Pentti Sipponen

The Vienna classification of gastrointestinal epithelial neoplasia

BACKGROUND Use of the conventional Western and Japanese classification systems of gastrointestinal epithelial neoplasia results in large differences among pathologists in the diagnosis of oesophageal, gastric, and colorectal neoplastic lesions. AIM To develop common worldwide terminology for gastrointestinal epithelial neoplasia. METHODS Thirty one pathologists from 12 countries reviewed 35 gastric, 20 colorectal, and 21 oesophageal biopsy and resection specimens. The extent of diagnostic agreement between those with Western and Japanese viewpoints was assessed by kappa statistics. The pathologists met in Vienna to discuss the results and to develop a new consensus terminology. RESULTS The large differences between the conventional Western and Japanese diagnoses were confirmed (percentage of specimens for which there was agreement and kappa values: 37% and 0.16 for gastric; 45% and 0.27 for colorectal; and 14% and 0.01 for oesophageal lesions). There was much better agreement among pathologists (71% and 0.55 for gastric; 65% and 0.47 for colorectal; and 62% and 0.31 for oesophageal lesions) when the original assessments of the specimens were regrouped into the categories of the proposed Vienna classification of gastrointestinal epithelial neoplasia: (1) negative for neoplasia/dysplasia, (2) indefinite for neoplasia/dysplasia, (3) non-invasive low grade neoplasia (low grade adenoma/dysplasia), (4) non-invasive high grade neoplasia (high grade adenoma/dysplasia, non-invasive carcinoma and suspicion of invasive carcinoma), and (5) invasive neoplasia (intramucosal carcinoma, submucosal carcinoma or beyond). CONCLUSION The differences between Western and Japanese pathologists in the diagnostic classification of gastrointestinal epithelial neoplastic lesions can be resolved largely by adopting the proposed terminology, which is based on cytological and architectural severity and invasion status.

Positive serum antibody and negative tissue staining for Helicobacter pylori in subjects with atrophic body gastritis

Helicobacter pylori is rarely found in gastric biopsy specimens from individuals with atrophic gastritis of the body mucosa. To determine if subjects with atrophic body gastritis have evidence of previous infection with H. pylori, immunoglobulin G antibody to H. pylori was measured by enzyme-linked immunosorbent assay in sera of 399 Finnish subjects. In 124 subjects, multiple biopsy specimens from body and antrum had been evaluated for the presence of H. pylori by Giemsa staining. Antibody correlated well with H. pylori staining except in the subgroup with atrophic body gastritis, in whom the prevalence of seropositivity (86%) was significantly greater than the prevalence of positive staining (33%) (P less than 0.001). Twenty-five subjects had positive antibody and negative staining. This group had a significantly higher prevalence of atrophic body gastritis (80%), lower maximal acid output, lower serum pepsinogen I levels, and higher serum gastrin concentrations than did seropositive subjects with H. pylori. These data suggest that most patients with atrophic body gastritis, despite having a low incidence of current overt infection, have been infected with H. pylori at some point in their lives.

Diagnostic value of decreasing IgG, IgA, and IgM antibody titres after eradication of Helicobacter pylori.

Titres of antibody to Helicobacter pylori are known to fall with eradication of bacteria. To find out what degree of fall would reliably indicate eradication, 144 patients with Helicobacter pylori infection were given antimicrobial therapy for 2 weeks and then followed up at 6 weeks, 6 months, and 12 months with serological tests, bacterial cultures, and histological studies of gastric specimens. 6 weeks after treatment IgG titres had fallen by 20-30% irrespective of the success of bacterial eradication. In the 121 bacteria-negative patients the decrease continued. 6 and 12 months after treatment the titre was 50% or less of pretreatment value in 97% of these patients. In the 23 patients who remained infected, the initial drop of IgG titres, if any, was followed by unchanged or slightly rising titres. IgA and IgM titres, initially raised in 64% and 4% of the patients, respectively, showed similar trends. The high sensitivity (97%) of the IgG antibody tests and a consistent fall within 6 months after eradication of H pylori infection made IgG the most useful immunoglobulin class for follow-up of antimicrobial therapy in individual patients. IgA antibodies were valuable in the 2% patients who had raised titres in this immunoglobulin class only. The few patients (5.5%) who had raised IgM titres also had high IgG titres. Serological tests thus are a cheap and reliable means of monitoring success of eradication of H pylori.

Differences in diagnostic criteria for gastric carcinoma between Japanese and Western pathologists

BACKGROUND There have been many studies on gastric carcinoma in populations with contrasting cancer risks. We aimed to find out whether the criteria for the histological diagnosis of early gastric carcinoma were comparable in Western countries and Japan. METHODS Eight pathologists from Japan, North America, and Europe individually reviewed 35 microscope slides: 17 gastric biopsy samples and 18 endoscopic mucosal resections taken from 17 Japanese patients with lesions ranging from early gastric cancer to adenoma, dysplasia, and reactive atypia. The pathologists were given a list of pathological criteria and a form on which they were asked to indicate the criteria on which they based each diagnosis. FINDINGS For seven slides most Western pathologists diagnosed low-grade adenoma/dysplasia, whereas the Japanese diagnosed definite carcinoma in four slides, suspected carcinoma in one, and adenoma in only two. Of 12 slides with high-grade adenoma/dysplasia according to most Western pathologists the Japanese gave the diagnosis of definite carcinoma in 11 and suspected in one. Of six slides showing high-grade adenoma/dysplasia with suspected carcinoma according to most Western pathologists the Japanese diagnosed definite carcinoma in all. There were no major differences in the diagnoses of three slides showing reactive epithelium and seven slides with clearly invasive carcinoma. When the opinion of the majority of the pathologists was taken as the final diagnosis there was agreement between Western and japanese in 11 of the 35 slides (kappa coefficient 0.15 [95% CI 0.01-0.29]). Presence of invasion was the most important diagnostic criterion for most Western pathologists whereas for the Japanese nuclear features and glandular structures were more important. INTERPRETATION In Japan, gastric carcinoma is diagnosed on nuclear and structural criteria even when invasion is absent according to the Western viewpoint. This diagnostic practice results in almost no discrepancy between the diagnosis of a superficial biopsy sample and that of the final resection specimen. This may also contribute to the relatively high incidence and good prognosis of gastric carcinoma in Japan when compared with Western countries.

Role of Helicobacter pylori in the pathogenesis of gastritis, peptic ulcer and gastric cancer.

Helicobacter pylori is the major causal factor in chronic gastritis. Its acquisition leads to a chronic, usually lifelong, inflammation of the gastric mucosa, which may gradually progress to atrophy (with intestinal metaplasia) in a significant proportion of infected individuals. This progression is probably multifactorial, being influenced by genetic or environmental factors in addition to H. pylori infection. The pathogenesis of peptic ulcer and gastric cancer is closely associated with H. pylori gastritis and its subsequent atrophic sequelae (atrophic gastritis). H. pylori-induced gastritis is an important risk factor in the multifactorial aetiology of these diseases. It causes a cascade of reactions that damage the gastric mucosa and epithelium in various ways. The specific mechanisms involved are largely unknown. Some are probably bacterium-related reactions, which are influenced by various virulence factors, and others are consequences of the mucosal inflammation and atrophy. The risk of peptic ulcer and gastric cancer in patients with H. pylori gastritis can be summarized as follows: i) the risk of both peptic ulcer and gastric cancer is low in individuals with a normal stomach; ii) the risk of peptic ulcer is approximately ten times higher and the risk of gastric cancer approximately twice as high in patients with non-atrophic H. pylori-positive gastritis as in those with a normal stomach; iii) these risks are further increased (twofold to threefold) when there is antral atrophy; whereas iv) in the presence of corpus atrophy the risk of gastric cancer remains high, but that of peptic ulcer decreases gradually to zero with increasing severity of corpus atrophy.

Favourable effect of an acidified milk (LC-1) on Helicobacter pylori gastritis in man

Objective The supernatant of Lactobacillus johnsonii La1 culture was shown to be bactericidal and to have a partial, acid-independent suppressive effect on Helicobacter pylori in humans. The aim of the present study was to investigate the effect of L. johnsonii La1-acidified milk (LC-1) on H. pylori infection. Design and methods Fifty-three volunteers infected with H. pylori as determined by positive 13C-urea breath test and positive serology were randomized to receive either LC-1 or a placebo 180 ml twice a day for 3 weeks. All subjects also received clarithromycin 500 mg bid during the last two weeks of acidified milk therapy. Oesophagogastroduodenoscopy and biopsies were performed at inclusion and repeated 4–8 weeks after the end of the treatment. H. pylori infection was confirmed by urease test and histology. H. pylori density and inflammation were scored using a modified Sydney classification. Results LC-1 ingestion induced a decrease in H. pylori density in the antrum (P = 0.02) and the corpus (P = 0.04). LC-1 also reduced inflammation and gastritis activity in the antrum (P = 0.02 and P = 0.01, respectively) and of activity in the corpus (P = 0.02). Clarithromycin eradicated H. pylori in 26% of the subjects; LC-1 did not improve the antibiotic effect. Conclusion These results suggest that H. pylori infection and gastritis can be down-regulated by LC-1.

The Risk of Gastric Carcinoma and Carcinoid Tumours in Patients with Pernicious Anaemia: A Prospective Follow-Up Study

BACKGROUND This endoscopic follow-up study was undertaken to evaluate the risk of gastric cancer (GC) and carcinoids in patients with pernicious anaemia (PA) and to analyse whether early detection of GC could be provided by regular endoscopic follow-up. METHODS Screening gastroscopy was performed in 71 patients with pernicious anaemia, and thereafter they were followed up with gastroscopies at 3-year intervals for a mean time of 5.8 years. Standardized incidence ratios (SIR) were calculated, the expected number being based on incidence rates in the whole Finnish population. RESULTS Two GCs were found during the follow-up period; one of these patients was asymptomatic and the other had abdominal symptoms. The SIR was 5.0 (95% confidence interval, 0.6-18). Eight carcinoids were detected, and all but one were removed endoscopically, and no metastases were found. The patients who had carcinoid tumours were younger at the diagnosis of PA than those who did not develop carcinoids (mean, 40 versus 55 years). Additionally, the patients with carcinoids had longer duration of PA (mean, 11 versus 5 years). CONCLUSIONS During the follow-up period the risk of GC was increased. The risk of gastric carcinoids seems to be very high in patients with pernicious anaemia when compared with a normal population, but they are mostly relatively benign tumours. Regular routine gastroscopic follow-up is not indicated in patients with pernicious anaemia.

Effects of supplemental α-tocopherol and β-carotene on colorectal cancer: results from a controlled trial (Finland)

AbstractBackground:Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and β-carotene might be associated with reduced risk of colorectal cancer. Methods:We tested the effects of α-tocopherol and β-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a double-blind, placebo-controlled trial among 29,133 50–69-year-old male cigarette smokers. Participants were randomly assigned to receive α-tocopherol (50 mg), β-carotene (20 mg), both agents, or a placebo daily for 5–8 years. Incident colorectal cancers (n = 135) were identified through the nationwide cancer registry, and 99% were histologically confirmed. Intervention effects were evaluated using survival analysis and proportional hazards models. Results:Colorectal cancer incidence was somewhat lower in the α-tocopherol arm compared to the no α-tocopherol arm, but this finding was not statistically significant (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.55–1.09; log-rank test p = 0.15). β-Carotene had no effect on colorectal cancer incidence (RR=1.05, 95% CI 0.75–1.47; log-rank test p = 0.78). There was no interaction between the two substances. Conclusion:Our study found no evidence of a beneficial or harmful effect for β-carotene in colorectal cancer in older male smokers, but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect. The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk.

Gastroesophageal Reflux Disease: Prevalence, Clinical, Endoscopic and Histopathological Findings in 1,128 Consecutive Patients Referred for Endoscopy due to Dyspeptic and Reflux Symptoms

Background and Aims: Gastroesophageal reflux disease (GERD) reportedly has increased in prevalence while Helicobacter pylori infection and peptic ulcer disease have been on the decrease. The aim of the present study was to examine the prevalence of GERD as well as the clinical, endoscopic and histologic variables that associate with GERD in patients referred for endoscopy. Patients and Methods: The study population was drawn from 1,562 consecutive patients referred for endoscopy. The exclusion criteria were previous H. pylori eradication, gastric surgery, anemia and weight loss. Thus 1,128 patients were enrolled in the present study. Results: Of the 1,128 patients, 199 (18%) were referred for endoscopy due to heartburn and/or regurgitation. GERD, defined as chronic (>6 months) heartburn and/or regurgitation with or without erosive esophagitis, Barrett’s esophagus, esophageal ulcer or stricture, was detected in 248 (22%) patients. Of the 248 GERD patients, 81 (33%) had endoscopy-negative GERD, but of those aged <50 years (n = 67), 57 (85%) were endoscopy-negative. The overall incidence of GERD was 307 per 100,000 population/year and that of endoscopy-positive GERD 207/100,000/year. The positive and negative predictive values of heartburn and regurgitation for endoscopy-positive GERD were 0.37 (95% CI 0.31–0.44) and 0.90 (95% CI 0.88–0.92), respectively. Independent risk factors for GERD were male sex (OR 1.9, 95% CI 1.3–2.7), previous medication for upper gastrointestinal symptoms (OR 2.7, 95% CI 1.7–4.1), the use of nonsteroidal anti-inflammatory drugs (NSAIDs; OR 2.0, 95% CI 1.3–3.0), histologic esophagitis (OR 2.2, 95% CI 1.5–3.2) and incomplete intestinal metaplasia at the gastroesophageal junction (OR 1.7, 95% CI 1.0–3.1). Chronic gastritis was protective against GERD (OR 0.7, 95% CI 0.5–0.9). No association was observed between GERD and H. pylori infection. The risk of patients aged <50 years (n = 407) of having major lesion (Barrett’s esophagus, esophageal stricture, peptic ulcer, esophageal/gastric carcinoma) was significantly lower than that of patients aged >50 years (n = 721; OR 0.5, 95% CI 0.3–0.9, p = 0.01). Conclusions: The correlation between reflux symptoms and endoscopy-positive GERD is poor and most GERD patients aged <50 years have endoscopy-negative GERD. The use of NSAIDs is a risk factor for GERD, whereas chronic gastritis, but not H. pylori infection, may protect against GERD. Incomplete intestinal metaplasia at the gastroesophageal junction is associated with GERD.

Histopathology of colorectal carcinomas and adenomas in cancer family syndrome

Seventy-five colorectal carcinoma patients (100 separate cancers) with verified cancer family syndrome were re-examined for the evaluation of histologic characteristics in carcinomas and adenomatous polyps in this inherited syndrome in a comparison with control patients with colorectal carcinoma but no hereditary background. In the cancer family syndrome group there were significantly more mucinous carcinomas (35 to 39 percent vs. 20 percent;P<0.05–0.01), and also more poorly differentiated tumors (24 vs. 12 percent) than in the control group. The differences could not be explained by the site or stage of the tumors or by the age or sex of the patients. Additional adenomas occurred quite often both in cancer family syndrome patients (19 percent) and in the controls (16 percent). In the cancer family syndrome group, however, there were more adenomas with moderate or severe dysplasia (P<0.01) and more adenomas with villous features (P<0.05) than in the control group. Mucinous histologic features in colorectal carcinoma, although not fully specific, might be characteristic of cancer family syndrome, and thus serve as one sign in the indentification of the syndrome. The presence of the adenoma-carcinoma sequence in cancer family syndrome also was supported, and the histologic aggressivity of the associated adenomas might signify an accelerated advancement of this phenomenon in cancer family syndrome.