I. C. Talbot

UPPER GASTROINTESTINAL CANCER IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSIS

102 patients with familial adenomatous polyposis underwent upper gastrointestinal endoscopy as a screening test for gastroduodenal adenomas. 100 had duodenal abnormalities (dysplasia in 94, and hyperplasia in 6), usually in the second and third parts of the duodenum (91%). The periampullary area was abnormal in 87 of 97 patients who had a biopsy specimen taken from this site (dysplasia 72, hyperplasia 13, and inflammation 2). By contrast, gastric dysplasia was found in only 6 patients. Classification of duodenal polyposis on a 5-grade scale (stages 0-IV), based on polyp number, size, histology, and severity of dysplasia, showed that 11 had stage IV disease: these patients are at greatest risk of malignant change and require close surveillance. The pattern of dysplasia observed in the upper gastrointestinal tract resembled the pattern of mucosal exposure to bile.

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.

Four-week open-label trial of metronidazole and ciprofloxacin for the treatment of recurrent or refractory pouchitis

Preliminary data suggest that short‐term antibiotic therapy with a single drug is effective for the treatment of patients with pouchitis. However, some patients are resistant to treatment.

Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis.

This study examined three features associated with colorectal carcinoma complicating ulcerative colitis: (a) the distribution of 157 cancers in 120 patients with ulcerative colitis treated at St Marks Hospital between 1947 and 1992; (b) the frequency at which dysplasia was found at a distance from the tumour in 50 total proctocolectomy specimens in which an average of 27 histology blocks were reviewed, and (c) the five year survival rate according to Dukess stage and participation in a surveillance programme. Of 157 carcinomas, 88 (56%) occurred in the rectosigmoid, 19 (12%) in the descending colon or splenic flexure, and 50 (32%) in the proximal colon. Among the 120 patients, the rectum or sigmoid colon contained cancer in 81 (67.5%). Dysplasia was detected in 41 of 50 reviewed proctocolectomy specimens (82%). Dysplasia distant to a malignancy occurred in 37 (74%); two were classified indefinite, probably positive, 19 were low grade, and 16 were high grade; in 18 specimens there was an elevated dysplastic lesion. Survival was related to the Dukess stage: about 90% of patients with Dukess A or B cancer were alive at five years. The five year survival of 16 patients in whom cancer developed during surveillance was 87% compared with 55% of 104 patients who did not participate in surveillance (p = 0.024).

Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome

Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz–Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27–73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype–phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

Early expression of cyclo‐oxygenase‐2 during sporadic colorectal carcinogenesis

Regular administration of non‐steroidal anti‐inflammatory drugs (NSAIDs) may reduce the incidence of colorectal cancer by targeting cyclo‐oxygenase‐2 (Cox‐2), a key enzyme in arachidonic acid metabolism. To evaluate the role of Cox‐2 in sporadic colorectal cancer development, Cox‐2 expression was investigated by immunohistochemistry in 85 adenomas, 53 carcinomas, 34 hyperplastic lesions and 104 samples of histologically normal mucosa adjacent to adenoma or carcinoma. In addition, Cox‐2 mRNA expression was assessed by reverse transcription‐polymerase chain reaction (RT‐PCR) in six adenomas and 14 carcinomas with paired grossly normal mucosa. Immunohistochemistry for the proliferation‐associated antigen Ki‐67 and in situ end labelling for demonstrating apoptotic bodies were also used to analyse the associations between Cox‐2 expression and proliferation and apoptosis. Cox‐2 protein expression was increased in 76/85 (89·4 per cent) adenomas and 44/53 (83·0 per cent) carcinomas compared with normal mucosa. Cox‐2 protein expression was unrelated either to the degree of dysplasia or to the size of the adenomas (p > 0·50, p > 0·10, respectively) or to differentiation, Dukes stage or lymph node metastasis of carcinomas (all p > 0·50). Interestingly, 20/34 (58·8 per cent) hyperplastic lesions adjacent to adenomas or carcinomas displayed expression higher than in normal mucosa (18·3 per cent) (p < 0·0001) but lower than in adenomas or carcinomas (p < 10−5, p < 0·001, respectively). There were no correlations between Cox‐2 protein expression and proliferative or apoptotic index in either adenomas or carcinomas (all p > 0·25). Cox‐2 mRNA expression was significantly increased in adenomas and carcinomas compared with normal mucosa (p < 0·005, p < 0·001, respectively). There were no differences between adenomas and carcinomas in either protein or mRNA levels (p > 0·25, p > 0·90, respectively). These data indicate that enhanced expression of Cox‐2 occurs early during colorectal carcinogenesis and may contribute to tumour formation. Copyright

Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients.

Multiple gastric and duodenal biopsy specimens from 102 asymptomatic patients with familial adenomatous polyposis, taken during a prospective endoscopic screening programme were examined. One hundred patients had microscopic gastroduodenal pathology, often in the absence of macroscopic lesions. Adenomas were found in 94 patients in the duodenum, in the second and third parts. Hyperplasia of villous and crypt epithelium was also seen, sometimes in the absence of adenomas: this may be a precursor of neoplastic change. In the stomach fundic gland polyps were the commonest abnormality, seen microscopically in 44 patients. Chronic antral gastritis was common in patients without fundic polyps. Gastric adenomas were present in six patients, all of whom also had duodenal adenomas. If duodenal adenomas in familial adenomatous polyposis have a similar malignant potential to those in the colorectum sequential endoscopy and biopsy are necessary to detect cancer in these patients.

Evidence for adenoma-carcinoma sequence in the duodenum of patients with familial adenomatous polyposis. The Leeds Castle Polyposis Group (Upper Gastrointestinal Committee).

AIMS--To explore the association between duodenal adenoma and carcinoma in patients with familial adenomatous polyposis (FAP). METHODS--A multicentre survey of 1262 patients with FAP yielded 47 cases of duodenal cancer. The association between adenoma and cancer was assessed in these cases. RESULTS--Adenomatous tissue was found within duodenal cancer in 29 of 44 (66%) patients with FAP and in mucosa adjacent to duodenal cancer in 31 of 42 (73%) such patients. Adenomas were found as a component of, or adjacent to, duodenal cancer in 38 of 45 (84%) patients. CONCLUSIONS--These observations support the existence of the adenomacarcinoma sequence in the duodenum of patients with FAP. Factors associated with malignant change included villous histology, moderate or severe dysplasia, and the presence of stage IV duodenal polyposis.