Robert D. Odze

Serrated Lesions of the Colorectum: Review and Recommendations From an Expert Panel

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid >5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.

AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and Economics Committee (Joel V. Brill, MD, Predictive Health, LLC) .

AGA Technical Review on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

This article has an accompanying continuing medical education activity on page e12. Upon completetion of reading this article, successful learners will be able to: 1. Understand the predisposing and protective factors for the development of colorectal neoplasia in patients with IBD 2. Understand the natural history of flat and raised dyspla-sia 3. Review the indications for colectomy in patients with flat and raised dysplasia 4. Review surveillance guidelines in patients with IBD 5. Understand the role of chromoendoscopy in detecting colorectal neoplasia in patients with IBD 6. Review the data on the use of chemopreventive agents to lower the risk of colorectal neoplasia in patients with IBD C olorectal carcinoma (CRC) complicating ulcerative co-litis (UC) was first recognized in 1925 by Crohn and Rosenberg, 1 but it was not until 1948 that Warren and Sommers reported CRC in a patient with Crohns disease (CD). 2 There has been much dispute regarding the magnitude of risk in both of these conditions. For many years it was believed that the risk in CD was insignificant. However, it is now recognized that the risk of developing CRC is equivalent, in both conditions given a similar extent and duration of disease. Inflammatory bowel disease (IBD) is relatively rare in the general population. Consequently Ͻ1% of all cases of CRC are attributable to IBD. However, it remains 1 of the 3 high-risk conditions predisposing to CRC, along with fa-milial adenomatous polyposis and Lynch Syndrome. Patients have up to a 1 in 5 chance of developing CRC after 30 years of disease. 3 Thus, it is an important issue for both the patient and the physician. The risk is not equivalent for all patients and depends on a number of factors. This necessitates an individualized and sensible approach to surveillance in patients with IBD. Patients with long-term UC have an increased risk of CRC, but the magnitude has been difficult to estimate. A number of factors have rendered the magnitude difficult to assess. First, a direct comparison between studies is difficult because of inconsistent methods used to calculate risk. Some studies reported the cumulative risk of developing CRC in a given population of patients with IBD, but unfortunately, many assume that all subjects have the same risk. Other studies have calculated the risk of CRC in IBD cohorts as a standardized incidence ratio (SIR) compared with a control population. These estimates can be adjusted for age …

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

The Peutz-Jegher Gene Product LKB1 Is a Mediator of p53-Dependent Cell Death

Here, we investigate the mechanism and function of LKB1, a Ser/Thr kinase mutated in Peutz-Jegher syndrome (PJS). We demonstrate that LKB1 physically associates with p53 and regulates specific p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in Peutz-Jegher patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. We propose that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.

Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis

BACKGROUND & AIMS Chronic ulcerative colitis (CUC)-associated adenoma-like DALMs (dysplasia-associated lesions or masses) pose a difficult clinical problem to both gastroenterologists and pathologists because they are difficult to distinguish endoscopically and pathologically from sporadic adenomas that develop coincidentally in patients with CUC. The aim of this study was to evaluate the outcome of CUC patients with an adenoma-like DALM treated conservatively and to compare the findings with CUC patients with a coincidental sporadic adenoma. METHODS Clinical, endoscopic, and pathological features and outcome of 24 CUC patients with an adenoma-like DALM were compared with those of 10 CUC patients with a coincidental sporadic adenoma and 49 non-CUC (control) patients with a sporadic adenoma. Patients were followed up for a mean of 42.4 and 41.2 months for the 2 CUC groups, respectively, and 37.0 months for the non-CUC controls by endoscopic surveillance. RESULTS Of the 24 CUC patients with adenoma-like DALMs (male/female ratio, 14/10; mean age, 61.5 years; mean duration of colitis, 10.4 years), 14 (58%) developed further adenoma-like DALMs within the follow-up interval. Only 1 patient (4%) developed an isolated focus of low-grade dysplasia, and none developed adenocarcinoma. Five of 10 (50%) CUC patients with sporadic adenomas developed further adenomas, and none of the patients in this group developed either dysplasia or adenocarcinoma. Of the 49 non-CUC control patients, 39% developed further adenomas. CONCLUSIONS CUC patients who develop an adenoma-like DALM that endoscopically and histologically resembles a sporadic adenoma, regardless of its location (either within or outside areas of documented colitis), may be treated with polypectomy and endoscopic surveillance because of its relatively benign course.

NSAIDs Modulate CDKN2A, TP53, and DNA Content Risk for Progression to Esophageal Adenocarcinoma

Background Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barretts esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE. Methods and Findings Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2–21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1–6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8–138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001). Conclusions A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.

Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis

BACKGROUND & AIMS A previously published study by our group suggested that adenoma-like dysplasia-associated lesions or masses (DALMs) in ulcerative colitis (UC) may be treated adequately by polypectomy and continued endoscopic surveillance. The length of follow-up evaluation in these patients averaged only 42 months. The purpose of this study was to evaluate the long-term outcome of our previously defined group of UC patients, all with adenoma-like DALMs, who were treated by polypectomy. METHODS The clinical, endoscopic, and pathologic outcome of 34 UC patients, 24 with an adenoma-like DALM, and 10 with a coincidental sporadic adenoma, 28 of whom were treated by polypectomy and continued endoscopic surveillance, and 6 by colonic resection, were compared with the outcome of 49 non-UC patients who were treated similarly for a sporadic adenoma. The mean length of follow-up evaluation averaged 82.1 months and 71.8 months for the 2 UC subgroups, respectively, and 60.4 months for the non-UC controls. RESULTS Overall, 20 of 34 UC patients (58.8%) developed at least one further adenoma-like DALM on follow-up evaluation. One patient had flat low-grade dysplasia present in the colon, which was resected within 6 months of the initial polypectomy, and another patient, with primary sclerosing cholangitis, developed adenocarcinoma 7.5 years after her initial polypectomy. There was no significant difference in the prevalence of polyp formation on follow-up evaluation between UC patients with an adenoma-like DALM (62.5%) and UC patients with a sporadic adenoma (50%), or between either of these 2 UC patient subgroups and the non-UC sporadic adenoma patient group (49%; P > 0.05). CONCLUSIONS UC patients who develop an adenoma-like DALM may be treated adequately by polypectomy with complete excision and continued endoscopic surveillance.

Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study

BACKGROUND Aspirin and other non-steroidal anti-inflammatory drugs (NSAID) probably decrease the risk of colorectal neoplasia; however their effect on development of oesophageal adenocarcinoma is less clear. We aimed to assess the role of NSAID in the development of oesophageal adenocarcinoma and precursor lesions in people with Barretts oesophagus--a metaplastic disorder that confers a high risk of oesophageal adenocarcinoma. METHODS We did a prospective study of the relation between duration, frequency, and recency of NSAID use and the risk of oesophageal adenocarcinoma, aneuploidy, and tetraploidy in a cohort of 350 people with Barretts oesophagus followed for 20,770 person-months. We used proportional-hazards regression to calculate hazard ratios (HR) adjusted for age, sex, cigarette use, and anthropometric measurements. FINDINGS Median follow-up was 65.5 months (range 3.1-106.9). Compared with never users, HR for oesophageal adenocarcinoma (n=37 cases) in current NSAID users was 0.32 (95% CI 0.14-0.76), and in former users was 0.70 (0.31-1.58). 5-year cumulative incidence of oesophageal adenocarcinoma was 14.3% (95% CI 9.3-21.6) for never users, 9.7% (4.5-20.5) for former users, and 6.6% (3.1-13.6) for current NSAID users. When changes in NSAID use during follow up were taken into account, the associations were strengthened: HR for oesophageal adenocarcinoma for current users at baseline or afterwards was 0.20 (95% CI 0.10-0.41) compared with never users. Compared with never users, current NSAID users (at baseline and follow-up) had less aneuploidy (n=35 cases; 0.25 [0.12-0.54]) and tetraploidy (n=45 cases; 0.44 [0.22-0.87]). INTERPRETATION NSAID use might be an effective chemopreventive strategy, reducing the risk of neoplastic progression in Barretts oesophagus.

Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett's esophagus.

A distinctive type of multilayered epithelium (ME) has been described at the neo-squamocolumnar junction and within columnar mucosa in patients with Barretts esophagus (BE). This epithelium has morphologic and ultrastructural features of both squamous and columnar epithelium. Multilayered epithelium may represent an early or intermediate stage of columnar metaplasia; therefore, we performed this study to determine the morphologic and biologic characteristics of this epithelium and to gain insight into its derivation. Esophageal mucosal biopsies containing ME from 17 patients with BE were evaluated morphologically, stained with a variety of mucin histochemical stains; and also immunostained with antibodies against cytokeratins (CK) 13 (squamous epithelium marker); 14 (basal squamous epithelium marker) 7, 8/18, 19, and 20 (columnar epithelium markers), MIB-1 (proliferation marker); villin (intestinal brush border protein); and TGF&agr;, EGFR, pS2, and hSP (enteric proliferation/differentiation regulatory peptides). The results were compared with normal esophageal squamous epithelium, normal gastric cardia epithelium, specialized-type intestinal epithelium (BE), and esophageal mucosal and submucosal gland duct epithelium. Multilayered epithelium expressed a pattern of mucin production (neutral mucin, sialomucin, and sulfomucin in 88%, 100%, and 71% of cases, respectively) and cytokeratin expression (CK 13 and 19 in the basal “squamoid” cells, CK 7, 8/18, 19, and 20 in the superficial “columnar” cells) similar to that of columnar epithelium in BE, and showed a high capacity for cellular proliferation (Ki-67-positive in 88% of cases) and differentiation (TGF&agr;, EGFR, pS2 and villin-positive in 100%, 100%, 93%, and 66% of cases, respectively). The mucosal gland duct epithelium showed a similar phenotypic pattern and, in one case, was seen to give rise to ME at the surface of the mucosa. These data provide evidence in support of the hypothesis that ME represents an early or intermediate stage in the development of esophageal columnar metaplasia (BE). The mucosal gland duct epithelium may contain progenitor cells that can give rise to ME.