The role of cell proliferation and crypt fission in adenoma aggressiveness: a comparison of ileoanal pouch and rectal adenomas in familial adenomatous polyposis.

AIM: In patients with familial adenomatous polyposis (FAP), ileoanal pouch cancer is rare whereas rectal cancer is common, despite polyp initiation at the two sites being similar at the molecular level. This study investigated whether the disparity in adenoma aggressiveness reflects underlying differences in histogenesis. METHOD: Normal mucosal biopsies and 2-3 mm adenomas from patients with FAP were dissected into individual crypts. Crypt area, morphology, fission and mitoses were analysed for crypts from pouch, rectum and supra-anastomotic ileum. Immunohistochemistry of similar archival samples was performed for lysozyme, ß-catenin and TP53 expression. RESULTS: The morphology of normal crypts was similar at each site, although crypt area differed. The area of normal pouch crypts was intermediate between rectum and ileum. The area of adenomatous crypts of rectum and pouch was similar, but the latter had increased asymmetrical fission. Crypt mitoses were proportional to area in all tissues, but crypt fission was reduced in adenomatous crypts from the rectum compared with the pouch. Pouch adenomas retained lysozyme expression as seen in normal ileum. Nuclear ß-catenin accumulation was similar, but TP53 expression was increased in rectal adenomas. CONCLUSION: Diminutive polyps from rectum and pouch differ in morphology and proliferation. Aggressiveness in rectal polyps is not conferred by increased crypt proliferation, fission, or activation of the Wnt signalling pathway. Increased TP53 expression suggests other molecular mechanisms may be responsible. While crypt mitoses are proportional to crypt area, the threshold for fission may be site specific, indicating that tissue origin may influence histogenesis and thus malignant potential.

Adrenal incidentaloma in familial adenomatous polyposis: a long-term follow-up study and schema for management.

PURPOSE: Adrenal incidentaloma is often diagnosed in patients with familial adenomatous polyposis, because they frequently undergo abdominal imaging and have a raised incidence of adrenal incidentaloma. This study investigates the natural history of adrenal incidentaloma in familial adenomatous polyposis, and suggests a schema for management. METHODS: An original cohort of 14 familial adenomatous polyposis patients with adrenal incidentaloma, identified prospectively 12 years ago, was followed up clinically and radiologically. A further group of 16 patients was also identified. All had lesions >1 cm. For both cohorts, characteristics of patients (genotype, age at diagnosis, concomitant diagnoses) and incidentaloma (size, laterality, rate of growth, outcome) are described. RESULTS: Overall, 3 of 30 patients underwent adrenalectomy; one patient had pheochromocytoma and another had an adenoma of borderline malignancy. A further three lesions were radiologically suspicious for malignancy at the time of diagnosis; one was in a patient who was unfit for surgery but died of nonadrenal causes after nine years. None of the lesions radiologically benign at diagnosis showed an aggressive course, but one patient required referral for surgery after 12 years because of a slow increase in size of the lesion. There were no associations with genotype. CONCLUSIONS: Familial adenomatous polyposis-associated adrenal incidentaloma may warrant long-term follow-up. Although the natural history is similar to lesions occurring sporadically, these patients have concomitant familial adenomatous polyposis-associated manifestations under radiologic surveillance. In this rare condition, development of a robust protocol will require evidence from worldwide patient cohorts. However, a tailored schema is suggested as a consistent basis for future modification.

Familial adenomatous polyposis and the small bowel: a loco-regional review and current management strategies.

Small-bowel tumours are an important cause of morbidity and death in patients with familial adenomatous polyposis. Intensive endoscopic surveillance is now standard in the long-term management of this condition. Thus, lesions occurring throughout the small bowel are increasingly noted by oesophagogastroduodenoscopy and flexible pouchoscopy. Some occur commonly de novo (in stomach, duodenum and ampulla), while others may occur following surgery (polyps of the ileostomy, ileoanal pouch, or small bowel above an anastomosis). These differ widely in incidence, natural history and management. This review provides a regional overview of these lesions, in terms of current research findings and management protocols.

APC mutation spectrum in ileoanal pouch polyps resembles that of colorectal polyps.

BACKGROUND: Ileoanal pouch polyps commonly develop following restorative proctocolectomy in patients with familial adenomatous polyposis (FAP). In FAP adenomas, the relationship between germline and somatic adenomatous polyposis coli (APC) mutations is determined by 'just right' beta-catenin signalling in tumour cells, with respect to the 20-amino acid beta-catenin-binding/degradation repeats (20AARs) in the APC protein. However, the relationship varies, with upper gastrointestinal polyps typically retaining three to four 20AARs and colonic polyps retaining one or two. The aim of this study was to establish the mutational spectrum in ileoanal pouch polyps, to ascertain whether polyp development resembled that typical of small or large bowel. METHODS: Some 151 pouch adenomas were screened from 46 patients with known germline APC mutations for 'second hits' acquired through loss of heterozygosity and truncating mutations. The number of 20AARs remaining after the 'second hit' was calculated. RESULTS: Loss of heterozygosity was rare in pouch polyps except when the germline mutation left one 20AAR. Overall, the combined alleles left two to three 20AARs in 40 of 51 polyps with an identified 'second hit'. This was significantly fewer than in upper gastrointestinal polyps, and more than in colorectal adenomas. CONCLUSION: Tissue environment appears to influence the position of the 'second hit' in pouch polyps and the mutations resemble those of large bowel polyps.