Sonic hedgehog (Shh) is an essential regulator of patterning processes throughout development, and CDX proteins act as the master regulators for intestinal development and differentiation. Shh and CDX2 seem to be interdependently linked with cellular differentiation through different signal cascades. We have recently shown that the loss of Shh and aberrant expression of CDX2 in Helicobacter pylori (H. pylori)-associated atrophic gastritis can be modified by H. pylori eradication prior to incomplete intestinal metaplasia. On the other hand, abnormal signaling of the hedgehog pathway has been reported in gastric cancer, especially diffuse-type cancer and advanced gastric cancer, and Shh acts as a proliferation factor in both the normal mucosa and malignant lesions. CDX2 expressed in the early stage of gastric carcinogenesis is associated with the intestinal phenotypic region and thus with a better outcome. However, it remains unclear how Shh and CDX2 are involved with intestinal transformation and further carcinogenesis.

The protracted inflammation of the gastric mucosa induces profound changes in the microenvironment of the gastric cells. These changes modify the molecular signals that orchestrate morphogenesis and cell differentiation in the stem cells of the crypts. The expression of this adjustment to the new microenvironment is evidenced by the appearance of differentiated metaplastic cells (intestinal, bronchial-ciliated, pancreatic or (pseudo) pyloric, all deriving from the same embryological origin). The inability of stem cells to readapt to the new microenvironment may lead to genomic aberrations such as the retention of cellular products (glassy cells) or to neoplastic transformation. In this report, parameters such as gastric mucosal inflammation, Helicobacter pylori, atrophy, intestinal metaplasia and/or pseudopyloric metaplasia found in gastric biopsy specimens were individually classified according to their extension in sections as grade 1 (focal distribution in sections from individual biopsy specimens) and grade 2 (present in the entire width-distance across-in sections from individual biopsy specimen). The rationale is that a biopsy grade 2 was harvested from a larger mucosal area having that particular change. Each individual parameter gives a score, and the sum of all individual scores gives the total score. The proposed system might allow monitoring the results of treatment in follow-up biopsies. Divergent clinical results in the frequency/incidence of gastritis (including body-autoimmune gastritis), of H pylori strains, of various metaplasias and neoplasias, in disparate geographical regions substantiate the conviction that these parameters are much influenced by the environment. This knowledge is crucial, considering that environmental diseases are theoretically preventable.

There are limited data regarding the prognostic value of the pattern of mucin expression in IM. To examine the role of the type of IM and pattern of mucin expression in IM as histological risk markers of gastric cancer, 80 patients with a history of endoscopic mucosal resection (EMR) for early gastric cancer and 80 sex and age-matched controls were studied. Serum levels of pepsinogen (PG) were measured by RIA, and MUC2, MUC5AC and MUC6 were evaluated immunohistochemically. There is a significant association between types of IM and atrophic scores or PG levels. The most incomplete IM (type II and III) preserving gastric mucin is the gastric and intestinal mixed (GI) type, whereas the complete type is the intestinal (I) type especially in the corpus lesser curve. Gastric cancer was most significantly associated with incomplete IM in the corpus lesser curve (OR=6.4; 95% CI, 2.0-21, p=0.002). Asynchronous multiple lesions were associated with incomplete IM in the corpus greater curve (OR=4.8; 95% CI, 1.4-16, p=0.01). Classification of IM obtained using fixed-point biopsy samples may enhance the ability of surveillance programs to detect patients at increased risk of gastric cancer.

Extensive intestinal metaplasia (EIM) has been reported in gastrectomies from patients dwelling in the Pacific and Atlantic basins.

To compare all the results in an attempt to explain the findings.

All sections from 3,421 gastrectomies were reviewed at various hospitals: 1946 in the Atlantic and 1475 in the Pacific basin. Sections with EIM showed IM encompassing one or more entire low power field (>or=5 mm in length/section) in one or more section.

In the Atlantic basin, EIM was present in 18.8% (153 of 814) of specimens with intestinal carcinoma (IC) and in 10.3% (65 of 630) of those with diffuse carcinoma (DC). In the Pacific basin, EIM was found in 62.9% (412 of 655) of gastrectomies with IC and in 33.3% (160 of 481) of those with DC. The numbers of specimens with EIM were significantly higher in the Pacific than in the Atlantic basin for both carcinoma phenotypes, particularly among elderly patients (>or=60 years).

The proportion of gastrectomies with EIM was higher among populations at a higher gastric cancer risk than in those with a lower cancer risk. EIM was mostly associated with IC rather than DC or with miscellaneous gastric diseases (841 control gastrectomies) in both basins. The proportion of gastrectomies with EIM was significantly higher in Vancouver than in New York and in Santiago de Chile than in Buenos Aires, even though these populations reside at approximately the same geographical latitude, but in different basins. Environmental factors seem to accelerate the evolution of EIM.

The absence of sonic hedgehog (Shh) correlates with the development of intestinal metaplasia (IM) suggesting the possibility of an association between Shh expression and neoplastic transformation.

To examine Shh expression in the noncancerous mucosa of patients with gastric cancer and compare it to Shh expression in Helicobater pylori-infected and uninfected controls. We also assessed the relationship between the type of IM and Shh expression.

Fifty-three patients with endoscopic mucosal resection (EMR) for early gastric cancer and 48 sex- and age-matched controls were studied. Two specimens each were obtained from the greater and lesser curves of the corpus and from the greater curve of the antrum. The histopathological grading used was the updated Sydney System. IM was categorized by staining with Alcian blue/high iron diamine. Expression of Shh was evaluated by immunostaining.

The Shh immunostaining in the corpus lesser curve significantly correlated with the scores of atrophy and IM. Shh staining in the antrum was significantly higher in H. pylori-negative controls than those in H. pylori-positive controls as well as in patients without IM compared to those with IM (p < 0.001). The Shh staining in the corpus lesser curve decreased in H. pylori-negative controls, -positive controls and the cancer group respectively (p= 0.003), and was significantly higher (p= 0.006) in the complete IM group compared to those in the incomplete IM group.

Loss of Shh is an early change that occurs in the mucosa prior to neoplastic transformation. Its loss correlates with the type of IM and may play a role in carcinogenesis.

We have proposed to divide intestinal metaplasia (IM) into two categories, i.e., a mixed gastric and intestinal (GI) type, and a solely intestinal (I) type, based on the residual gastric phenotype cells. The GI-mixed-type IM can be identified by the presence of both cells with either gastric or intestinal phenotypes in a single gland. This study is conducted to elucidate whether cells in the GI-mixed-type IM glands can simultaneously present both gastric and intestinal phenotypes. MUC5AC, MUC2, CD10 and villin expressions were investigated in 20 samples from five gastric cancer cases, directly using either AlexaFluor 488- or 568-labeled specific monoclonal antibodies and observed by fluorescent microscopy and confocal laser-scanning microscopy. GI-mixed IM glands comprise a population expressing MUC5AC and MUC2, MUC5AC and villin, and MUC5AC and CD10. MUC2 and villin expressions were reciprocally increased with decreasing MUC5AC expression, while CD10 expression was limited to cells with only a residual MUC5AC expression or no expression. These results suggest that a heterogeneous cell population with both gastric and intestinal phenotypes would develop into a single intestinal phenotype, as reflected in the progression of intestinal metaplasia from GI-mixed-type- to I-type IM-type glands.

A cohort of individuals (n = 136) with lesions as severe as atrophic chronic gastritis (ACG) was cross-sectionally evaluated for the validity assessment of pepsinogen I (PGI) and pepsinogen II (PGII) serum levels for the diagnosis of intestinal metaplasia (IM) and gastric dysplasia. PGI/PGII ratio [median (range)] was 4 (0.5-7.5) in patients with ACG (n = 35); 4.6 (1.9-6.8) in type I IM (n = 18); 4.2 (1.4-5.9) in type II or type III IM limited to the antrum and incisura (n = 20); 2.4 (0.4-5.6) in extensive incomplete IM (n = 38); and 1.3 (0.4-6.4) in low-grade dysplasia (n = 23) (P = .002). Using histopathologic data as a reference test, the area under the receiver operating characteristic curves (CI 95%) was 0.73 (0.64-0.82) for extensive IM, 0.72 (0.58-0.85) for the diagnosis of dysplasia, and 0.81 (0.66-0.95) for the diagnosis of high-grade dysplasia. Using a PGI/PGII ratio of < or =3 as the cutoff for dysplasia diagnosis, the sensitivity was 70% (62-78%), the specificity was 65% (57-73%), and the negative predictive value estimates were over 90%. No differences in PG levels according to age or gender were observed. Helicobacter pylori did not significantly influence validity measurement estimates. PGI/PGII serum level ratio can be used even in the management of patients with a high a priori probability for a positive test. It may be useful for the exclusion of more advanced lesions (extensive IM and neoplastic lesions).

To devise a follow up model for patients with gastric cancer associated lesions, such as atrophic chronic gastritis (ACG) and intestinal metaplasia (IM).

Cohort study of 144 patients, followed for a minimum of one year, in whom at least two upper gastrointestinal endoscopic biopsies in flat gastric mucosa provided a diagnosis of ACG, IM, or low grade dysplasia (LGD).

Of those diagnosed with ACG at first endoscopic biopsy (entry biopsy), 12% progressed to LGD in outcome biopsy, as did 8% of those with type I IM, 38% with type II or III IM, and 32% with LGD. Type of IM at entry independently predicted progression to LGD and cancer. Type II and III IM had a higher rate of progression to LGD than type I IM, which showed an indolent behaviour similar to ACG. Patients with type II or III IM were at higher risk for development of dysplasia, and 7% of patients with type III IM at first biopsy progressed to high grade dysplasia (HGD), whereas no cases of ACG or type I/II IM progressed to HGD during the first three years.

Patients with ACG or IM could possibly be allocated to different management schedules, based on differences in rate and proportion of progression to LGD or HGD. Less intensive follow up (two/three yearly with "serological evaluation" (pepsinogen)) may suit those with ACG or type I IM. Patients with type III IM may benefit from six to 12 monthly improved endoscopic examination (magnification chromoendoscopy).

The aim of this study was to define the reproducibility and accuracy of magnification chromoendoscopy for the diagnosis of lesions associated with gastric cancer (intestinal metaplasia and dysplasia).

A total of 136 patients with previously diagnosed lesions and 5 gastrectomy specimens were studied. Endoscopic examination was performed with a magnification endoscope after methylene blue (1%) spraying. According to differences in color and mucosal pattern, groups and subgroups of endoscopic images were defined, and biopsies taken (n = 462). Five endoscopists were asked to classify individually 2 endoscopic images per subgroup on 2 separate occasions.

Three groups of endoscopic images were defined: nonmetaplastic, nondysplastic mucosa (I); metaplastic mucosa (II); and dysplastic mucosa (III). Ten subgroups were defined according to pit pattern: round small (IA), round and tubular small (IB), coarse round (IC), and course round pits with a straight pit (ID); blue irregular marks (IIA), blue round and tubular pits (IIB), blue villi (IIC), and blue small pits (IID); and loss of clear pattern, with depression (IIIA) or with slight elevation (IIIB). The kappa statistic for intraobserver agreement on the classification of endoscopic images in groups was 0.86; for interobserver agreement, it was 0.74. For classification into subgroups, kappa values ranged from 0.48 to 0.78. For 85% of the areas classified endoscopically as Group I (n = 146), no mucosal lesions or gastritis was described at histologic examination; for 83% of those in Group II (n = 198), intestinal metaplasia was found. Subgroups IIA and IIB were more often associated with complete intestinal metaplasia (62%), and IIC and IID with incomplete metaplasia (67%); in Group III (n = 118), dysplasia was diagnosed histopathologically in 33%. For the diagnosis of dysplasia, specificity was 81% (95% CI [77%, 85%]) and negative predictive value 99% (95% CI [99%, 100%]).

Gastric endoscopic patterns with chromoendoscopy and magnification seem reproducible and valid for the diagnosis of lesions associated with gastric cancer. This procedure may improve the follow-up of individuals at high-risk of gastric cancer, at least for the exclusion of severe lesions.

Intestinal type metaplasia plays a role in intestinal type gastric carcinoma development. Ascorbic acid demonstrates a protective effect against gastric carcinogenesis, due to its ability to inactivate oxygen free-radicals as well as its nitrite-scavenging effects.

To assess whether long-term ascorbic acid administration following Helicobacter pylori eradication could affect intestinal metaplasia regression in the stomach.

Sixty-five patients were included in the study. The inclusion criterion was the presence of intestinal metaplasia on the gastric mucosa after H. pylori eradication. An upper gastrointestinal endoscopy was performed and 3 biopsy specimens were taken in the antrum, 3 in the gastric body, and 2 in the incisura angularis. Patients were randomized to receive 500 mg of ascorbic acid o.d., after lunch (32 patients) for 6 months or no treatment (33 patients). All patients underwent to endoscopic control at the end of the 6 months.

H. pylori infection recurrence was detected in 6 (9.4%) patients (three from each group), and these patients were excluded from further analysis. We were unable to find evidence of intestinal metaplasia in any biopsied site of the gastric mucosa in 9/29 (31%) patients from the ascorbic acid group and in 1/29 (3.4%) of the patients from the control group (P=0.006). Moreover, a further six (20.7%) patients from the ascorbic acid group presenting chronic inactive pangastritis with widespread intestinal metaplasia at entry, showed less extensive antritis with intestinal metaplasia at control, whilst a similar finding was only seen in one patient from the control group (P=0.051).

The administration of ascorbic acid significantly helps to resolve intestinal metaplasia of the gastric mucosa following H. pylori eradication, and its use as a chemoprevention treatment should be considered.

Mucins are high molecular weight glycoproteins that are heavily glycosylated with many oligosaccharide side chains linked O-glycosidically to the protein backbone. With the recent application of molecular biological methods, the structures of apomucins and regulation of mucin genes are beginning to be understood. At least nine human mucin genes have been identified to date. Although a complete protein sequence is known for only three human mucins (MUC1, MUC2, and MUC7), common motifs have been identified in many mucins. The pattern of tissue and cell-specific expression of these mucin genes are emerging, suggesting a distinct role for each member of this diverse mucin gene family. In epithelial cancers, many of the phenotypic markers for pre-malignant and malignant cells have been found on the carbohydrate and peptide moieties of mucin glycoproteins. The expression of carbohydrate antigens appears to be due to modification of peripheral carbohydrate structures and the exposure of inner core region carbohydrates. The expression of some of the sialylated carbohydrate antigens appears to correlate with poor prognosis and increased metastatic potential in some cancers. The exposure of peptide backbone structures of mucin glycoproteins in malignancies appears to be due to abnormal glycosylation during biosynthesis. Dysregulation of tissue and cell-specific expression of mucin genes also occurs in epithelial cancers. At present, the role of mucin glycoproteins in various stages of epithelial cell carcinogenesis (including the preneoplastic state and metastasis), in cancer diagnosis and immunotherapy is under investigation.

Gastric atrophy and intestinal metaplasia are considered the earliest phenotypic changes in the cascade of events leading from normal mucosa to intestinal-type gastric cancer, and epidemiological evidence links Helicobacter pylori to gastric epithelial malignancies. To evaluate any causal relationship between bacterial infection and atrophic metaplastic lesions, gastric pathology was histologically and histochemically evaluated in 267 consecutive, nonulcerous, untreated subjects, with attention given the phenotypes of intestinal metaplasia. The prevalence of Helicobacter pylori infection was 61%. Intestinal metaplasia (particularly types II and III) was significantly associated with both Helicobacter pylori detection (chi 2 LR: P < 0.002) and increasing age (chi 2 LR: P < 0.002). Using logistic regression analysis, the development of intestinal metaplasia proved more significantly linked with Helicobacter pylori infection [odds ratio = 4.55 (95% confidence interval: 1.51-13.7)], than with age [odds ratio = 1.03 (95% CI: 1.01-1.06)], with no interaction. In conclusion, Helicobacter pylori can be considered among the major causal agents of mucosal lesions involved in the multistep process of gastric carcinogenesis, justifying any attempt to eradicate this bacterial infection.

Eighty-two selected gastric mucosal biopsy or resection specimens were stained both conventionally, to classify subtypes of intestinal metaplasia and carcinoma, and immunohistochemically with a mouse monoclonal antibody (MMM-17), raised against normal human colonic mucin, which has an affinity for di- and/or tri-O-acetylated sialomucin. The aims of the study were to reassess the prevalence of O-acetylated sialomucins in normal, metaplastic and carcinomatous gastric mucosa and to investigate whether the production of these mucins by intestinal metaplasia is related to its associated mucosal pathology. O-acetylated sialomucins were not seen in normal mucosa. They were, however, prevalent in all sub-types of metaplastic (64.8%) and carcinomatous (42.9%) mucosa. Type 1 intestinal metaplasia was significantly more likely to contain this type of mucin if Helicobacter pylori infection was identifiable in the adjacent gastric mucosa (81.0% v. 38.5%, P < 0.025). Type 3 showed a similar, albeit nonsignificant, relationship (100% v. 62.5%). O-acetylated sialomucins are, therefore, much more prevalent in gastric intestinal metaplasia and carcinoma than previously recognized by conventional staining techniques. The production of this type of mucin by intestinal metaplasia may reflect an adaptive response to alterations in the luminal environment such as an increase in bacterial content.

The control of colorectal cancer is currently dependent on early detection, and its prevention requires the recognition and treatment of its precursor lesions. The adenoma has been established as the precursor of colorectal carcinoma in the general population. Among patients with inflammatory bowel disease (IBD), dysplasia is associated with, and precedes, invasive carcinoma. In this section criteria are described for the histological detection of preinvasive and early invasive neoplasia in the large intestine of patients with and without IBD. The therapeutic implications of these diagnoses are stressed. A brief review of subcellular changes, including genetic alterations, in colorectal neoplasia is included.

Gastric adenocarcinoma is among the most common malignancies worldwide. Its etiopathogenesis is complex and, as yet, incompletely understood; however, diet, infection with Helicobacter pylori, and genetic factors are involved. It may be classified into two main types, intestinal and diffuse. The intestinal type has decreased in incidence, whereas the diffuse tumors as well as those confined to the cardia are increasing. Numerous conditions, such as gastritis, gastric atrophy, and intestinal metaplasia (IM), are associated with intestinal type gastric cancer in retrospective studies, but only epithelial dysplasia has a positive predictive value for malignancy. These precursor conditions and lesions are analyzed for their clinicopathological significance in this review, which concludes with a brief summary of curable (early) forms of gastric cancer.

Immunohistochemistry using the PC10 antibody to proliferating cell nuclear antigen (PCNA) was applied to archival material from mucosa adjacent to gastric carcinoma ('normal', hyperplasia, complete and incomplete intestinal metaplasia and dysplasia) and non-cancer controls (normal and complete intestinal metaplasia). Overall, increased PCNA indices, with expansion and altered location of the proliferative zones, were observed in carcinoma fields and compared with controls (P < 0.001). These differences were particularly significant in 'normal' mucosa far from carcinoma as compared with normal in controls (P < 0.001). In carcinoma 'fields' distinct patterns of PCNA expression were noted in complete and incomplete intestinal metaplasia. Similarly, in dysplastic lesions high PCNA indices were present either throughout the gland or found predominantly in the upper compartment. We conclude that these differences in PCNA index and staining patterns might prove useful in monitoring the evolution of the disease in the follow-up of patients at risk of developing gastric cancer.

The aim of this study was to try to place gastric intestinal metaplasia, type III (type III IM) in the stepwise chain of events from atrophic gastritis to cancer. A number of dysplastic, periulcer regenerative, and type III IM lesions were qualitatively diagnosed (and graded) blindly and independently by several pathologists. These lesions were further analysed by means of quantitative parameters, with the aim of differentiating dysplastic from regenerative changes. Inconsistencies between the qualitative and quantitative classification (about 7 per cent of cases) were eliminated and homogeneous groups (low-grade dysplasia, high-grade dysplasia, regenerative changes) were obtained. These cases were taken as the gold standard against which type III IM was compared. The results indicate that the great majority (91.4 per cent) of cases of type III IM fulfil the nuclear and architectural criteria for low-grade dysplasia.

The quantitative distribution of different types of mucins in diffuse and intestinal-type gastric carcinomas and in the carcinomas of the small intestine and colon was compared with that of mucins in normal gastric and intestinal mucosa. The series consisted of 54 patients resected for carcinomas of the stomach or intestine. With regard to the histogenesis of the intestinal-type gastric carcinoma, the mixed composition of mucins indicated that the complete type of intestinal metaplasia cannot be the origin of the carcinoma. The intestinal type rather seems to originate from the regenerating epithelium in chronic atrophic gastritis with incomplete type of intestinal metaplasia. In the diffuse type of carcinoma a relative abundance of neutral mucins typical of normal gastric mucosa was demonstrated. This supports the hypothesis that this tumour type originates from nonmetaplastic gastric epithelium and the intestinal characteristics of diffuse carcinomas develop in the neoplastic tissue.

A follow up study with biopsy was initiated in 1982 to define the relations between variants of intestinal metaplasia and the evolution of chronic atrophic gastritis and gastric ulcer. All patients (58 with chronic atrophic gastritis and 66 with gastric ulcer) had intestinal metaplasia at the start of the study. In the six year period to 1988 a total of 241 biopsies were performed on the patients with chronic atrophic gastritis and 243 on the patients with gastric ulcer. Initially, 81% of the patients with chronic atrophic gastritis presented with type I intestinal metaplasia and 14% with type III intestinal metaplasia. During follow up type I was predominant, often associated with grades 2 and 3 active disease (81%) and 45% of these patients reverted to a non-intestinal metaplasia status by the third year of follow up. In contrast, type III metaplasia was more common in the absence of appreciable inflammation (78% of biopsy specimens), being persistent in five of seven patients in the third year of follow up, and was found to be associated with dysplasia in three of these patients. Similarly, the initial biopsy specimen showed type I metaplasia in most patients with gastric ulcer (82%) and type III in only 4%. Type I metaplasia was also predominant in these patients (80%), particularly in active disease (68%), gradually regressing with healing. In contrast, type III was associated with delayed ulcer healing and reactivation (75%; six of eight patients). We conclude that (a) type I is a short term reactive process which regresses with healing; (b) type III is related to prolonged injury and chronicity and may regress or progress to dysplasia; (c) persistent and more immature forms of metaplasia may carry an increased risk of malignancy.

Type I and type III intestinal metaplasia in gastric mucosa have been examined using morphometric methods. Tissue (volume per cent gland, lumen, epithelium, goblet cell vacuoles) and nuclear parameters (area, with related standard deviation, and form factors) were used as indicators of gland crowding, nuclear-cytoplasmic ratio, nuclear atypia, and pleomorphism. In type III intestinal metaplasia, there is significantly (i) greater nuclear pleomorphism, (ii) a higher nuclear-cytoplasmic ratio, and (iii) smaller and less numerous goblet cell vacuoles in both the upper and the lower parts of the crypts. These two parameters have significantly higher values in the lower than in the upper part of individual crypts. No cell population with large pleomorphic nuclei characterized type III metaplasia, though there was more variation in nuclear size.

This work is based on the follow-up evaluation of 67 moderate (MD) or severe gastric dysplasias (SD) diagnosed by endoscopic biopsy. Forty-one patients had moderate gastric dysplasia, 22 (53.65%) had regression of MD, 14 patients (34.4%) had persistence, three (7.31%) had progression to SD, and two (4.87%) had transformation in gastric adenocarcinoma. Twenty-six patients were diagnosed with severe gastric dysplasia: in 12 patients (46.15%) gastric lesions regressed to normality (five cases), mild (six cases) or moderate dysplasia (one case); six patients (23.07%) showed persistent histologic changes of SD in the subsequent biopsy specimens; eight patients (30.7%) presented progression of lesions to gastric adenocarcinoma after 1 to 79 months of follow-up evaluation. The authors conclude that moderate and severe gastric dysplasias are preneoplastic lesions and a valuable marker of gastric cancer risk; the risk of gastric cancer after moderate or severe dysplasia is of 9.52%, excluding those cases with short follow-up. The authors claim that these patients may receive a conservative clinical treatment with frequent endoscopic studies until the appearance of either early carcinoma to indicate gastrectomy, or no dysplasia at all or mild dysplasia in specimens from at least two consecutive biopsies.

The monoclonal antibody AM-3 was raised against mucins extracted from human colorectal carcinomas. It reacted strongly with sections of paraffin wax embedded colorectal carcinoma. In colonic adenoma tissue the percentage of cells expressing the epitope detected by AM-3 correlated with the degree of dysplasia. In contrast to immunohistochemical staining, which did not show the presence of the antigen in histologically normal mucosa, the more sensitive enzyme linked immunosorbent assay (ELISA) and immunoblot assays showed that it was weakly expressed in this tissue. AM-3 reacted with variable frequency with several normal and malignant human tissues, indicating that the detected epitope is not restricted to colonic tissue. In colonic carcinomas it is present on a sialomucin of apparent relative molecular mass of more than 440,000. These data suggest that the antigen detectable with AM-3 may be useful in the assessment of premalignant changes in colonic adenomas.

A silver technique for nucleolar organizer regions (AgNOR) was applied to sections from 156 gastric biopsies and gastrectomy specimens. These included normal controls, normal gastric mucosa from carcinoma-bearing stomachs, intestinal metaplasia types I and III, dysplasia and carcinoma. AgNOR counts gradually increased from normal, through intestinal metaplasia, to carcinoma. This finding supports the chronic atrophic gastritis-intestinal metaplasia-dysplasia-carcinoma sequence concept for gastric carcinogenesis. Normal gastric mucosa was different from all lesions, including normal mucosa from carcinoma-bearing stomachs. Significantly higher AgNOR counts were observed in tumours compared to all other lesions except dysplasia. Dysplasia differed from intestinal metaplasia type I but not from type III. Eighty-five per cent of metaplasia cases overlapped with carcinoma and 19% with normal controls. The spread of AgNOR values in intestinal metaplasia reinforces the concept that this lesion is a heterogeneous entity reflecting a dynamic and continuous process. The AgNOR technique may contribute to the assessment of the stage of evolution of 'borderline' lesions.

Gastric dysplasia is regarded as a pre-neoplastic lesion and is generally believed to have higher potential for malignant transformation with increasing grade. To obtain consistency in diagnosis and management, reproducible diagnostic criteria are needed. We have used the classification system of the International Study Group on Gastric Cancer--ISGGC and investigated the interobserver variation in histological diagnosis. A Kappa statistic of 0.579, which reflects moderate agreement, was obtained for variation between two experienced pathologists. The prevalence of type III intestinal metaplasia was studied and found to occur in 55% of dysplastic areas, but in only 9% of hyperplastic areas (P less than 0.01). In addition, the correlation of mean nucleolar organizer region (AgNOR) counts with diagnostic categorization was investigated. A significant inter-observer variation was found between an experienced pathologist and a postgraduate student and only one of the observers obtained statistically significant separation of mean AgNOR counts between the categories of high-grade dysplasia, low-grade dysplasia, atypical hyperplasia, simple hyperplasia and normal.

Columnar cell lined lower oesophagus (CELLO), often considered to be a precancerous lesion, is characterized by a glandular mucosa with a predominance of sulphomucins in the specialized epithelium. This histochemical abnormality can be correlated with abnormal differentiation which may also be studied by anti-mucus antibodies (anti-M1, anti-M3, anti-SIMA, anti-LIMA). The purpose of this prospective study is to define the mucin profile in a large population of CELLO by immunohistochemistry and to compare it with the results of histochemistry. Biopsies of 79 patients with reflux oesophagitis were included. Thirty-eight had CELLO and 41 had a histologically normal cardia. Six surgical specimens of oesophageal adenocarcinomas were also included. The histochemical methods confirmed the preponderance (57.9%) of type III intestinal metaplasia (IM) found in 57.9% of cases. The immunohistochemical methods showed a similar antigenic profile of type II and III IM with positivity of anti-SIMA and anti-M3 antibodies in the goblet cells, and positivity of anti-LIMA antibodies in both the goblet and intermediate cells of the specialized epithelium. The mucus secreting cells of the oesophageal adenocarcinomas had the same immunohistochemical profile. These results are similar to those of Filipe et al. in type II and III IM surrounding gastric adenocarcinomas. Immunohistochemical methods allow us to subdivide type II and type III IM into 2 subgroups according to the positivity or negativity of the anti-LIMA antibodies in the intermediate cells. Among the 41 normal cardias in patients with reflux oesophagitis, 10 contain sulphomucin secreting cells positive with anti-LIMA antibodies. We suggest that this anti-LIMA positivity may be a step preceding type III IM in specialized epithelium.

The expression of two intestinal mucin-associated antigens large intestine mucin antigen (LIMA) and small intestine mucin antigen (SIMA) were investigated by indirect immunoperoxidase staining of rectal mucosa from patients suffering from ulcerative colitis with (n = 6) and without (n = 31) associated carcinoma and in noncolitic controls (n = 40). The aim was to assess the relationship between antigen patterns and malignant change. SIMA, which is localised predominantly in the small intestine, is virtually undetectable in the normal adult colonic mucosa. However, this antigen is present in the foetal colon and colonic carcinoma. LIMA is expressed in normal colonic mucosa, but absent from the small intestine. LIMA staining patterns were not significantly different among the three groups. In contrast, expression of SIMA was significantly higher in the patients who had developed carcinoma (6/6) than in the noncancer group (7/71) (P less than 0.001). The presence of SIMA was also significantly related to areas of dysplasia compared to normal (P = .03) or inflammation (P less than .05), but it did not differ from mucosa showing "indefinite" atypia. The finding of 31% SIMA-positive biopsies associated with severe inflammation in colitis with active disease, but no evidence of malignancy, is difficult to explain at the present stage. A followup study would be necessary to determine its significance. Perhaps the most important finding is the increased frequency of SIMA-positive foci in histologically normal mucosa in carcinoma patients compared with the noncancer group (P less than .001), suggesting a field change. These observations may be prove useful for the identification of patients who may be at risk of developing carcinoma.