adenomatous polyposis coli gene. PCR products from heterozygous patients for deletions of this gene formed four distinct bands on polyacrylamide gel electrophoresis. The four fragments were subsequently purified and both strands of each fragment were directly sequenced, using an automated DNA sequencer and the same primers as those for PCR amplification. It was found that the two slower migrating fragments were “bulge” heteroduplexes, while the other two were homoduplexes made up of two wild-type strands and two deletion-mutant strands, respectively. The sites of deletions in the adenomatous polyposis coli gene could be exactly determined in four of the five patients. In an attempt to identify deletion-carriers of familial adenomatous polyposis at the presymptomatic stage, a family study was also carried out, and two children were found to have the same mutations as those of their affected parents. The direct sequencing of heteroduplex fragments generated during PCR amplification is a potentially useful method for detecting mutations of not only the adenomatous polyposis coli gene but also many other genes of genetic diseases. © 1993 Wiley-Liss, Inc.     

Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation

Desmoid tumours are generally very rare but occur about 100 times more frequently in the colorectal cancer predisposition syndrome familial adenomatous polyposis (MIM 175100), being represented in about 10% of patients. In addition to desmoid disease occurring in familial adenomatous polyposis (FAP) there exist familial infiltrative fibromatosis (MIM 135290) kindreds where there is no evidence of FAP. Previously we have described a kindred with familial infiltrative fibromatosis (FIF) in which desmoid tumours were associated with nonpolyposis colorectal cancer. FAP is caused by mutations in the APC gene and various genotype-phenotype relationships have been defined including reports that colorectal polyposis is less severe with mutations 5' to codon 157 and that the risk of desmoid tumours is high in FAP patients with APC gene mutations between codons 1444 and 1598. There is relatively little information on the phenotype of APC gene mutations 3' to codon 1598; however, one large family has been reported with a mutation at codon 1987 which presents with a highly variable phenotype which includes desmoid disease. We screened our original FIF kindred and three further families with a similar phenotype for mutations in the APC gene. A 4 bp frameshift deletion in codon 1962 was identified in the original FIF kindred and two further apparently unrelated families. Haplotype analysis suggests a common origin for the APC mutation in all three families. Affected individuals had no evidence of congenital hypertrophy of the retinal pigment epithelium. Colorectal polyposis was variable, and most affected patients had either none or a few late onset polyps. These findings demonstrate (i) that FAP and FIF are allelic, and (ii) that APC gene mutations which truncate the APC protein distal to the beta-catenin binding domain are associated with desmoid tumours, absent CHRPE and variable but attenuated polyposis expression.      

APC intragenic haplotypes in familial adenomatous polyposis

Genetic epidemiological studies are useful for the knowledge of the association of markers and genes involved in diseases. In the present work, we studied the frequency of four adenomatous polyposis coli intragenic RFLP markers often used in risk evaluation in a population of 10 familial adenomatous polyposis patients from 10 unrelated Portuguese familial adenomatous polyposis families not sharing the same mutation, and in a population of 55 unrelated healthy Portuguese volunteers. We compared the frequency obtained to normal and affected populations and to results already reported in other populations. We observed allelic frequencies for the Portuguese population that agree with the published ones. The intragenic polymorphisms show strong gametic disequilibrium suggesting little recombination between them. We observed haplotype frequencies significantly different in patients and controls. The gametic disequilibrium may be due to a common founder for a proportion of apparently unrelated probands.     

Cell proliferation and ultrastructural changes of the duodenal mucosa of patients affected by familial adenomatous polyposis

Patients affected by familial adenomatous polyposis (FAP) are at risk of developing duodenal neoplasia. Our objective was to detect early abnormalities of the epithelial cell proliferation and ultrastructure of apparently normal duodenal mucosa of FAP patients. Biopsy specimens were taken from the duodenal mucosa. Cell proliferation was studied by immunohistochemistry with proliferating cell nuclear antigen (PCNA), and ultrastructure, by transmission electron microscopy. We found that the PCNA labeling index for duodenal mucosa of patients with FAP was higher in comparison to the case of hospital controls without cancer risk (P = 0.019). Moreover, ultrastructural changes related to an impairment of cell adhesion function were found in all biopsies of FAP patients but not in the duodenal mucosa of the controls. We conclude that alterations of cell proliferation kinetics and epithelial adherens junction structures were phenotypic characteristics of histologically normal duodenal mucosa of FAP patients. These abnormalities may be considered as intermediate biomarkers of neoplasia and potential surrogate endpoints in chemoprevention studies.     

Genetic alterations during colorectal-tumor development

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.     

Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps

We studied a large kindred with a history of colorectal cancer of early onset. Proctosigmoidoscopic examination of 51 family members identified only 2 with familial polyposis coli, which strongly predisposes those who have it to colorectal cancer and which is defined as the presence of more than 100 polyps in the colon. However, eight family members had 2 to 40 colonic polyps. We suspected that in this family, colorectal cancer was the result of a mutation in the gene on chromosome 5 that is responsible for familial polyposis coli. To test our hypothesis, we obtained genotypic information on 81 family members with respect to seven polymorphic DNA markers previously shown to be linked to the locus for familial polyposis coli. Multilocus analysis of the data demonstrated genetic linkage (lod score, 5.58) between these markers and the locus responsible for the defined syndrome of colonic polyps or colorectal cancer in this kindred. These findings constitute evidence that the genetic defect in this family is a mutation in the gene that causes familial polyposis coli. We conclude that mutations at the genetic locus for familial polyposis coli may be the cause of other, more subtle syndromes involving an inherited susceptibility to colonic adenomatous polyps and colorectal cancer.     

Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis.

In order to detect accompanying gastric lesions, we examined 22 patients with familial adenomatosis of the colon belonging to 14 families. Various gastric lesions were confirmed in 15 patients (68.2 per cent) belonging to 13 families. The lesions were found histologically to be adenoma in nine cases, fundic gland polyposis in six, carcinoma in three, and microcarcinoid in two. Fundic gland polyposis consisting of simple hyperplasia of the fundic glands seems to be the gastric lesion specific to familial adenomatosis of the colon and rectum. Familial adenomatosis coli not only affects the colon and rectum, but is also capable of inducing tumorigenicity in other organs. The stomach is one of the organs in which extracolonic lesions occur.     

Class II HLA antigen expression in familial polyposis coli is related to the degree of dysplasia

Class II HLA antigen expression was studied in 30 polyps from 3 patients who were diagnosed with familial polyposis coli. The highest levels of this expression were associated with the most severe grades of dysplasia (p less than 0.00001), the sequence of positivity being HLA-DR greater than DQ greater than DP. No association was observed between the expression of these antigens and the presence of a specific inflammatory leukocytic infiltrate. Our results imply that HLA class II molecule expression is somehow related to malignant transformation in familial polyposis coli in accordance with the adenoma-dysplastic adenoma-adenocarcinoma sequence. Thus these antigens may be useful markers to tumoral progression.     

Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients.

Multiple gastric and duodenal biopsy specimens from 102 asymptomatic patients with familial adenomatous polyposis, taken during a prospective endoscopic screening programme were examined. One hundred patients had microscopic gastroduodenal pathology, often in the absence of macroscopic lesions. Adenomas were found in 94 patients in the duodenum, in the second and third parts. Hyperplasia of villous and crypt epithelium was also seen, sometimes in the absence of adenomas: this may be a precursor of neoplastic change. In the stomach fundic gland polyps were the commonest abnormality, seen microscopically in 44 patients. Chronic antral gastritis was common in patients without fundic polyps. Gastric adenomas were present in six patients, all of whom also had duodenal adenomas. If duodenal adenomas in familial adenomatous polyposis have a similar malignant potential to those in the colorectum sequential endoscopy and biopsy are necessary to detect cancer in these patients.