The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression

OBJECTIVE: The reported risk of progression from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or carcinoma (CA) in Barrett's esophagus varies. However, the validity of a diagnosis of LGD may be questioned because of interobserver variability. METHODS: A search of the Cleveland Clinic Foundation surgical pathology files between 1986 and 1997 yielded biopsy specimens from 43 patients with Barrett's esophagus diagnosed and coded as LGD. Patients with concurrent or prior diagnoses of HGD or carcinoma were excluded. The LGD cases were randomized and blindly reviewed by three gastrointestinal (GI) pathologists along with cases originally diagnosed as Barrett's esophagus without dysplasia (ND; n = 28), indefinite for dysplasia (IND; n = 14), or HGD (n = 15). Each pathologist classified every biopsy specimen as ND, IND, LGD, or HGD, and interobserver agreements were determined by kappa statistics (K). Follow-up data were available on 25 patients originally diagnosed with LGD. Progression was defined as a subsequent diagnosis of HGD or CA on esophageal biopsy or resection specimens. RESULTS: Agreement between two GI pathologists for a diagnosis of LGD was fair (K = 0.28) and poor (K = 0.21 and -0.04). Individual GI pathologists agreed with the original diagnosis of LGD in 70%, 56%, and 16% of cases. The 25 patients with follow-up included 21 men and four women (mean age, 67 yr) with a mean follow-up of 26 months (range: 2-84 months). Seven patients (28%) with follow-up developed HGD (five patients) or CA (two patients), 2-43 months (median: 11 months) after a diagnosis of LGD. The individual GI pathologists' diagnosis did not correlate with progression. However, when at least two GI pathologists agreed on LGD, there was a significant association with progression (seven of 17 patients, 41%, p = 0.04). When all three GI pathologists agreed on a diagnosis of LGD, four of five patients progressed (p = 0.012). In contrast, of the eight patients with follow-up and no agreement among GI pathologists for a diagnosis of LGD, none progressed. CONCLUSIONS: A high degree of interobserver variability is seen in the histological diagnosis of Barrett's esophagus-related LGD. Although the number of observations is low, a consensus diagnosis of LGD among GI pathologists suggests an increased risk of progression from LGD to HGD or carcinoma.     

p53 expression in low grade dysplasia in Barrett's esophagus: correlation with interobserver agreement and disease progression

OBJECTIVES: The frequency of progression from low grade dysplasia (LGD) to high grade dysplasia/carcinoma (HGD/ CA) in Barrett's esophagus (BE) varies among studies. Current assessment is made more difficult because of pathologists' interobserver variability in diagnosing LGD. We recently conducted an interobserver study on LGD and reported a positive correlation between the extent of agreement among GI pathologists and progression of LGD. In the current study, we analyzed the immunohistochemical staining for p53 in patients diagnosed with LGD with known clinical outcome and interobserver agreement data. METHODS: Fixed, paraffin-embedded endoscopic biopsy specimens from 16 patients diagnosed with LGD in BE were immunostained for p53 (DO-7, Dako, Carpinteria, CA). Hematoxylin and eosin-stained and immunostained sections were examined in tandem to determine whether the LGD areas in question stained for p53. The p53 immunoreactivity was correlated with clinical progression and with the interobserver agreement among three GI pathologists. RESULTS: The overall mean follow-up was 23 months (range 2-84 months). LGD areas in seven of eight patients (88%) who progressed to HGD/CA stained positively for p53 compared to only two of eight nonprogressors (25%). A correlation with clinical progression was seen for p53 positivity (p = 0.017; log-rank test), and for either p53 positivity or complete agreement among three GI pathologists on LGD diagnosis (p = 0.014; log-rank test). The p53 staining demonstrated 88% sensitivity and 75% specificity for progression of LGD to HGD/CA. Adding complete interobserver agreement on LGD among three experienced GI pathologists to p53 positivity resulted in improved sensitivity with no change in specificity (100% and 75%, respectively). CONCLUSIONS: In conjunction with histological evaluation by GI pathologists for a diagnosis of LGD, immunohistochemical staining for p53 can be used as an adjunctive test, as it correlated with progression to HGD/CA in this series.     

Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in Barrett's esophagus

OBJECTIVES: Previous studies that evaluated extent of high-grade dysplasia (HGD) as a risk factor for esophageal adenocarcinoma (EA) in Barrett's esophagus (BE) were conflicting, and no prior study has evaluated extent of low-grade dysplasia (LGD) as a risk factor. The aim of this discovery study was to evaluate the hypothesis that extent of LGD and HGD are risk factors for progression to EA. METHODS: We evaluated baseline biopsies from 77 BE patients with dysplasia including 44 who progressed to EA and 33 who did not progress during follow-up. The total numbers of LGD and HGD crypts were determined separately by counting all crypts and the extent of LGD, HGD, and total dysplasia were correlated with EA outcome. RESULTS: Thirty-one and 46 patients had a maximum diagnosis of LGD and HGD, respectively. When the crypts were stratified by dysplasia grade, the mean number of LGD crypts per patient was borderline higher in progressors (93.9) compared with nonprogressors (41.2, P= 0.07), and the mean proportion of LGD crypts per patient was significantly higher in progressors (46.4%vs 26.0%, P= 0.037). Neither the mean number of HGD crypts per patient (P= 0.14) nor the mean proportion of HGD crypts per patient (P= 0.20) was significantly associated with EA outcome. CONCLUSIONS: The extent of LGD is a significant risk factor for the development of EA in BE in this study. Although the presence of HGD is significantly associated with a greater relative risk for development of EA, the extent of HGD was not an independent risk factor for progression.     

Management of low and high-grade dysplasia in inflammatory bowel disease: the gastroenterologists' perspective and current practice in the United Kingdom

BACKGROUND: Colonic dysplasia is a precursor to colorectal cancer (CRC) in inflammatory bowel disease (IBD). There is a risk of progression of both low-grade dysplasia (LGD) and high-grade dysplasia (HGD) to CRC over 5 years. The current British Society of Gastroenterology guidelines advocate colectomy when possible or at least colonoscopic surveillance every 6 months. AIM: To obtain an overview of the gastroenterologists' perspective on various aspects of colonic dysplasia in IBD and to understand current management practice in the UK. METHODS: A national postal survey of 551 gastroenterologists listed in the British Society of Gastroenterology Handbook 2003. RESULTS: Some 56% of questionnaires were returned; 255 out of 551 completed questionnaires were included in the final analysis. A total of 70% considered LGD to be premalignant, whereas all considered HGD to be premalignant. Only 13% offered routine colectomy for LGD compared with 84% for HGD. More than a third felt that flat LGD might not have concurrent CRC, of which 95% performed surveillance colonoscopies in this group. A small proportion of the remaining gastroenterologists treated flat LGD surgically (13%), whereas 85% considered that LGD with dysplasia-associated lesion or mass (DALM) constituted a high risk of concurrent CRC, but only 52.5% offered total colectomy to this group. There was a wide variation in the frequency of surveillance for LGD in flat mucosa and DALM. A majority agreed that LGD progressed to HGD (82%) and CRC (75%). However, their perception of the risk of progression to either HGD or CRC over 5 years varied widely. All agreed that HGD may have coexistent CRC, and 98% thought it progressed to CRC. Patients were more likely to be treated with colectomy for flat HGD (77%) and HGD in the presence DALM (86%); 38% of gastroenterologists felt that over 30% of patients have coexistent CRC in HGD, and 10% continued to manage them conservatively. CONCLUSION: There are wide variations in the perceptions and management of LGD in IBD in the UK compared with HGD, in which there seems to be more uniform agreement. The need for more research in this area and a national agreement on management is paramount. Until this is reached gastroenterologists will remain open to criticism and litigation.     

Natural history of low grade dysplasia in patients with primary sclerosing cholangitis and ulcerative colitis

Background and AimPatients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) are at increased risk of colon cancer. The aim of this study was to determine the natural history of LGD and its progression to high grade dysplasia (HGD)/colorectal cancer (CRC) in PSC–UC patients.MethodsTen PSC–UC patients with LGD who underwent surveillance colonoscopy from 1996 to 2011 were evaluated. Raised dysplasia was defined as a discrete raised lesion located in an area involved by either quiescent or active colitis that was endoscopically resected, while flat dysplasia was defined as the absence of documentation of a raised lesion.ResultsOf the 10 patients with LGD, 3 (30%) progressed to raised HGD over a mean follow-up of 13 ± 11 months. Three of 10 patients had initial raised LGD while 7 had flat LGD. The location of HGD was in the proximal colon in all 3 patients. However all 3 patients who progressed to HGD had initial dysplasia located in the distal colon and had flat morphology. The incidence rate for detection of HGD/CRC was 9.4 cases per 100 person years at risk. Patients with LGD with flat morphology had an incidence rate of 17.8 cases per 100 person years at risk. HGD occurred more frequently within the first year of initial detection of LGD (23.5 per 100 patient years of follow-up).ConclusionsOne-third of patients with LGD progressed to HGD/CRC in PSC–UC. Most patients progress within the first year of diagnosis of LGD supporting early colectomy in PSC–UC patients with LGD.     

p53 protein overexpression in low grade dysplasia (LGD) in Barrett's esophagus: immunohistochemical marker predictive of progression

OBJECTIVES: The presence of low grade dysplasia (LGD) within Barrett's esophagus (BE) has a multitude of ramifications. Identification of markers that could risk stratify LGD would be of great clinical benefit. We aimed to prospectively evaluate the prognosis of the immunohistochemical overexpression of p53 protein in BE colocalized to LGD. METHODS: Consecutive BE patients in whom LGD was found had a repeat esophagogastroduodenoscopy within 8-12 wk per an ongoing prospective study. At each esophagogastroduodenoscopy, a therapeutic scope was used in conjunction with the Seattle Biopsy Protocol. Patients were observed until development of multifocal high grade dysplasia (mHGD), presence of an HGD dysplasia-associated lesion or mass (DALM) lesion, or frank adenocarcinoma. p53 protein overexpression was determined by computerized immunoquantitation using image analysis software on step serial-sectioned specimens of BE segment(s) harboring LGD. Kaplan-Meier survival curves were made on the ability of p53 staining colocalized to areas of LGD to predict progression to mHGD, HGD DALM, or cancer during prospective follow-up. RESULTS: Forty-eight BE patients with LGD were observed for a mean of 41.2+/-22.5 months. During this period, five of 48 patients progressed to mHGD with a focus in which intramucosal cancer could not be excluded (one), mHGD/DALM with one or more foci in which intramucosal cancer could not be excluded (two), cancer (one), or mHGD (one). Twelve had persistent LGD and 31 had regressed to no dysplasia. p53 staining was positive and colocalized to areas of LGD in 4/31 of patients that regressed, 3/12 that persisted, and 3/5 that progressed. Kaplan-Meier curves differed significantly between p53 positive and negative patients for outcome defined as progression of LGD. CONCLUSIONS: p53 colocalization with LGD at index LGD diagnosis is a risk factor for progression of LGD. This can potentially be used to risk stratify BE LGD patients in terms of surveillance intervals or enrollment into secondary prevention studies.     

Progression from low-grade dysplasia to malignancy in patients with Barrett's esophagus diagnosed by two or more pathologists

AIM To evaluate annual incidence of low grade dysplasia(LGD) progression to high grade dysplasia(HGD) and/or esophageal adenocarcinoma(EAC) when diagnosis was made by two or more expert pathologists.METHODS Studies evaluating the progression of LGD to HGD or EAC were included. The diagnosis of LGD must be made by consensus of two or more expert gastrointestinal pathologists. Articles were searched in Medline, Pubmed, and Embase. Pooled proportions were calculated using fixed and random effects model. Heterogeneity among studies was assessed using the I2 statistic. RESULTS Initial search identified 721 reference articles, of which 53 were selected and reviewed. Twelve studies(n = 971) that met the inclusion criteria were included in this analysis. Among the total original LGD diagnoses in the included studies, only 37.49% reached the consensus LGD diagnosis after review by two or more expert pathologists. Total follow up period was 1532 patient-years. In the pooled consensus LGD patients, the annual incidence rate(AIR) of progression to HGD and or EAC was 10.35%(95%CI: 7.56-13.13) and progression to EAC was 5.18%(95%CI: 3.43-6.92). Among the patients down staged from original LGD diagnosis to No-dysplasia Barrett's esophagus, the AIR of progression to HGD and EAC was 0.65%(95%CI: 0.49-0.80). Among the patients down staged to Indefinite for dysplasia, the AIR of progression to HGD and EAC was 1.42%(95%CI: 1.19-1.65). In patients with consensus HGD diagnosis, the AIR of progression to EAC was 28.63%(95%CI: 13.98-43.27). CONCLUSION When LGD is diagnosed by consensus agreement of two or more expert pathologists, its progression towards malignancy seems to be at least three times the current estimates, however it could be up to 20 times the current estimates. Biopsies of all Barrett's esophagus patients with LGD should be reviewed by two expert gastroenterology pathologists. Follow-up strict surveillance programs should be in place for these patients.     

Role of chronic atrophic gastritis of the body-fundus and achlorhydria in the development of epithelial dysplasia and gastric carcinoma

BACKGROUND/AIM: Chronic atrophic gastritis of the body-fundus with hypo-achlorhydria has been long since considered the precursor of gastric cancer (GC). A study has been made about the histological pattern of the body-fundic mucosa (oxyntic area) in course of preneoplastic lesions (epithelial dysplasia), associated or progressed to gastric cancer, in order to evaluate the real association with chronic atrophic gastritis and, therefore, with a reduced acid secretion. METHODOLOGY: The study of the histological condition of the body-fundic mucosa and of the acid secretion has been effected in 120 cases of epithelial dysplasia (ED) from January 1990 to November 1997. The casuistry is composed of 70 cases of low grade dysplasia (LGD) and 50 cases of high grade dysplasia (HGD). Gastric biopsy specimens were studied for dyspepsia: for each patient, at least 8 specimens were obtained from the lesion area and in surrounding areas. Besides, at least 4 biopsies have been performed in the opposite gastric region. ED diagnosis was effected according to well defined criteria. The histological study of gastric mucosa in gastritis was effected or revised in accordance with the updated Sydney system (Houston). Stimulated acid secretion was expressed as Maximal Acid Output (MAO), which is the amount of HCl produced in one hour, following stimulation with pentagastrin (6 micro-g/kg). The clinical outcome subdivision of ED was made using the criteria of Rugge et al. (12). RESULTS: HGD significantly associates with GC in comparison with LGD. The histological evaluation of the oxyntic area shows severe chronic atrophic gastritis (SCAG) in a low percentage of cases (15/120: 12.5%): LGD 9/70: 12.85% ; HGD 6/50: 12%. Complete achlorhydria has been noted in 5 cases of LGD and in 1 case of HGD only. In case of GC (43 subjects) SCAG has been evidenced in 10 cases and complete achlorhydria in 5 cases. CONCLUSIONS: From the data of the present experience emerges that the presence of SCAG of the oxyntic area in course of ED or early GC is limited to a low percentage of cases. Such concepts induce to modify some indications related to the endoscopic surveillance and, in accordance with the American Society of Gastrointestinal Endoscopy we are stating that there are no sufficient data to support subsequent endoscopic surveillance for the subjects with atrophic gastritis.     

Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis patients with extensive colitis under colonoscopic surveillance

BackgroundThe management of low-grade dysplasia (LGD) in ulcerative colitis (UC) patients remains unclear.AimThe aim of our study was to study the risk of progression of LGD to advanced neoplasia (AN), defined as high-grade dysplasia (HGD) or colorectal cancer (CRC) for UC patients undergoing surveillance based on location and morphology of LGD.Methods997 UC patients underwent 3152 surveillance colonoscopies from 1998 to 2011. Kaplan–Meier estimates and incidence rates calculated.ResultsOf the 102 patients with LGD (65 raised and 37 flat), 5 (4.9%) patients progressed to AN (3 HGD and 2 CRC) after a median follow-up of 36 months (interquartile range 18–71 months). Initial location of dysplasia was in the proximal colon in 47, distal colon in 55 patients. Four of the 5 (80%) patients with AN had initial dysplasia in the distal colon. Distal colonic LGD had an incidence rate for AN of 2.1 cases per 100 person years at risk, while proximal LGD had an incidence of 0.5 cases per 100 person years. Flat LGD in the distal colon was more likely to progress to AN [hazard ratio = 3.6; 95% confidence interval, CI (1.3–10.6)]. Twenty of the 102 patients (15 flat and 5 raised) underwent colectomy: 2 (10%) had evidence of AN in colectomy (1 HGD and 1 CRC), 9 had LGD and remaining 9 did not have dysplasia.ConclusionsThe frequency of progression of LGD to AN is low. Flat dysplasia located in the distal colon is associated with a greater risk of progression to AN.     

Influence of body mass index on the prevalence and progression of dysplasia in Barrett’s esophagus: a retrospective analysis*

Objective: High body mass index (BMI) is a risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). Our aim was to determine if prevalence of dysplasia in BE varies by BMI and study the effect of BMI on progression to high-grade dysplasia (HGD) or EAC.

Materials and methods: This is a retrospective review of patients with endoscopic evidence of BE confirmed by presence of intestinal metaplasia on histology from January 2000 to December 2012 at Cleveland Clinic. Patient demographics, BMI and endoscopic findings such as length of BE, dysplasia in BE and size of hiatal hernia were reviewed. Dysplasia was classified as no dysplasia (NDBE), low-grade dysplasia (LGD), HGD and EAC.

Results: In this cohort of 1239 patients, average BMI was 29.8?±?6?kg/m². There were 228 (18.4%) in group with BMI <25, 236 (19%) in BMI group 25–27.4, 262 (21.1%) in BMI 27.5–29.9, 303 (24.5%) in BMI 30–34.9, 126 (10.2%) in BMI 35–39.9 and 86 (6.8%) in BMI ≥40. Lower BMI groups had lower prevalence of dysplasia while higher BMI groups had higher prevalence of dysplasia (p?=?0.002). During mean follow up of 31.6?±?26 months, there were 14 cases of HGD/EAC in NDBE group and 29 cases of HGD/EAC in LGD group. BMI or BMI change was not associated with progression to HGD/EAC in NDBE.

Conclusions: High BMI was associated with higher prevalence of dysplasia in BE. But once in a surveillance program, higher BMI is not associated with progression of dysplasia in NDBE.     

Cyclooxygenase-2 expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence

OBJECTIVE: Increased expression of the inducible cyclooxygenase 2 (COX-2) enzyme has been detected in esophageal and colonic adenocarcinoma, and intake of aspirin and non-steroidal anti-inflammatory drugs, known COX-2 inhibitors, have been associated with reduced tumor formation. Elevated COX-2 mRNA but variable protein expression has been demonstrated in Barrett's epithelium, and we have, therefore, sought to evaluate the expression of COX-2 protein throughout the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. METHODS: Paraffin-embedded esophageal biopsies from 56 different patients with Barrett's esophagus were analyzed for COX-2 expression by immunohistochemistry. Twenty contained nondysplastic intestinal and gastric metaplasia, 12 demonstrated low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 12 contained invasive adenocarcinoma. RESULTS: Epithelial expression of COX-2 protein was detected in 75% (15/20) of benign cases, 83% (10/12) of cases with LGD, and 100% of cases with HGD or adenocarcinoma. Using a semiquantitative analysis, median staining scores for the groups were 2, 3, 14, and 13, respectively (scale 0-16), with the expression being significantly higher in the HGD and cancer groups compared to benign and LGD groups (p < 0.001). CONCLUSIONS: This study demonstrates clear COX-2 expression in the epithelial cells in Barrett's metaplasia, confirms elevated expression in adenocarcinoma, and shows that the elevation in expression occurs in the progression from LGD to HGD.     

Risk of progression of Barrett's esophagus in patients with cirrhosis

AIM To study Barrett's esophagus(BE) in cirrhosis and assess progression to esophageal adenocarcinoma(EAC) compared to non-cirrhotic BE controls.METHODS Cirrhotic patients who were found to have endoscopic evidence of BE confirmed by the presence of intestinal metaplasia on histology from 1/1/2000 to 12/1/2015 at Cleveland Clinic were included. Cirrhotic patients were matched 1:4 to BE controls without cirrhosis. Age, gender, race, BE length, hiatal hernia size, Child-Pugh(CP) class and histological findings were recorded. Cases and controls without high-grade dysplasia(HGD)/EAC and who had follow-up endoscopies were studied for incidence of dysplasia/EAC and to assess progression rates. Univariable conditional logistic regression was done to assess differences in baseline characteristics between the two groups. RESULTS A total of 57 patients with cirrhosis and BE were matched with 228 controls(BE without cirrhosis). The prevalence of dysplasia in cirrhosis and controls weresimilar with 8.8% vs 12% with low grade dysplasia(LGD) and 12.3 % vs 19.7% with HGD or EAC(P = 0.1). In the incidence cohort of 44 patients with median follow-up time of 2.7 years [interquartile range 1.0, 4.8], there were 7 cases of LGD, 2 cases of HGD, and 2 cases of EAC. There were no differences in incidence rates of HGD/EAC in nondysplastic BE between cirrhotic cases and noncirrhotic controls(1.4 vs 1.1 per 100 person-years, P = 0.8). In LGD, cirrhotic patients were found to have higher rates of progression to HGD/EAC compared to control group though this did not reach statistical significance(13.7 vs 8.1 per 100 personyears, P = 0.51). A significant association was found between a higher CP class and neoplastic progression of BE in cirrhotic patients(HR =7.9, 95%CI: 2.0-30.9, P = 0.003). CONCLUSION Cirrhotics with worsening liver function are at increased risk of progression of BE. More frequent endoscopic surveillance might be warranted in such patients.     

Clinical Outcomes of Endoscopic Resection for Low-Grade Dysplasia and High-Grade Dysplasia on Gastric Pretreatment Biopsy: Korea ESD Study Group

Background/AimsSome cases of gastric low-grade dysplasia (LGD) and high-grade dysplasia (HGD) on forceps biopsy (FB) are diagnosed as gastric cancer (GC) after endoscopic resection (ER). This study aims to evaluate the clinical outcomes of ER for gastric LGD and HGD on pretreatment FB and to identify the factors that predict pathologic upstaging to GC.MethodsPatients who underwent ER for LGD and HGD on pretreatment FB from March 2005 to February 2018 in 14 hospitals in South Korea were enrolled, and the patients’ medical records were reviewed retrospectively.ResultsThis study included 2,150 cases of LGD and 1,534 cases of HGD diagnosed by pretreatment FB. In total, 589 of 2,150 LGDs (27.4%) were diagnosed as GC after ER. Helicobacter pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration significantly predicted GC. A total of 1,115 out of 1,534 HGDs (72.7%) were diagnosed with GC after ER. Previous history of GC, H. pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration were significantly associated with GC. As the number of risk factors predicting GC increased in both LGD and HGD on pretreatment FB, the rate of upstaging to GC after ER increased.ConclusionsA substantial proportion of LGDs and HGDs on pretreatment FB were diagnosed as GC after ER. Accurate ER procedures such as endoscopic submucosal dissection should be recommended in cases of LGD and HGD with factors predicting pathologic upstaging to GC.     

Are ulcers a marker for invasive carcinoma in barrett''s esophagus? data from a diagnostic variability study with clinical follow-up

OBJECTIVES: We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers. METHODS: A group of pathologist participants were asked to contribute patients' initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients. RESULTS: There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients. CONCLUSION: If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.     

Safety and efficacy of endoscopic spray cryotherapy for Barrett's dysplasia: results of the National Cryospray Registry

Retrospective series have shown the efficacy of endoscopic spray cryotherapy in eradicating high‐grade dysplasia (HGD) in Barrett's esophagus (BE); however, prospective data are lacking, and efficacy for low‐grade dysplasia (LGD) is unclear. The aim of this study was to assess the efficacy and safety of spray cryotherapy in patients with LGD or HGD. A multicenter, prospective open‐label registry enrolled patients with dysplastic BE. Spray cryotherapy was performed every 2–3 months until there was no endoscopic evidence of BE and no histological evidence of dysplasia, followed by surveillance endoscopies up to 2 years. Primary outcome measures were complete eradication of dysplasia (CE‐D) and complete eradication of all intestinal metaplasia (CE‐IM). Ninety‐six subjects with Barrett's dysplasia (67% HGD; 65% long‐segment BE; mean length 4.5 cm) underwent 321 treatments (mean 3.3 per subject). Mean age was 67 years, 83% were male. Eighty patients (83%) completed treatment with follow‐up endoscopy (mean duration 21 months). In patients with LGD, rate of CE‐D was 91% (21/23) and rate of CE‐IM was 61% (14/23). In HGD, CE‐D rate was 81% (46/57) and CE‐IM was 65% (37/57). In patients with short‐segment BE (SSBE) with any dysplasia, CE‐D was achieved in 97% (30/31) and CE‐IM in 77% (24/31). There were no esophageal perforations or related deaths. One subject developed a stricture, which did not require dilation. One patient was hospitalized for bleeding in the setting of non‐steroidal anti‐inflammatory drug use. In the largest prospective cohort to date, data suggest endoscopic spray cryotherapy is a safe and effective modality for eradication of BE with LGD or HGD, particularly with SSBE.     

Chromosome 4 hyperploidy represents an early genetic aberration in premalignant Barrett's oesophagus

BACKGROUND AND AIMS: Characterisation of the underlying molecular mechanisms that promote Barrett's progression may ultimately lead to identification of potential predictive genetic markers that classify patients' malignant risk. In an attempt to understand these causative pathways, fluorescence in situ hybridisation (FISH) was used in this study to determine when specific genetic alterations arise during Barrett's associated neoplastic progression. METHODS: Endoscopic cytology brushings were obtained from 28 patients with Barrett's metaplasia, 28 with dysplasia (20 low grade dysplasia (LGD) and eight with high grade dysplasia (HGD)), and seven with adenocarcinoma, together with paired control brushings from regions of normal proximal squamous cell epithelium. The exfoliated epithelial cells were washed and deposited onto slides. Probes specific for the centromeres of chromosomes 4, 8, 20, and Y, and locus specific probes for the tumour suppressor genes p16, p53, and Rb were subsequently hybridised. RESULTS: Aneuploidy was found early in progression, with metaplastic tissues displaying increased copy numbers of chromosomes 4 and 8. Chromosome 4 hyperploidy was found in 89%, 90%, 88%, and 100% of metaplasias, LGD, HGD, adenocarcinomas, respectively, while chromosome 8 hyperploidy occurred in 71%, 75%, 100%, and 100% of patients with the respective staging. Loss of the p16 tumour suppressor gene also presented in metaplastic epithelium (7%) but most other genetic aberrations were only seen in HGD. CONCLUSIONS: Genetic instability arises well before dysplasia in Barrett's oesophagus, with chromosome 4 and 8 hyperploidy representing the earliest and most common alterations identified. As these aberrations are widespread at all the premalignant stages, there may be genes on chromosomes 4 and 8 that are involved in both the initiation and progression of Barrett's oesophagus.     

The Risk Factors for Discrepancy After Endoscopic Submucosal Dissection of Gastric Category 3 Lesion (Low Grade Dysplasia)

Background

Treatment with endoscopic submucosal dissection (ESD) for gastric category 3 lesion (low grade dysplasia, LGD) diagnosed by endoscopic forceps biopsy (EFB) is controversial.

Aims

The purpose of the present study was to validate the use of ESD for gastric LGD diagnosed by EFB and to evaluate predictable factors for pathologic upgrade diagnosis to category 4 (high grade dysplasia, HGD) or 5 (early gastric cancer, EGC) lesions.

Methods

Between November 2008 and October 2011, a retrospective analysis of a prospective database was conducted at a single tertiary referral center. A total of 218 ESD procedures were carried out for gastric LGD lesions identified by EFB. The under-diagnosis rate by EFB and the predictable factors for upgrade diagnosis to category 4 or 5 lesions were analyzed.

Results

Pathologic discrepancy between EFB and surgical resection was 20.1 % (44/218). Thirty eight lesions (17.4 %) were diagnosed HGD or EGC by ESD. Gastric HGD lesions were 14 cases (6.4 %) and EGC lesions were 24 cases (23 mucosal and 1 submucosal cancer) (11.0 %). Multivariate analysis revealed that lesion diameter more than 1 cm (OR 3.496 [95 % CI 1.375–8.849]), surface redness (OR 6.493 [95 % CI 2.557–16.666]) and nodular surface (OR 2.762 [95 % CI 1.237–6.172]) were significant risk factors.

Conclusions

Endoscopic resection can be recommended if a LGD lesion has risk factors such as a size of 1 cm or greater, surface redness or surface nodulariy. For lesions without the risk factors, follow-up endoscopy may be recommended.     

Low- and high-grade non-invasive gastric neoplasia (formerly dysplasia): cytological differentiation (gastro-entero-pancreatic antigens) in association with p53 pattern expression

BACKGROUND/AIMS: In order to better define the evolutive potentiality of non-invasive neoplasia (formerly dysplasia) a study of the cytological differentiation and of the behavior of p53 in relation to the clinical progress has been performed. METHODOLOGY: Gastro-entero-pancreatic antigens, p53 and Ki-67 expression were evaluated in 120 cases of epithelial gastric dysplasia: 70 cases of low-grade dysplasia (LGD) and 50 cases of high-grade dysplasia (HGD). For the cytological study four antigens were studied: two of them gastric (pepsinogen C, gastric foveolar M1), one enteric (CAR-5) and one pancreatic (DU-PAN-2). Routinely processed tissue sections of a colon carcinoma known to contain mutant p53 were used as positive controls for p53 immunohistochemistry. For Ki-67 immunohistochemistry, routinely processed tissue sections of normal lymph node and tonsil were used as staining controls. RESULTS: The study of the coexpression of the gastro-entero-pancreatic antigens showed how all cases of non-invasive neoplasia associated with or progressed to gastric carcinoma (GC) were characterized by entero-pancreatic markers and, in particular, in case of LGD p53 expression positivity was evidenced in 66.6% of cases. Ki-67 hyperproliferation is present in 100% of cases. CONCLUSIONS: The cytological study, only if confirmed by wider casuistries, could represent further information in order to better define the follow-up and the therapeutical decisions in case of non-invasive gastric neoplasia therefore, the immunophenotypic study in association with p53 could lead to more personalized therapeutical choices.     

Is Endoscopic Mucosal Resection a Sufficient Treatment for Low-Grade Gastric Epithelial Dysplasia?

Background/Aims

The rate of diagnosis of gastric adenoma has increased because esophagogastroduodenoscopy is being performed at an increasingly greater frequency. However, there are no treatment guidelines for low-grade dysplasia (LGD). To determine the appropriate treatment for LGD, we evaluated the risk factors associated with the categorical upgrade from LGD to high grade dysplasia (HGD)/early gastric cancer (EGC) and the risk factors for recurrence after endoscopic treatment.

Methods

We compared the complication rates, recurrence rates, and remnant lesions in 196 and 56 patients treated with endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR), respectively, by histologically confi rming low-grade gastric epithelial dysplasia.

Results

The en bloc resection rate was significantly lower in the EMR group (31.1%) compared with the ESD group (75.0%) (p<0.001). However, no significant difference was observed in the prevalence of remnant lesions or recurrence rate (p=0.911) of gastric adenoma. The progression of LGD to HGD or EGC caused an increase in the incidence of tumor lesions >1 cm with surface redness and depressions.

Conclusions

For the treatment of LGD, EMR resulted in a higher incidence of uncertain resection margins and a lower en bloc resection rate than ESD. However, there was no signifi cant difference in recurrence rate.     

Long-term follow-up of Barrett's high-grade dysplasia

OBJECTIVE: The management of Barrett's high-grade dysplasia (HGD) remains controversial. The aims of this study were to evaluate prospectively the outcome of unifocal HGD (uHGD) in patients with Barrett's esophagus, and to determine demographic and endoscopic features predictive of progression to multifocal HGD (mHGD) and/or adenocarcinoma. METHODS: Consecutive Barrett's patients in whom uHGD was found at initial endoscopy or during surveillance underwent intensification of medical treatment and repeat endoscopy. The study endpoint was progression to mHGD or adenocarcinoma or HGD in conjunction with a dysplasia-associated lesion or mass (DALM). HGD diagnosis was confirmed by a second, blinded pathologist. RESULTS: A total of 15 Barrett's patients with uHGD met inclusion criteria and have been prospectively followed for a mean +/- SD of 36.8 +/- 23.2 months. All were white and male, with a mean age +/- SD of 61.4 +/- 14.9 yr. Barrett's length varied from 1 to 13 cm (mean, +/- SD, 6.8 +/- 4 cm). Overall, eight (53.3%) uHGD progressed: four of 15 (26.7%) to frank cancer between 17 and 35 months of follow-up, two of 15 (13.3%) to mHGD with DALM in conjunction with one or more foci of possible intramucosal cancer after 12-91 months of follow-up, one of 15 (6.7%) to mHGD with a focus of possible intramucosal cancer after 14 months, and one of 15 (6.7%) to mHGD after 29 months. Seven of 15 (46.7%) uHGD have regressed, five to no dysplasia and two to LGD, over the course of follow-up ranging from 24 to 73 months (mean +/- SD, 43.3 +/- 19.9). All three patients with short-segment Barrett's esophagus with uHGD regressed. Fisher's exact test revealed that Barrett's length > or =3 cm and presence of hiatal hernia approached significance (p < 0.08) in predicting uHGD progression to mHGD/DALM/cancer. However, use of the log-rank test to account for differences in length of follow-up show no significance for hiatal hernia or Barrett's length. CONCLUSIONS: Barrett's uHGD has a high risk for progressing to mHGD or cancer. Justification of an observational approach to uHGD should be discouraged. Markers of uHGD progression, as well as regression, are needed.