Polypoide Dysplasie bei chronisch-entz��ndlicher Darmerkrankung

Polypoid dysplasia in inflammatory bowel disease (IBD) is categorized as DALM (dysplasia associated lesion or mass) or ALM (adenoma-like mass). DALMs are etiologically related to the underlying inflammatory disease, have a high risk of cancer and remain an indication for colectomy. Sporadic adenomas occur coincidentally according to the adenoma-carcinoma sequence. They are adequately treated by polypectomy. More recently, a special group of lesions has been termed as "adenoma-like DALM" which shows a morphological overlap with sporadic adenomas in spite of arising against the background of chronic IBD. Adenoma-like DALMs may possess a lower risk of malignancy in contrast to non-adenoma-like DALMs. They may be treated adequately by polypectomy and continued monitoring if the lesion has been excised completely and there is no evidence of flat dysplasia elsewhere in the colon.     

Dysplastic lesions in inflammatory bowel disease show increased positivity for the stem cell marker aldehyde dehydrogenase

The chronic inflammatory state in patients with inflammatory bowel disease places them at a substantially elevated risk for developing colorectal carcinoma. Moreover, distinguishing an inflammatory phenotype from dysplasia in inflammatory bowel disease can be difficult and has significant patient management implications. To this end, we studied the expression of the cancer stem cell marker aldehyde dehydrogenase to determine whether expression is increased in dysplastic lesions arising in inflammatory bowel disease. We studied 54 patients with inflammatory bowel disease who underwent surgical resection. Of the 54 patients, 13 exhibited high-grade dysplasia or adenocarcinoma, 19 exhibited low-grade dysplasia, and 22 displayed only inflammatory atypia. Staining for aldehyde dehydrogenase was evaluated in the cytoplasm of epithelial and stromal cells. We determined the intensity of staining (0 to 3+) and the percentage of cells staining positively. Positive staining for aldehyde dehydrogenase was observed in 92% (12/13) of cases with high-grade dysplasia/adenocarcinoma and in 95% (18/19) of cases with low-grade dysplasia. Cases with inflammatory atypia showed positive staining in 45% (10/22) of cases. The sensitivity for aldehyde dehydrogenase in epithelial cells as a marker for dysplasia was 95%; specificity was 55%. For stromal cells adjacent to dysplasia, sensitivity was 44%; and specificity was 68%. Although the sensitivity of aldehyde dehydrogenase for dysplasia was excellent, specificity was less than ideal. Our findings support the hypothesis that dysplasia in inflammatory bowel disease is associated with increased aldehyde dehydrogenase positivity, which supports the cancer stem cell hypothesis.     

The bcl-2 proto-oncogene and the gastrointestinal epithelial tumor progression model.

We report overexpression of the proto-oncogene bcl-2 in gastrointestinal adenocarcinoma and its precursor lesions. The bcl-2 proto-oncogene is centrally involved in the oncogenesis of human follicular lymphoma via a chromosomal translocation t(14;18)(q32;q21) and is also expressed in the epithelial regenerative compartment or the basal crypts of the normal colon and small intestine. We describe an immunohistochemical analysis of fixed, paraffin-embedded tissue using both a polyclonal rabbit and a monoclonal mouse antibody to the Bcl-2 protein. In addition to confirming bcl-2 expression in normal colonic and small intestinal crypts, we also observed expression in the gastric epithelial regenerative compartment, the mucous neck region. No increased expression was found in nonneoplastic or inflammatory gastrointestinal conditions, including ulcerative colitis, Crohn's disease, or inflammatory or hamartomatous polyps. Increased bcl-2 expression, however, was present in hyperplastic colonic polyps and in the majority of dysplastic lesions, from the earliest precursors through large adenomas, high grade flat dysplasia, and adenocarcinoma, all in comparison with adjacent internal control normal epithelium. Increased expression was present in dysplastic glandular lesions from all gastrointestinal sites, including colon, small bowel, and stomach. Furthermore, bcl-2 expression was frequently abnormal in nondysplastic epithelium surrounding dysplastic lesions, suggesting that altered expression occurred before the development of morphological dysplasia. Specifically, directly contiguous morphologically nondysplastic epithelium often showed abnormal bcl-2 expression throughout the full length of the crypt-villus axis. This expression pattern gradually diminished to involve only the crypt base (the normal pattern of expression), proceeding away from malignant or dysplastic lesions. Abnormal bcl-2 immunoreactivity in 1), the earliest precursor dysplastic lesions and its persistence throughout neoplastic progression and 2), contiguous morphologically unaltered nondysplastic epithelium suggests that bcl-2 alterations occur early during the morphological and molecular sequence of events leading to gastrointestinal epithelial neoplasia.     

各类大肠息肉粘液组织化学变化及其与大肠癌的关系

210 various colo-rectal polyps including 46 inflammatory polyps, 21 juvenile polyps, 9 hyperplastic polyps, 65 tubular adenomas, 51 familial polyps, 11 villous adenomas, 7 adenomatous polyps with focal cancer, and 14 carcinoma of the large bowel were investigated by HE,HID-AB,PAT-KOH-PAS staining in order to study the mucin changes of these lesions. N-acetylated and C7,C9 O-acetylated sialomucin were mainly obtained in those adenomas with moderate and severe dysplasia (55-64.3%) and the proportion was even higher in cases of villous adenomas, familial polyps, adenomas with focal cancer and advanced carcinoma. These mucins might be assumed as a criteria in representing malignant transformation.     

Flat adenomas of the colon

Twenty-nine flat adenomas of the colon from 18 patients were identified by histologic review of 340 surgically or colonoscopically removed adenomas from 210 patients. All lesions had a radial diameter of 1.0 cm or less. Twelve of 29 flat adenomas (41%) contained high-grade epithelial dysplasia, while only five of 127 polypoid tubular adenomas 1.0 cm in diameter or less (4%) contained high-grade epithelial dysplasia. Nine patients had multiple flat adenomas, and two patients had concurrent flat, ulcerated colonic carcinomas without an identifiable polypoid precursor adenoma. Colonoscopically and grossly, the lesions were described as sessile or flat, slightly raised plaques, which might be easily missed on colonoscopic examination. These findings suggest that flat adenomas may be a subtype of colonic adenomas with a propensity for development of high-grade epithelial dysplasia at a small size. These lesions may be precursors of small, flat, ulcerated colonic carcinomas. Heightened colonoscopic surveillance of patients in whom flat adenomas have been identified may be warranted.     

Expression of MUC1 and MUC2 mucins and relationship with cell proliferative activity in human colorectal neoplasia

Our previous studies on MUC1 and MUC2 mucin expression in various human neoplasms have found that MUC1 expression is related with a poor outcome whereas MUC2 expression is related with a favorable outcome. In the present study, we examined the alteration of MUC1 and MUC2 antigens on malignant transformation of colorectal mucosa, and also its relationship with cell proliferative activity (Ki-67 labeling index) of neoplastic epithelial cells in 200 adenomas and 58 carcinomas. In the 200 adenomas, we analyzed a total of 400 adenomatous lesions (mild dysplasia, 200 lesions; moderate dysplasia, 153 lesions; severe dysplasia, 47 lesions). MUC1 was expressed in carcinomas (24%) and adenomas with severe dysplasia (4%), but was not expressed in adenomas with mild or moderate dysplasia. MUC2 was expressed in a significantly greater number of adenomas with mild dysplasia (72%) than in adenomas with moderate dysplasia (45%) or severe dysplasia (47%), as well as in the carcinomas (38%; P < 0.0001). The Ki-67 labeling index was significantly lower in the MUC2-positive cases than in the MUC2-negative cases in the adenomas with mild dysplasia (13.6 vs 24.2%; P < 0.0001) or moderate dysplasia (25.7 vs 44.4%; P < 0.0001), and in the carcinomas (32.5 vs 48.4%; P < 0.05). In conclusion, the data from our study indicate that increased MUC1 expression and reduced MUC2 expression may be related to malignant transformation of colorectal neoplasia. We also demonstrated that decreased MUC2 expression, which is correlated with increased Ki-67 labeling, may play an important role in the progression of colorectal adenomatous change.     

Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma

Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.     

Immunohistochemical and histochemical study on colorectal adenomas and polyps]

Immunohistochemical staining and histochemical approach for mucin were applied in studying 58 cases of colorectal adenomas. Among them, there were 13 cases of multiple adenomas (polyps), 5 cases of inflammatory polyps and 5 cases of juvenile polyps. The results indicated that positive expression of both McAb MC5 and Ulex europaeus agglutinin-1(UEA-1) were correlating with the degree of dysplasia, the histological type and the size of adenomas. The positive expression of peanut agglutinin (PNA) was correlating with the degree of dysplasia. Moderate and heavy stainings were mainly seen in adenomas accompanying with moderate and severe dysplasia, as well as adenomas with early carcinomatous changes. PAT-KOH-PAS method could sensitively reflect the occurrence of dysplasia and malignancy of the adenomas. These findings support the concept of an adenoma(dysplasia)-carcinoma sequence. In comparing multiple adenomas (number of adenomas > 100) with the solitary ones, a notable difference was obtained in the expression of McAb MC5. It's concluded that combined use of certain immunohistochemical and histochemical stainings is well be useful in detecting the malignant potentiality of adenoma.     

Polypen im Kolorektum

Non-neoplastic and non-hamartomatous colorectal polyps or tumor-like lesions comprise a very heterogeneous group of changes in the colorectal mucosa or the colon wall. Mucosal prolapse-associated lesions and inflammatory polyps, which are predominantly associated with chronic inflammatory bowel disease, are the most prominent examples for polypoid lesions difficult to distinguish from neoplastic lesions such as adenomas, hyperplastic/serrated polyps/adenomas and invasive carcinomas. The considerably less frequent tumor-like lesions like heterotopias, endometriosis, amyloid tumors and pseudolipomatous changes are histologically often well defined and should be considered in the differential diagnosis of colorectal lesions. The etiology, endoscopic and histological appearance of these entities and their most important differential diagnoses are discussed.     

Serrated precursor lesions

The so-called serrated pathway has in recent years been well established as a second route of colorectal carcinogenesis. Sessile serrated polyps, especially sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA) were identified as precursor lesions of this pathway. Activating mutations in either the BRAF (in SSAs) or the KRAS oncogene (in TSAs) have been determined as the initiating molecular alterations, followed by epigenetic methylation of CpG islands in promoter regions of genes which are implicated in cell cycle control or DNA repair. These findings have led to a paradigm shift in gastrointestinal pathology as lesions without cytological dysplasia, such as SSAs and certain forms of hyperplastic polyps, are now accepted to be precancerous lesions. In addition, carcinomas that have developed through the serrated pathway of colorectal carcinogenesis show varying biological behavior relevant for the clinical management of these tumors depending on the molecular aberrations.     

Filiform serrated adenomatous polyposis arising in a diverted rectum of an inflammatory bowel disease patient

A 54-year-old man, previously colectomized for inflammatory bowel disease, developed carcinoma in the inflamed rectum stump. The malignant growth was surrounded by a filiform polyposis, grossly considered as pseudopolyps. The histology disclosed, however, a morphology corresponding to the recently described filiform subset of serrated adenoma (FSA). The clustering of the FSA amounted to a filiform serrated adenomatous polyposis, a hitherto unreported observation. It is speculated that neoplastic transformation of pre-existing pseudopolyps and prolaps-related events lead to this peculiar morphology. Minor zones with a villous structure were admixed as were small areas of traditional serrated adenoma and patches of flat dysplasia. Although a combined gastric and intestinal (positivity for MUC5AC, MUC2, MUC6, CDX2) immunoprofile characterized the adenomatous component, a downregulation of the gastric mucin along with a loss of the serrated attribute accompanied the malignant transformation. An added dynamic shift during the adenoma carcinoma sequence included the acquisition of CK7 expression in the malignant portion. Gastric mucin may play a role in the initial step of the neoplastic evolution and CK7 may denote neoplastic progression. This case confirms the notion of a widely variegated morphology of precursor lesions of colorectal carcinoma arising in a chronically inflamed bowel as opposed to the generally more monotonous appearance of adenomas in a sporadic context.     

Dysplasia in Chronic Ulcerative Colitis: A Molecular Approach to Its Differential Diagnosis

Ulcerative colitis-related epithelial dysplasia represents a premalignant lesion, which may lead to the development of ulcerative colitis-related adenocarcinoma. The proper management of this condition requires proctocolectomy before the acquisition of the invasive phenotype. Patients with chronic ulcerative colitis, however, like the general population, may develop sporadic colorectal adenomas not related to the presence of the inflammatory bowel disease. These adenomas are also characterized by epithelial dysplasia, but their detection carries very different clinical implications. It is therefore essential to distinguish between chronic ulcerative colitis-related dysplasia and sporadic colorectal adenomas. The gross and histologic features do not provide a definite distinction between these two different types of dysplasia of the colonic epithelium. Recent developments in the molecular genetics may provide the necessary means. Int J Surg Pathol 8(1):11-16, 2000     

Combined alpha-methylacyl coenzyme A racemase/p53 analysis to identify dysplasia in inflammatory bowel disease

Identification of dysplasia in inflammatory bowel disease represents a major challenge for both clinicians and pathologists. Clear diagnosis of dysplasia in inflammatory bowel disease is sometimes not possible with biopsies remaining "indefinite for dysplasia." Recent studies have identified molecular alterations in colitis-associated cancers, including increased protein levels of alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2. In order to analyze the potential diagnostic use of these parameters in biopsies from inflammatory bowel disease, a tissue microarray was manufactured from colons of 54 patients with inflammatory bowel disease composed of 622 samples with normal mucosa, 78 samples with inflammatory activity, 6 samples with low-grade dysplasia, 12 samples with high-grade dysplasia, and 66 samples with carcinoma. In addition, 69 colonoscopic biopsies from 36 patients with inflammatory bowel disease (28 low-grade dysplasia, 8 high-grade dysplasia, and 33 indefinite for dysplasia) were included in this study. Immunohistochemistry for alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2 was performed on both tissue microarray and biopsies. p53 and alpha-methylacyl coenzyme A racemase showed the most discriminating results, being positive in most cancers (77.3% and 80.3%) and dysplasias (94.4% and 94.4%) but only rarely in nonneoplastic epithelium (1.6% and 9.4%; P < .001). Through combining the best discriminators, p53 and alpha-methylacyl coenzyme A racemase, a stronger distinction between neoplastic tissues was possible. Of all neoplastic lesions, 75.8% showed a coexpression of alpha-methylacyl coenzyme A racemase and p53, whereas this was found in only 4 of 700 nonneoplastic samples (0.6%). alpha-methylacyl coenzyme A racemase/p53 coexpression was also found in 10 of 33 indefinite for dysplasia biopsies (30.3 %), suggesting a possible neoplastic transformation in these cases. Progression to dysplasia or carcinoma was observed in 3 of 10 p53/alpha-methylacyl coenzyme A racemase-positive, indefinite-for-dysplasia cases, including 1 of 7 cases without and 2 of 3 cases with p53 mutation. It is concluded that combined alpha-methylacyl coenzyme A racemase/p53 analysis may represent a helpful tool to confirm dysplasia in inflammatory bowel disease.     

p27 Expression in Inflammatory Bowel Disease-Associated Neoplasia : Further Evidence of a Unique Molecular Pathogenesis

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the transition from G1 to S phase of the cell cycle, protects against inflammatory injury and promotes epithelial differentiation. Because p27 protein has been shown to be abnormally expressed both in dysplasia associated with Barrett's esophagus and in sporadic colorectal adenomas, we used immunohistochemistry to evaluate p27 expression in inflammatory bowel disease (IBD)-associated dysplasia and carcinomas. Normal, inflamed, and transitional mucosa, sporadic adenomas, and sporadic colonic carcinomas were studied as controls. In normal colonic epithelium p27 expression was restricted to the superficial, terminally differentiated cells. In colitic and inflamed diverticular mucosa p27 was expressed in the base of the crypts in 86 and 70% of cases, respectively. Similarly, in transitional mucosa adjacent to sporadic carcinomas p27 was expressed in the base of the crypts in all cases. Strong p27 expression extended more frequently from the base of the crypts to superficial cells in IBD-associated dysplasia than in sporadic adenomas (P < 0.007). Twenty of 20 (100%) IBD-associated carcinomas showed low p27 expression (<50% nuclei positive) compared to 6 of 20 (30%) stage-matched sporadic colorectal carcinomas (P < 0.001). We conclude (i) aberrant p27 protein expression in inflamed and IBD-associated nondysplastic mucosa is indistinguishable from that found in transitional mucosa adjacent to sporadic carcinomas; (ii) p27 is overexpressed in dysplastic lesions, perhaps as an attempt to counterbalance proliferative stimuli; and (iii) IBD-associated colorectal carcinomas have significantly lower p27 expression, commonly associated with poor prognosis, than stage-matched sporadic colorectal carcinomas. These findings further substantiate the existence of divergent molecular pathogenetic pathways between these types of carcinomas and suggest an intrinsically more aggressive behavior of IBD-associated colon carcinomas compared to sporadic ones.     

Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status

Although the serrated neoplasia pathway is thought to give rise to the majority of sporadic microsatellite instability-high (MSI-H) colon cancer, the exact proportion of these tumors that arise from serrated precursors has not been fully studied. Tubular and tubulovillous adenomas with features of the serrated neoplasia pathway have been described, and unlike sessile serrated adenomas, these lesions lack BRAF mutations. The contribution of these adenomas to sporadic MSI-H colon cancer is unclear. To this end, we conducted an analysis of right-sided sporadic MSI-H and microsatellite stable (MSS) colon cancer, with emphasis on precursor lesions. Overall 25% (19/75) of MSI-H colon cancer had a precursor, of which only 4 were recognized histologically as arising from a sessile serrated adenoma, and the remaining were best classified as adenomas. Of the 31 (of 89) MSS colon cancers with a precursor, only 1 was a sessile serrated adenoma (P=0.06). Histological analysis of the precursor adenomas to sporadic MSI-H colon cancer demonstrated a high frequency of crypt serrations compared with MSS colon cancer (93 vs 36%, P<0.001). BRAF mutations were found in 57/75 (76%) sporadic MSI-H and 10/89 (11%) MSS colon cancers (P<0.001). Molecular analysis demonstrated BRAF mutations in 11/12 adenoma and 3/3 sessile serrated adenoma precursors adjacent to BRAF-mutated MSI-H colon cancer. Similarly, all 4 precursors to BRAF-mutated MSS colon cancer were also BRAF mutated. The presence of BRAF mutations in these adenomatous precursors suggests that they represent sessile serrated adenomas with complete cytologic dysplasia. Finally, patients with sporadic MSI-H colon cancer were more likely to harbour synchronous sessile serrated adenomas (20 vs 8%; P=0.023). This is the largest study to rigorously evaluate the precursor and synchronous lesions in patients with right-sided colon cancer. Detailed molecular and histological analysis of these lesions confirms the importance of serrated precursors in the development of sporadic MSI-H colon cancer.     

Solitary and synchronous adenomas of the colon and rectum: comparison of malignancy parameters

The histological, mucin histochemical and immunohistochemical features were evaluated of 74 solitary and 73 synchronous colorectal adenomas which were endoscopically removed from 124 patients. Of the patients, 60% had a single adenoma, whereas 40% had at least two adenomas in their colorectum. Comparing the incidence of synchronous adenomas in both sexes revealed a statistically significant higher incidence (P less than 0.005) in males. The localization of the solitary and synchronous adenomas in the large bowel was similar. Moreover, parameters of malignant change within the adenomas (size, predominant type of mucosal growth and degree of dysplasia-with the exception of severe dysplasia) as well as signs of dedifferentiation (relative proportions of goblet and columnar cells) were also similar. Mucin staining intensities (periodic acid-Schiff, high iron diamine and alcian blue) and the immunoreactivity patterns of secretory component and carcinoembryonic antigen, both cytoplasmic and on the surface of the epithelial cells, were also identical in both groups of adenomas. Thus, neither the routine histological nor the mucin- and immunohistochemical features differed between the groups, except for severe dysplasia. It is concluded that there is no inherent difference in malignant potential between solitary and synchronous adenomas, with the possible exception of the degree of dysplasia.     

Overexpression of Fas ligand (FasL) during malignant transformation in the large bowel and in Barrett's metaplasia of the esophagus

Esophageal and colorectal adenocarcinomas overexpress Fas ligand (FasL), which can protect them from immune surveillance. The aim of this work was to determine whether FasL expression, and therefore FasL-dependent immune evasion, occurs early during malignant transformation in Barrett's metaplasia (BM) of the esophagus, and in the large intestine. Sections of formalin-fixed and paraffin-embedded tissue from esophageal and large bowel biopsies and resection specimens were immunostained for FasL using standard immunoperoxidase technique. The percentage of positive cells was correlated with the degree of dysplasia in BM and with the size and villous architecture of colorectal adenomas. In BM, FasL was detected in 55% of cases negative for dysplasia, and was associated with inflammation in almost all positive cases. By contrast, all cases of BM (100%) with low- or high-grade dysplasia were FasL-positive. In the large intestine, 25% of small adenomas were negative for FasL, and FasL overexpression was significantly more frequent in larger adenomas and in adenomas with tubulovillous or villous morphology. Our results suggest that (1) FasL overexpression is acquired early during malignant transformation of BM and the large bowel and (2) FasL overexpression occurs relatively earlier during malignant progression of BM than the large bowel, probably as a result of the preceding repeated inflammation.     

Colonic and duodenal flat adenomas in children with classical familial adenomatous polyposis

Flat adenomas of the colon and duodenum have been described as associating with familial adenomatous polyposis (FAP), its attenuated variant, and the so-called hereditary nonpolyposis colorectal cancer. There seem to be no report on the occurrence of flat adenomas in pediatric patients with family history of FAP. We are reporting 4 children from 2 cancer-prone families in whom colonic and duodenal moderately dysplastic flat adenomas were found. Gastrointestinal endoscopy and biopsies were performed in 3 female siblings (7, 9, and 11 years old) and 1 male (9 years old) when referred for screening owing to familial history of bowel cancer (family 1) or evidence of bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE), which is known to be associated with FAP (family 2). Endoscopic visualization of the mucosa was improved by use of 0.2% indigo carmine solution spray. Biopsies were routinely processed for H&E and immunohistochemistry staining. Present patients were asymptomatic, with the exception of 2 weeks rectal bleeding in 1 of them. The colonic videoendoscopy showed in 2/3 siblings hundreds of flat or slightly raised plaques less than 1 cm in diameter as well as some classic polyps throughout the colon. The other sibling showed 40 flat-topped lesions with minimal elevation and central umbilication in the cecum. Upper endoscopy demonstrated a few flat lesions in the nonperiampullary area of the duodenum in 2/4 patients. The colonic videoendoscopy performed on the 9-year-old boy revealed multiple small sessile polyps. Microscopic study demonstrated tubular adenomas with a few neoplastic crypts, slight disarray of the overall architecture, and moderate (low-grade) dysplasia of the epithelium. These features were more obvious at the center and superficial areas of the adenomas. The 4 children had multiple flat adenomas of the colon and duodenum (2/4) matching with those described in adult patients. Flat adenomas in the context of FAP probably represent early stages of the adenoma development. Careful endoscopic-histologic correlation may result in increasing recognition of these lesions at the pediatric age.     

Assessment of dysplasia in colorectal adenomas: an observer variation and morphometric study.

Observer variation in the grading of dysplasia in 100 colorectal adenomas has been analysed by kappa statistics. Intraobserver agreement was only 70% and 67% for the two principal observers, and, as would be expected, interobserver agreement was even lower at 59% and 66%. Although the kappa values were significantly different from chance at the 0.1% level, there were substantial disagreements. When the study was extended to four observers, agreement between observer pairings was considerably worse (as low as 34%), and in four pairings the kappa values did not differ significantly from those expected by chance alone even at the 5% level. In an endeavour to improve agreement we adopted a percentage estimation grading method; but this failed to achieve any improvement when comparing overall grades. The percentage estimates of the two observers, however, showed a highly significant correlation. To identify the cytological features given most weight by the principal observers in assessing dysplasia we undertook morphometry on 30 adenomas using an image analysis computer. The nuclear to cytoplasmic ratio, variation in nuclear area, and variation in nuclear height above the basement membrane showed significant differences between mild, moderate, and severely dysplastic epithelia. While evaluation of these parameters therefore appears to be most important in the subjective interpretation of dysplasia, this study has shown that such evaluation is poorly standardised between observers and poorly reproduced within observers. Our findings of poor agreement in the grading of dysplasia in colorectal adenomas has serious implications for the assessment of dysplasia in inflammatory bowel disease, where the added problem of reactive cellular atypia brings greater complexity to these subjective judgments.