Ashley B. Price

The Sydney System: Histological division

Gastritis, inflammation of the gastric mucosa, represents the stomach’s response to injury. A continuing dilemma has been the very large size of the population with gastritis in contrast to the lack of knowledge about specific causes. The discovery of Helicobacter pylori as the major cause of inflammation of the gastric antrum has helped resolve this As a result, accurate and uniform documentation of gastritis from gastric endoscopic biopsies assumes prime importance for understanding the dynamics of gastritis and has a major contribution to make to the study of the natural history of peptic ulcer disease and also, perhaps, to the evolution of gastric cancer. Increasing numbers of papers are appearing in the literature documenting the pathology of gastritis, its relation to H. pylori and the response to therapeutic agents.+” At present, a variety of classifications and systems of grading are in use, making it difficult to compare the results.10*12-21 It is therefore appropriate to review the existing classifications and to produce a system that, in the light of new knowledge, will find widespread acceptance. This was the remit given to a small multidisciplinary Working Party by the Scientific Committee of the 9th World Congresses in Gastroenterology. The Working Party sought additional advice from an ad hoc Advisory Group of European pathologists sharing a special interest in gastric pathology. T o gain widespread acceptance, any proposed classification must be simple, easy to apply, flexible, correlate with existing classifications, be sensitive to monitoring therapy and appeal to generalists as well as dedicated gastroenterologists, and diagnosticians as well as research workers.

Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis

Background and aims: Colonoscopic surveillance for cancer in longstanding extensive ulcerative colitis relies heavily on non-targeted mucosal biopsies. Chromoendoscopy can aid detection of subtle mucosal abnormalities. We hypothesised that routine pancolonic indigo carmine dye spraying would improve the macroscopic detection of dysplasia and reduce the dependence on non-targeted biopsies. Patients and methods: One hundred patients with longstanding extensive ulcerative colitis attending for colonoscopic surveillance underwent “back to back” colonoscopies. During the first examination, visible abnormalities were biopsied, and quadrantic non-targeted biopsies were taken every 10 cm. Pancolonic indigo carmine (0.1%) was used during the second colonoscopic examination, and any additional visible abnormalities were biopsied. Results: Median extubation times for the first and second colonoscopies were 11 and 10 minutes, respectively. The non-targeted biopsy protocol detected no dysplasia in 2904 biopsies. Forty three mucosal abnormalities (20 patients) were detected during the pre-dye spray colonoscopy of which two (two patients) were dysplastic: both were considered to be dysplasia associated lesions/masses. A total of 114 additional abnormalities (55 patients) were detected following dye spraying, of which seven (five patients) were dysplastic: all were considered to be adenomas. There was a strong trend towards statistically increased dysplasia detection following dye spraying (p = 0.06, paired exact test). The targeted biopsy protocol detected dysplasia in significantly more patients than the non-targeted protocol (p = 0.02, paired exact test). Conclusions: No dysplasia was detected in 2904 non-targeted biopsies. In comparison, a targeted biopsy protocol with pancolonic chromoendoscopy required fewer biopsies (157) yet detected nine dysplastic lesions, seven of which were only visible after indigo carmine application. Careful mucosal examination aided by pancolonic chromoendoscopy and targeted biopsies of suspicious lesions may be a more effective surveillance methodology than taking multiple non-targeted biopsies.

Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis

BACKGROUND/AIMS Cancer surveillance in patients with ulcerative colitis is of unproven benefit. This study assesses the efficacy and analyzes factors limiting the success of a surveillance program during a 21-year period in 332 patients with ulcerative colitis to the hepatic flexure and disease duration exceeding 10 years. METHODS Clinical assessment and sigmoidoscopy with biopsy was undertaken yearly. Colonoscopy and biopsy every 10 cm throughout the colon was performed every 2 years or more often if dysplasia was found. Only biopsy specimens reported as showing dysplasia were reviewed. RESULTS Surveillance contributed to detection of 11 symptomless carcinomas (8 Dukes A, 1 Dukes B, and 2 Dukes C), but 6 symptomatic tumors (4 Dukes C and 2 disseminated) presented 10-43 months after a negative colonoscopy. Dysplasia without carcinoma was confirmed in 12 symptomless patients who underwent colectomy. The 5-year predictive value of low-grade dysplasia for either cancer or high-grade dysplasia was 54% using current criteria. CONCLUSIONS Surveillance identified some patients at a curable stage of cancer or with dysplasia. Limiting factors were failure to include patients with presumed distal colitis, biennial colonoscopy, the number of biopsy specimens at each colonoscopy, and variation in histological identification and grading of dysplasia.

Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk

Background and aims: The risk of colorectal cancer is increased in ulcerative colitis (UC). Patients with UC have diverse colonoscopic appearances. Determining colonoscopic markers for cancer risk could allow patient risk stratification. Patients and methods: Following on from an earlier study which demonstrated a correlation between inflammation severity and neoplasia risk, a case control study was performed to look for colonoscopic markers of colorectal neoplasia risk in UC. Each patient with neoplasia detected between 1988 and 2002 was matched with two non-dysplastic colitic controls. Data were collected on post-inflammatory polyps, scarring, strictures, backwash ileitis, a shortened, tubular, or featureless colon, severe inflammation, and normal looking surveillance colonoscopies. Results: Cases (n = 68) and controls (n = 136) were well matched. On univariate analysis, cases were significantly more likely to have post-inflammatory polyps (odds ratio (OR) 2.14 (95% confidence interval 1.24–3.70)), strictures (OR 4.22; 1.08–15.54), shortened colons (OR 10.0; 1.17–85.6), tubular colons (OR 2.03; 1.00–4.08), or segments of severe inflammation (OR 3.38; 1.41–10.13), and less likely to have had a macroscopically normal looking colonoscopy (OR 0.40; 0.21–0.74). After multivariate analysis, a macroscopically normal looking colonoscopy (OR 0.38; 0.19–0.73), post-inflammatory polyps (2.29; 1.28–4.11), and strictures (4.62; 1.03–20.8) remained significant. The five year risk of colorectal cancer following a normal looking colonoscopy was no different from that of matched general population controls. Conclusions: Macroscopic colonoscopic features help predict neoplasia risk in UC. Features of previous/ongoing inflammation signify an increased risk. A macroscopically normal looking colonoscopy returns the cancer risk to that of the general population: it should be possible to reduce surveillance frequency to five years in this cohort.

Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine

Background—The “topical” effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage. Aim—To examine the possible mechanism of the “topical” phase of damage in the small intestine. Methods—Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode. Results—The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the “topical” phase of NSAID induced damage. Conclusion—Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the “topical” phase of damage induction.

Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat

The pathogenesis of NSAID‐induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation.

Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures

The clinicopathological features in 4 patients are described where nonsteroidal antiinflammatory drugs appear to have caused small intestinal strictures. Two patients had rheumatoid arthritis and 2 patients had osteoarthritis; all had received nonsteroidal antiinflammatory drugs for 1.5-30 yr. Three patients had an initial illness characterized by diarrhea, profound weight loss, and hypoalbuminemia. Intestinal radiology at this stage ranged from subtle changes to those of Crohns disease. Three patients underwent surgery. At operation the bland external appearance contrasted with the striking mucosal appearances of multiple concentric, circumferential, diaphragmatic strictures that caused luminal stenosis to a pinhole. These septa were due to submucosal fibrosis and the histopathological picture appears to represent a new nosological entity.

A New Prognostic Staging System for Rectal Cancer

Objective:To clarify the appropriateness of tumor “budding,” a quantifiable histologic variable, as 1 parameter in the construction of a new prognostic grading system for rectal cancer. Summary Background Data:Patient division according to an accurate prognostic prediction could enhance the effectiveness of postoperative adjuvant therapy and follow-up. Patients and Methods:Tumor budding was defined as an isolated cancer cell or a cluster composed of fewer than 5 cells in the invasive frontal region, and was divided into 2 grades based on its number within a microscopic field of ×250. We analyzed 2 discrete cohorts comprising 638 and 476 patients undergoing potentially curative surgery. Results:In the first cohort, high-grade budding (10 or more foci in a field) was observed in 30% of patients and was significantly associated with a lower 5-year survival rate (41%) than low-grade budding (84%). Similarly, in the second cohort, the 5-year survival rate was 43% in high-grade budding patients and 83% in low-grade budding patients. In both cohorts, multivariate analyses verified budding to be an independent prognosticator, together with nodal involvement and extramural spread. These 3 variables were given weighted scores, and the score range was divided to provide 5 prognostic groups (97%; 86%; 61%; 39%; 17% 5-year survival). The model was tested on the second cohort, and similar prognostic results were obtained. Conclusions:We propose that because of its relevance to prognosis and its reproducibility, budding is an excellent parameter for use in a grading system to provide a confident prediction of clinical outcome.

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen

BACKGROUND Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs. AIMS We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity. SUBJECTS Thirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments. METHODS Gastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase. RESULTS Nimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B2 (TXB2) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB2 by 29%. Production of prostaglandin E2 and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E2 formation in plasma, was markedly suppressed by both treatments. INTERPRETATION Nimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.

Endoscopic mucosal resection of 161 cases of large sessile or flat colorectal polyps

Objective. Large sessile or flat colorectal polyps, which are traditionally treated surgically, may be amenable to endoscopic mucosal resection (EMR), often using a piecemeal method. Appropriate selection of lesions and a careful technique may enhance the efficacy of EMR for polyps ≥20 mm in diameter without compromising safety. The aim of this study was to identify the factors that may be predictive of the risk of polyp recurrence. Material and methods. A retrospective analysis was conducted on the outcome of 161 polyps ≥20 mm in diameter, treated by piecemeal EMR at a single centre using the “lift and cut” technique. All records were reviewed for polyp size, site, morphology and histology. Polypectomy technique, patient follow-up, polyp recurrence and surgical interventions were also recorded. Results. Over an 8-year period, 161 colonic polyps measuring ≥20 mm were removed by EMR. Follow-up data were available for 149 cases (93%) with a mean polyp diameter of 32.5 mm; the total success rate of endoscopic polyp removal was 95.4%. The number of cases requiring 1, 2, 3, 4 and 6 attempts at EMR was 89 (60%), 36 (24%), 14 (9%), 2 (1.3%) and 1 (0.7%), respectively. Recurrence was significantly related to polyp size (p<0.001). There was no statistically significant relationship between site and recurrence. Seven patients (4.6%) underwent surgical intervention after EMR because of failed clearance. There were no post-EMR perforations and significant bleeding was reported in only two patients (1.7%). Conclusions. With careful attention to technique, piecemeal EMR is a safe option for the resection of most sessile and flat colorectal polyps ≥20 mm in size. A stricter follow-up may be required for larger lesions because of a higher risk of recurrence.