Lori S. Lutzke

Endoscopic and Surgical Treatment of Mucosal (T1a) Esophageal Adenocarcinoma in Barrett's Esophagus

BACKGROUND & AIMS Endoscopic therapy is emerging as an alternative to surgical therapy in patients with mucosal (T1a) esophageal adenocarcinoma (EAC) given the low likelihood of lymph node metastases. Long-term outcomes of patients treated endoscopically and surgically for mucosal EAC are unknown. We compared long-term outcomes of patients with mucosal EAC treated endoscopically and surgically. METHODS Patients treated for mucosal EAC between 1998 and 2007 were included. Patients were divided into an endoscopically treated group (ENDO group) and a surgically treated group (SURG group). Vital status information was queried using an institutionally approved internet research and location service. Statistical analysis was performed using Kaplan-Meier curves and Cox proportional hazard ratios. RESULTS A total of 178 patients were included, of whom 132 (74%) were in the ENDO group and 46 (26%) were in the SURG group. The mean follow-up period was 64 months (standard error of the mean, 4.8 mo) in the SURG group and 43 months (standard error of the mean, 2.8 mo) in the ENDO group. Cumulative mortality in the ENDO group (17%) was comparable with the SURG group (20%) (P = .75). Overall survival also was comparable using the Kaplan-Meier method. Treatment modality was not a significant predictor of survival on multivariable analysis. Recurrent carcinoma was detected in 12% of patients in the ENDO group, all successfully re-treated without impact on overall survival. CONCLUSIONS Overall survival in patients with mucosal EAC when treated endoscopically appears to be comparable with that of patients treated surgically. Recurrent carcinoma occurs in a limited proportion of patients, but can be managed endoscopically.

Epidemiology and Natural History of Intestinal Metaplasia of the Gastroesophageal Junction and Barrett's Esophagus: A Population-Based Study

OBJECTIVES:Population-based data on the epidemiology and outcomes of subjects with intestinal metaplasia of the gastroesophageal junction (IMGEJ) and Barretts esophagus (BE) are limited. The objectives of this study were to (i) estimate the incidence of IMGEJ and BE diagnosed from clinically indicated endoscopy in Olmsted County, MN, over three decades (1976–2006) and prevalence as of 1 January 2007, (ii) compare baseline characteristics of subjects with IMGEJ and BE, and (iii) study the natural history and survival of both cohorts.METHODS:This was a population-based cohort study. The study setting was Olmsted County, MN. Patients with BE (columnar segment >1 cm with intestinal metaplasia) and IMGEJ (intestinal metaplasia in biopsies from the gastroesophageal junction) from 1976 to 2006 in Olmsted County, MN, were identified using Rochester Epidemiology Project resources. Demographic and clinical data were abstracted from medical records and pathology confirmed by gastrointestinal pathologists. The association of baseline characteristics with overall and progression-free survival was assessed using proportional hazards regression models. Outcome measures were baseline characteristics and overall survival of subjects with IMGEJ compared to those with BE.RESULTS:In all, 487 patients (401 with BE and 86 with IMGEJ) were identified and followed for a median interval of 7 (BE subjects) to 8 (IMGEJ subjects) years. Subjects with BE were older, heavier, reported reflux symptoms more often, and had higher prevalence of advanced neoplasia than those with IMGEJ. No patient with IMGEJ progressed to esophageal adenocarcinoma (EAC) in contrast to BE subjects who had a cumulative risk of progression of 7% at 10 years and increased risk of death from EAC (standardized mortality ratio 9.62). The overall survival of subjects with BE and IMGEJ did not differ from that expected in similar age- and sex-distributed white Minnesota populations.CONCLUSIONS:Subjects with IMGEJ appear to have distinct clinical characteristics and substantially lower cancer progression risk compared to those with BE.

Significance of Neoplastic Involvement of Margins Obtained by Endoscopic Mucosal Resection in Barrett's Esophagus

OBJECTIVES:Although EMR has been used for elimination of neoplasia in BE, the significance of positive carcinoma margins and depth of invasion on endoscopic resection pathology has not been assessed using a valid standard. The aim of this study was to assess the accuracy of tumor staging by EMR using esophagectomy as the standard.METHODS:Medical records of patients, who underwent endoscopic resection for esophageal carcinoma or high-grade dysplasia in BE followed by esophagectomy, were reviewed. Data were abstracted from a prospectively maintained EMR database. Endosonography and endoscopic resection were performed by a single experienced endoscopist. Two experienced GI pathologists interpreted all histological results. Standard statistical tests were used to compare continuous and categorical variables.RESULTS:Twenty-five patients were included in the study. Three patients had mucosal carcinoma and 16 had submucosal carcinoma following endoscopic resection. Surgical pathology staging was consistent with preoperative EMR staging in all patients. No patient with negative mucosal resection margins had residual tumor at the resection site at esophagectomy. In patients with submucosal carcinoma, 8 had residual carcinoma at the EMR site at surgery and 5 patients had metastatic lymphadenopathy.CONCLUSIONS:Tumor staging using EMR pathology is accurate when compared with surgical pathology following esophagectomy. Negative margins on EMR pathology correlate with absence of residual disease at the EMR site at esophagectomy. Submucosal carcinoma on EMR specimens was associated with a high prevalence of residual disease at surgery (50%) and metastatic lymphadenopathy (31%).

Utility of Biomarkers in Prediction of Response to Ablative Therapy in Barrett's Esophagus

BACKGROUND & AIMS Photodynamic therapy (PDT) has been shown to be effective in the treatment of high-grade dysplasia (HGD)/mucosal carcinoma in Barretts esophagus (BE). Substantial proportions of patients do not respond to PDT or progress to carcinoma despite PDT. The role of biomarkers in predicting response to PDT is unknown. We aimed to determine if biomarkers known to be associated with neoplasia in BE can predict loss of dysplasia in patients treated with ablative therapy for HGD/intramucosal cancer. METHODS Patients with BE and HGD/intramucosal cancer were studied prospectively from 2002 to 2006. Biomarkers were assessed using fluorescence in situ hybridization performed on cytology specimens, for region-specific and centromeric probes. Patients were treated with PDT using cylindric diffusing fibers (wavelength, 630 nm; energy, 200 J/cm fiber). Univariate and multiple variable logistic regression was performed to determine predictors of response to PDT. RESULTS A total of 126 consecutive patients (71 who underwent PDT and 55 patients who did not undergo PDT and were under surveillance, to adjust for the natural history of HGD), were included in this study. Fifty (40%) patients were responders (no dysplasia or carcinoma) at 3 months after PDT. On multiple variable analysis, P16 allelic loss (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.10-0.96) predicted decreased response to PDT. BE segment length (OR, 0.71; 95% CI, 0.59-0.85), and performance of PDT (OR, 7.17; 95% CI, 2.50-20.53) were other independent predictors of loss of dysplasia. CONCLUSIONS p16 loss detected by fluorescence in situ hybridization can help predict loss of dysplasia in patients with BE and HGD/mucosal cancer. Biomarkers may help in the selection of appropriate therapy for patients and improve treatment outcomes.

Depth of Submucosal Invasion Does Not Predict Lymph Node Metastasis and Survival of Patients With Esophageal Carcinoma

BACKGROUND & AIMS There is controversy over the outcomes of esophageal adenocarcinoma with superficial submucosal invasion. We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in patients with esophageal adenocarcinoma. METHODS Pathology reports of esophagectomy samples collected from 1997 to 2007 were reviewed. Specimens from patients with esophageal adenocarcinoma and submucosal invasion were reviewed and classified as superficial (upper 1 third, sm1) or deep (middle third, sm2 or deepest third, sm3) invasion. Outcomes studied were presence of metastatic lymphadenopathy and overall survival. Variables of interest were analyzed as factors that affect overall and cancer-free survival using Cox proportional hazards modeling. A multivariate model was constructed to establish independent associations with survival. RESULTS The study included 80 patients; 31 (39%) had sm1 carcinoma, 23 (29%) had sm2 carcinoma, and 26 (33%) had sm3 carcinoma. Superficial and deep submucosal invasion were associated with substantial rates of metastatic lymphadenopathy (12.9% and 20.4%, respectively). The mean follow-up time was 40.5 +/- 4 months and the mean overall unadjusted survival time was 53.8 +/- 4.1 months. Factors significantly associated with reduced survival time included the presence of metastatic lymph nodes (hazard ratio [HR], 2.89; confidence interval [CI], 1.13-6.88) and esophageal cancer recurrence (HR 6.39, CI 2.40-16.14), but not depth of submucosal invasion. CONCLUSIONS Patients with sm1 esophageal carcinoma have substantial rates of metastatic lymphadenopathy. Endoscopic treatment of superficial submucosal adenocarcinoma is not advised for patients that are candidates for surgery.

A comparison of conventional cytology, DNA ploidy analysis, and fluorescence in situ hybridization for the detection of dysplasia and adenocarcinoma in patients with Barrett's esophagus ☆ ☆☆

New detection methods with prognostic power are needed for early identification of dysplasia and esophageal adenocarcinoma (EA) in patients with Barretts esophagus (BE). This study assessed the relative sensitivity and specificity of conventional cytology, DNA ploidy analysis with digital image analysis (DIA), and fluorescence in situ hybridization (FISH) for the detection of dysplasia and adenocarcinoma in endoscopic brushing specimens from 92 patients undergoing endoscopic surveillance for BE. FISH used probes to 8q24 (C-MYC), 9p21 (P16), 17q12 (HER2), and 20q13. Four-quadrant biopsies taken every centimeter throughout visible Barretts mucosa were used as the gold standard. The sensitivity of cytology, DIA, and FISH for low-grade dysplasia was 5%, 5%, and 50%, respectively; for high-grade dysplasia (HGD), 32%, 45%, and 82%, respectively; and for EA, 45%, 45%, and 100%, respectively. FISH was more sensitive (P < .05) than cytology and DIA for low-grade dysplasia, HGD, and EA. The specificity of cytology, DIA, and FISH among patients (n = 14) with tissue showing only benign squamous mucosa was 93%, 86%, and 100% (P = .22), respectively. All patients with a polysomic FISH result had HGD and/or EA within 6 months (n = 33). There was a significant difference between FISH categories (negative, 9p21 loss, gain of a single locus, and polysomy) for progression to HGD/EA (P < .001). These findings suggest that FISH has high sensitivity for the detection of dysplasia and EA in BE patients, with the power to stratify patients by FISH abnormality for progression to HGD/EA. Additional studies are needed to further evaluate the clinical use of FISH.

Contribution of intraoperative enteroscopy in the management of obscure gastrointestinal bleeding

Obscure gastrointestinal bleeding remains a significant diagnostic challenge. Our aims were (1) to determine the efficacy of intraoperative enteroscopy (IOE) in identifying lesions responsible for obscure gastrointestinal bleeding and (2) to determine the outcome of patients after treatment of these lesions. We retrospectively reviewed all patients who underwent IOE for obscure gastrointestinal bleeding from 1992 to 1998. Patients were divided into those with overt and those with occult gastrointestinal bleeding. Follow-up was complete in 67 patients (96%), with a median of 32 months (range 1 to 91 months). Seventy patients (52 overt and 18 occult) underwent IOE after extensive preoperative evaluation. Median duration of bleeding was 12 months, requiring a median of 14 blood transfusions. Risk factors for bleeding were identified in 46 patients (61 %). A lesion was identified and treated in 52 patients (74%)—39 in the overt group and 13 in the occult group. Lesions identified were vascular (54%), ulcerations (31%), tumors (11%), and small bowel diverticula (4%). Overall, 35 patients (52%) were found to have one or more lesions at IOE that were treated surgically and had no further bleeding. IOE, through a mid-small bowel enterotomy, has low morbidity and is effective in that it identified a treatable lesion in 74% of patients, which led to cure of bleeding in 52%.

Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus

BACKGROUND The incidence and risk factors for recurrence of dysplasia after ablation of Barretts esophagus (BE) have not been well defined. OBJECTIVE To determine the rate and predictors of dysplasia/neoplasia recurrence after photodynamic therapy (PDT) in BE. SETTING Retrospective analysis of a prospective cohort of BE patients seen at a specialized BE unit. METHODS Patients underwent a standard protocol assessment with esophagogastroduodenoscopy and 4-quadrant biopsies every centimeter at 3-month intervals after ablation. Recurrence was defined as the appearance of any grade of dysplasia or neoplasia after 2 consecutive endoscopies without dysplasia. Entry histology, demographics, length of BE, presence and length of diaphragmatic hernia, EMR, stricture formation, nonsteroidal anti-inflammatory drug use, smoking, and the presence of nondysplastic BE or squamous epithelium were assessed for univariate associations. Time-to-recurrence analysis was done by using Cox proportional hazards regression. A multivariate model was constructed to establish independent associations with recurrence. RESULTS A total of 363 patients underwent PDT with or without EMR. Of these, 261 patients were included in the final analysis (44 lost to follow-up, 46 had residual dysplasia, and 12 had no dysplasia at baseline). Indication for ablation was low-grade dysplasia (53 patients, 20%), high-grade dysplasia (152 patients, 58%), and intramucosal cancer (56 patients, 21%). Median follow-up was 36 months (interquartile range 18-79 months). Recurrence occurred in 45 patients. Median time to recurrence was 17 months (interquartile range 8-45 months). Significant predictors of recurrence on the multivariate model were older age (hazard ratio [HR] 1.04, P=.029), presence of residual nondysplastic BE (HR 2.88, P=.012), and a history of smoking (HR 2.68, P=.048). LIMITATIONS Possibility of missing prevalent dysplasia despite aggressive surveillance. CONCLUSION Recurrence of dysplasia/neoplasia after PDT ablation is associated with advanced age, smoking, and residual BE.

Safety of prior endoscopic mucosal resection in patients receiving radiofrequency ablation of Barrett's esophagus.

BACKGROUND & AIMS Radiofrequency ablation (RFA) is safe and effective treatment for flat dysplasia associated with Barretts esophagus (BE). However, there are limited data on the safety of RFA in patients who had prior endoscopic mucosal resection (EMR), which might increase the risk of complications. We compared complications and histologic outcomes between patients who had EMR before RFA and those who received only RFA. METHODS We performed a retrospective analysis of data collected from patients treated for BE, associated with dysplasia or intramucosal cancer, at the Mayo Clinic in Rochester, Minnesota, from 1998-2009. Patients were divided into groups that had RFA after EMR (group 1, n = 44) or only RFA (group 2, n = 46). We compared the incidence of complications (strictures, bleeding, and esophageal perforation) and histologic features (complete resolution of dysplasia and complete resolution of intestinal metaplasia [CR-IM]) between groups. Logistic regression analysis was performed to assess predictors of stricture formation. RESULTS Stricture rates were 14% in group 1 and 9% in group 2 (odds ratio, 1.53; 95% confidence interval [CI], 0.26-9.74). The rates of CR-IM were 43% in group 1 and 74% in group 2 (odds ratio, 0.33; 95% CI, 0.14-0.78). The rates of complete resolution of dysplasia were 76% in group 1 and 71% in group 2 (odds ratio, 1.28; 95% CI, 0.39-4.17). The adjusted odds ratio for CR-IM in group 1 (adjusting for age, segment length, and grade of dysplasia) was 0.50 (95% CI, 0.15-1.66). CONCLUSIONS Stricture rates among patients who receive only RFA are comparable to those of patients who had prior EMR. EMR appears safe to perform prior to RFA.

Comparative diagnostic performance of volumetric laser endomicroscopy and confocal laser endomicroscopy in the detection of dysplasia associated with Barrett’s esophagus

BACKGROUND AND AIMS Probe-based confocal laser endomicroscopy (pCLE) and volumetric laser endomicroscopy (VLE) (also known as frequency domain optical coherence tomography) are advanced endoscopic imaging modalities that may be useful in the diagnosis of dysplasia associated with Barretts esophagus (BE). We performed pCLE examination in ex-vivo EMR specimens and compared the diagnostic performance of using the current VLE scoring index (previously established as OCT-SI) and a novel VLE diagnostic algorithm (VLE-DA) for the detection of dysplasia. METHODS A total of 27 patients with BE enrolled in a surveillance program at a tertiary-care center underwent 50 clinically indicated EMRs that were imaged with VLE and pCLE and classified into neoplastic (N = 34; high-grade dysplasia, intramucosal adenocarcinoma) and nonneoplastic (N = 16; low-grade dysplasia, nondysplastic BE), based on histology. Image datasets (VLE, N = 50; pCLE, N = 50) were rated by 3 gastroenterologists trained in the established diagnostic criteria for each imaging modality as well as a new diagnostic algorithm for VLE derived from a training set that demonstrated association of specific VLE features with neoplasia. Sensitivity, specificity, and diagnostic accuracy were assessed for each imaging modality and diagnostic criteria. RESULTS The sensitivity, specificity, and diagnostic accuracy of pCLE for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The optimal diagnostic performance of OCT-SI showed a sensitivity of 70% (95% CI, 52-84), specificity of 60% (95% CI, 36-79), and diagnostic accuracy of 67%; (95% CI, 58-78). The use of the novel VLE-DA showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI (P < .01). CONCLUSION The use of a new VLE-DA showed enhanced diagnostic performance for detecting BE dysplasia ex vivo compared with the current OCT-SI. Further validation of this algorithm in vivo is warranted.