Flat Neoplasia Research Articles

Rectal Aberrant Crypt Foci Identified Using High-Magnification-Chromoscopic Colonoscopy: Biomarkers for Flat and Depressed Neoplasia

Aberrant crypt foci may represent preneoplastic lesions in the human colon. The prevalence of aberrant crypt foci detected using magnification chromoscopic colonoscopy is known to follow a stepwise progression from normal subjects to those with exophytic adenomas and colon cancer. No studies have addressed the prevalence of rectal aberrant crypt foci in patients with flat and depressed colonic lesions that cluster within the right hemi-colon and may undergo de novo neoplastic transformation. All patients underwent total colonoscopy by a single endoscopist using the Olympus CF240Z magnifying colonoscope. Flat and depressed lesions were diagnosed using targeted indigo carmine chromoscopy. Prior to extubation, pan high-magnification-chromoscopy using indigo carmine was applied to the rectum and the distal 10 cm of mucosa examined using forward and retroflexed views. Aberrant crypt foci were defined as two or more crypts with dilated or slit-like openings that were raised above the adjacent mucosa. Using high-magnification chromoscopic colonoscopy we assessed the prevalence and dysplastic features of aberrant crypt foci in three groups: endoscopically "normal" subjects, patients with flat/depressed adenoma, and flat/depressed cancer. Two thousand five hundred and fifty-nine patients underwent colonoscopy of which 1,000 were eligible for inclusion. The median number of aberrant crypt foci per patient in the endoscopically normal, adenoma, and cancer group was 1 (range: 0-5), 9 (range: 0-22), and 38 (range: 14-64), respectively. The estimated relative risk of dysplastic aberrant crypt foci when comparing the flat adenoma group with the endoscopically "normal" group was 4.68 (95% CI: 2.23-9.91) with the relative risk for flat cancer versus endoscopically normal group being 21.8 (95% CI: 10.9-23.8). Patients with >5 flat adenomas had higher crypt foci densities than those with <5 adenomas (r=0.53; p<0.001). The number of aberrant crypt foci in normal patients, patients with flat adenoma, and flat cancer follow a stepwise incremental change as previously observed for exophytic adenomas and cancer. Detection of aberrant crypt foci in the rectum may be a useful biomarker for proximal colonic flat neoplasia and could be used at index flexible sigmoidoscopic screening to stratify risk of proximal colonic neoplasia. Patients with dysplastic aberrant crypt foci of high density should receive total colonoscopy.

Colorectal flat neoplasia.

An attempt has been made to evaluate the clinicopathological characteristics of flat colorectal neoplastic lesions, and analyse the factors associated with the malignancy. A total of 115 flat neoplastic lesions, > or = 5 mm in size, diagnosed in 87 patients by colonoscopy, were investigated. The rectum was the most common location. Almost half (49.6%) of the flat neoplasms were small (5-10 mm), 27.8% were 11-20 mm and the remainder (22.6%) larger than 20 mm. The surface was smooth in 55.7%, granular in 20.0% and nodular in 24.3%. Histologically, the flat lesions were tubular, tubulovillous and villous adenomas in 69.6%, 20.9% and 5.2%, respectively. Five lesions (4.3%) were composed of carcinomas without adenoma. High-grade dysplasia, intramucosal carcinoma and invasive carcinoma were diagnosed in 9.6%, 7.8% and 6.1% of all flat neoplasms, respectively. Univariate analysis demonstrated that the location, size, surface pattern and histologic type of the flat lesions were factors associated with malignancy. However, in multivariate analysis, the size of the flat lesions was the only significant risk factor for malignant transformation. Flat neoplastic lesions of the colorectum have a relatively high rate of malignancy, and size is the most important factor associated with malignancy.

P53 overexpression in flat serrated adenomas and flat tubular adenomas of the colorectal mucosa.

The expression of the p53 protein was investigated in flat serrated neoplasias as well as in other histological phenotypes of flat or exophytic hyperplasias or neoplasias of the colorectal mucosa. A total of 104 such lesions were analyzed: 24 were flat serrated neoplasias (22 flat serrated adenomas and 2 flat serrated adenocarcinomas), 26 flat tubular adenomas, 17 flat hyperplastic polyps, 29 exophytic tubular and/or villous neoplasias (23 adenomas and 6 exophytic adenocarcinomas) and the remaining 8, exophytic hyperplastic polyps. Deparaffinized, rehydrated sections were treated immunohistochemically to detect those overexpressing the p53 protein. Lesions having slight (+), moderate (++) or intense ( ) staining were considered immunoreactive. The results showed that 50% of the flat serrated adenomas with low-grade dysplasia (LGD) and 66.7% of those with high-grade dysplasia (HGD) had p53 immunoreactivity. None of the flat tubular or of the exophytic adenomas with LGD expressed p53, but immunoreactivity was present in 61.5% of the flat tubular adenomas with HGD and in 52.3% of the exophytic adenomas with HGD. All adenocarcinomas had an intense p53 reaction. Weak p53 expression was demonstrated by 11.7% of the flat hyperplastic polyps but none of the exophytic polyps reacted. The occurrence of p53 expression in flat serrated adenomas with LGD suggested that, despite its low histological profile, one-half of those lesions could be biologically already committed to independent growth. The occurrence of p53 expression in nearly 12% of the flat hyperplastic polyps was totally unexpected and deserves further investigation. Flat serrated adenoma emerges as a novel, independent histological entity among the various phenotypes of flat neoplasias of the colorectal mucosa.

Flat adenoma-adenocarcinoma sequence in the colon of rats

As there is an increased awareness of the existence of a "flat adenoma-adenocarcinoma sequence" in the colonic mucosa of human subjects, the aims of the study were to assess whether flat colonic adenocarcinomas in rats are also preceded by flat adenomas, as is reported in humans, and to determine the frequency of flat lesions compared with exophytic lesions in the colon of rats. The colonotropic carcinogen 1,2-dimethylhydrazine was injected subcutaneously in 300 Sprague-Dawley rats for 27 weeks. A total of 358 tumors developed in 278 of the 300 rats. Of the 60 adenomas found at histology, 25 percent were flat adenomas. Of the 298 adenocarcinomas, 12.7 percent had originated in a flat adenoma. Of the 180 colonic neoplasias (adenomas or adenocarcinomas), 29.4 percent were flat neoplasias (flat adenomas or adenocarcinomas arising in a flat adenoma), and the remaining 70.6 percent were exophytic neoplasias (tubulo or villous adenomas or adenocarcinomas arising in exophytic adenomas). From the 298 colonic adenocarcinomas, 1 was a intramucosal adenocarcinoma, 87 were overt adenocarcinomas, and 90 were lymphoid-associated carcinomas; in those 298 adenocarcinomas, no preneoplastic lesion could be recorded. In 208 animals, biopsies were taken from macroscopically visible colonic lesions, and, in the remaining 70 animals, the entire colon was processed for histologic examination. Flat adenomas were found in 3.8 percent of the 208 biopsy specimens and in 10 percent of the 70 colectomy specimens. Further, of the 40 adenomas found in biopsy specimens, 20 percent were flat adenomas, and, of the 20 adenomas found in colectomy specimens, 35 percent were flat adenomas. The study reported herein indicates the existence of a "flat adenoma-adenocarcinoma sequence" in the colonic mucosa of Sprague-Dawley rats. The flat lesions of the colon constituted approximately one-third of the total neoplastic lesions seen in the rat following injections of 1,2-dimethylhydrazine. More flat adenomas were detected at histologic examination of the entire colon than in biopsies obtained from the macroscopically visible colonic lesions. Consequently, flat adenomas may be overlooked by naked-eye examination.