High-grade Dysplasia In Barrett's Esophagus Research Articles

Circumferential ablation of Barrett's esophagus that contains high-grade dysplasia: a U.S. multicenter registry

The management strategies for Barrett's esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and esophagectomy. To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD. Multicenter U.S. registry. Sixteen academic and community centers; treatment period from September 2004 to March 2007. Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists. A prior EMR was permitted, provided that residual HGD remained in the BE region for ablation. Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment. Histologic complete response (CR) end points: (1) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (2) all biopsy specimens were negative for any dysplasia (CR-D), and (3) all biopsy specimens were negative for IM (CR-IM). A total of 142 patients (median age 66 years, interquartile range [IQR] 59-75 years) who had BE HGD (median length 6 cm, IQR 3-8 cm) underwent circumferential ablation (median 1 session, IQR 1-2). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninety-two patients had at least 1 follow-up biopsy session (median follow-up 12 months, IQR 8-15 months). A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%. A nonrandomized study design, without a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up. Endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multicenter registry, the intervention safely achieved a CR for HGD in 90.2% of patients at a median of 12 months of follow-up.

Is the Risk of Concomitant Invasive Esophageal Cancer in High-Grade Dysplasia in Barrett’s Esophagus Overestimated?

Recent studies have claimed long neoplasia-free survival rates with endoscopic mucosal resection of high-grade dysplasia (HGD) in Barrett's esophagus (BE). However, reports have contended that approximately 40% of patients who have esophagectomy for HGD have occult invasive cancer. The aim of this study was to use explicit criteria to determine the true prevalence of invasive adenocarcinoma in reports of patients who had esophagectomy for HGD in BE. Studies reporting rates of esophageal cancer in patients who underwent esophagectomy for HGD in BE were gathered using MEDLINE and PUBMED. We defined invasive esophageal adenocarcinoma (IEAC) as tumor with submucosal invasion or beyond. Intramucosal carcinoma (IMC) was not considered IEAC. Twenty-three articles were selected for analysis. Most investigators reported rates of invasive cancer in the esophagectomy specimen, and the pooled average was 39.9% among the 441 patients who underwent an esophagectomy for HGD. Reported rates varied from 0% to 73%. A total of 267 patients had American Joint Committee on Cancer stage 0 postoperatively, 132 patients had stage I, 23 patients had stage IIa, 10 patients had stage IIb, and 9 patients had stage III. Fourteen studies provided differentiation between intramucosal and submucosal invasion. Among 213 patients, only 12.7% had IEAC, whereas 87.3% had HGD or IMC. The IEAC rate of 11% among patients with visible lesions is greater than the rate of 3% among patients with no visible lesion. By using strict pathologic definitions of invasive disease, the present study indicates the true prevalence of IEAC in BE and HGD may have been overestimated significantly. Separating IMC from IEAC is clinically relevant because endoscopic techniques potentially may treat IMC.

Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett's high-grade dysplasia

Barrett's esophagus (BE) with high-grade dysplasia (HGD) is a risk factor for development of esophageal carcinoma. Photodynamic therapy (PDT) with Photofrin (PHO) has been used to eliminate HGD in BE. Our purpose was to compare PHOPDT plus omeprazole with omeprazole only (OM). Five-year follow-up of a randomized, multicenter, multinational, pathology-blinded HGD trial. 30 sites in 4 countries. 208. Patients with BE and HGD were randomized (2:1) to PHOPDT (n=138) or OM (n=70) into a 2-year trial followed up for 3 more years. PHOPDT patients received 2 mg/kg PHO intravenously followed by endoscopic laser light exposure of Barrett's mucosa at a wavelength of 630 nm within 40 to 50 hours to a maximum of 3 courses at least 90 days apart. Both groups received 20 mg of OM twice daily. Pathologists at one center assessed biopsy specimens in a blinded fashion. HGD ablation status over 5 years of follow-up. At 5 years PHOPDT was significantly more effective than OM in eliminating HGD (77% [106/138] vs 39% [27/70], P<.0001). A secondary outcome measure preventing progression to cancer showed a significant difference (P=.027) with about half the likelihood of cancer occurring in PHOPDT (21/138 [15%]) compared with OM (20/70 [29%]), with a significantly (P=.004) longer time to progression to cancer favoring PHOPDT. Not all patients were available for follow-up. This 5-year randomized trial of BE patients with HGD demonstrates that PHOPDT is a clinically and statistically effective therapy in producing long-term ablation of HGD and reducing the potential impact of cancer compared with OM.

How light dosimetry influences the efficacy of photodynamic therapy with 5-aminolaevulinic acid for ablation of high-grade dysplasia in Barrett’s esophagus

Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) is a novel treatment for high-grade dysplasia (HGD) in Barrett's esophagus (BE). Our aim was to evaluate the effectiveness of differing light doses. Patients with HGD in BE received oral ALA (60 mg/kg) activated by low (500 J/cm), medium (750 J/cm), high (1,000 J/cm), or highest (1,000 J/cm x2) light dose at 635 nm. Follow-up was by regular endoscopy with quadrantic biopsies. Twenty-four patients were treated. Successful eradication of HGD was significantly correlated with light dose (log rank, p < 0.01). Six of eight patients (75%) treated with the highest light dose, one of two treated with high dose (50%), two of nine (22%) receiving medium light dose, and zero of five receiving low light dose had successful eradication of HGD (median follow-up 45 months, range 1-78 months). No skin photosensitivity or esophageal strictures occurred. The efficacy of ALA-PDT for eradication of HGD in BE is closely related to the light dose used. With a drug dose of 60 mg/kg and light at 635 nm, we recommend a minimum light dose of 1,000 J/cm of esophagus. This dose appears safe.

High-grade dysplasia in Barrett's esophagus is associated with increased expression of calgranulin A and B

Objective. Patients with Barrett's esophagus (BE) are at risk of developing esophageal adenocarcinoma, which is usually preceded by dysplastic changes of the metaplastic mucosa. The aim of this study was to increase the understanding of the development of dysplastic lesions in BE through the identification of genes that are differentially transcribed in these tissue types. Material and methods. Paired biopsy samples from non-dysplastic BE, and high-grade dysplasia from a single patient were used for histological evaluation and gene expression profile analysis. In addition, relative mRNA levels of differentially expressed genes were tested to validate the association with the presence or absence of dysplasia by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) (58 biopsy samples containing squamous epithelium, non-dysplastic BE, high-grade dysplasia, or adenocarcinoma from 23 unrelated patients) and immunohistochemistry (9 sets of paired non-dysplastic/high-grade dysplasiac samples from 9 unrelated patients). Results. Microarray results from high-grade dysplasia showed 866 genes with a>2-fold difference in mRNA levels compared with non-dysplastic BE. Subsequent comparison of mRNA levels of the 22 genes with a>10-fold difference in 76 unrelated biopsies showed that only two of these genes, i.e. calgranulin A (S100A8; p=0.017) and calgranulin B (S100A9; p=0.022), were consistently up-regulated in high-grade dysplasia, as were protein levels for calgranulin A and B. Conclusions. This is the first report of an association between the calprotectin complex, which is involved in chemotaxis of neutrophils, and the progression towards high-grade dysplasia in BE. It remains to be established whether differentially expressed proteins in biopsies form BE can be used to facilitate the diagnosis of advanced dysplasia in BE.

Expression of α-methylacyl–coenzyme A racemase in dysplastic Barrett's epithelium

Although identification of epithelial dysplasia in Barrett's esophagus (BE) is critically important because of a significant risk of progression to invasive adenocarcinoma, the diagnosis of dysplasia may be challenging. Among confounding factors are interobserver variability, tangential sectioning, and severe mucosal inflammation leading to architectural and cytologic atypia similar to that of dysplasia. alpha-methylacyl-coenzyme A racemase (AMACR) is an enzyme involved in beta-oxidation of branched fatty acids and an established marker of prostate cancer. It is expressed in colon adenomas and adenocarcinomas but not in normal colonic epithelium suggesting a role in development of gastrointestinal malignancies. We investigated whether expression of AMACR can be used to identify dysplasia of BE and to distinguish it from reactive atypia. Ninety-six routinely processed biopsy and/or resection specimens (23 negative for dysplasia; 19, low-grade dysplasia; 22, high-grade dysplasia; 16, reactive atypia; and 16, esophageal adenocarcinoma) were immunostained using a monoclonal anti-AMACR antibody p504S. AMACR staining was uniformly negative in the groups negative for dysplasia and with reactive atypia. Only 2 (11%) of 19 specimens with low-grade dysplasia showed positive immunostaning, compared with 14 (64%) of 22 in high-grade dysplasia group. Of 16 specimens, 12 (75%) showed positive staining for AMACR in the adenocarcinoma group. Our data suggest that AMACR immunoreactivity is moderately sensitive in identification of high-grade dysplasia in BE and is highly specific in distinguishing high-grade dysplasia from reactive atypia. Further validation and prospective studies are warranted.

Circumfrential Ablation of Barrett Esophagus with Persistent High-Grade Dysplasia Following Photodynamic Therapy with Halo 360

Purpose: Photodynamic therapy (PDT) is an FDA approved treatment for Barrett esophagus (BE) with high-grade dysplasia (HGD). It is unknown whether patients with persistent HGD following treatment with PDT could benefit from another ablative technique.We report initial safety and efficacy of the HALO360 bipolar balloon electrode in treatment of patients with BE and persistent HGD after treatment with PDT. Methods: Patients previously treated with PDT with persistent HGD confirmed by two pathologists and refusing repeat PDT or surgery were treated with the HALO360 bipolar balloon electrode. Patients underwent repeat treatment at 3 month intervals until all Barrett's epithelium was ablated. Lugol's chromoendoscopy with targeted biopsies from endoscopically visible Barrett and random biopsies from the ablated segment of original Barrett were obtained at regular follow-up interval to assess for dysplasia and residual Barrett epithelium. Endoscopic mucosal resection (EMR) was utilized for nodular HGD or early stage adenocarcinoma (ACA). Adverse events with the procedure were recorded. Results: Five patients with residual HGD after treatment with PDT have been treated with HALO360 bipolar balloon electrode. Two patients had complete ablation of HGD, 3 were found to have residual areas of focal nodular HGD/early stage ACA on follow-up and were treated with EMR. Two out of three had complete resection of ACA with EMR. One patient had involvement of the deep margin of the EMR with ACA and opted to undergo repeat PDT. All 3 patients were cancer/dysplasia free at the last follow-up. No adverse events were recorded. Conclusions: Ablation of BE with persistent HGD or early stage esophageal ACA following treatment with PDT is effective using HALO360 balloon electrode and EMR for nodular disease. Patient tolerance and safety with the procedure has been excellent. Long term follow-up is needed to establish the efficacy of this treatment.

High-Frequency Probe Ultrasonography Has Limited Accuracy for Detecting Invasive Adenocarcinoma in Patients with Barrett's Esophagus and High-Grade Dysplasia or Intramucosal Carcinoma: A Case Series

To evaluate prospectively the accuracy of preoperative high-frequency (20 MHz) probe ultrasonography (HFPUS) for detecting invasive cancer in patients referred for esophagectomy because of an endoscopic biopsy diagnosis of high-grade dysplasia (HGD) or intramucosal carcinoma (ICA) in Barrett's esophagus (BE). Nine consecutive male patients (median age of 69 yr) who were referred for esophagectomy for HGD or ICA in BE agreed to participate. We performed conventional upper gastrointestinal endoscopy followed by HFPUS using a through-the-scope ultrasound probe (20 MHz), and we compared our preoperative findings with the pathologist's findings in the resected esophageal specimens. There was complete agreement between the postoperative pathological findings and the preoperative HFPUS findings in only 4 of the 9 patients. HFPUS resulted in two false-negative diagnoses of esophageal cancer (both had T1 lesions in the resected specimens), one false-positive diagnosis of esophageal cancer, and two errors in tumor staging (1 understaged, 1 overstaged). HFPUS has limited accuracy for identifying invasive cancer in patients found to have HGD or IMC in BE. Pending further refinements in technology, clinical management decisions in such patients should not be based solely on the results of HFPUS.

AMACR Immunostaining is Useful in Detecting Dysplastic Epithelium in Barrett's Esophagus, Ulcerative Colitis, and Crohn's Disease

Alpha-methylacyl-CoA racemase (AMACR) catalyzes the racemization of alpha-methyl, branched carboxylic coenzyme A thioesters, and is overexpressed in a variety of neoplasms, such as prostate and colon cancer. The aim of this study was to evaluate AMACR expression in the metaplasia-dysplasia-carcinoma sequence in Barrett's esophagus (BE), ulcerative colitis (UC), and Crohn's disease (CD) and to determine whether its expression can be used to detect dysplastic epithelium in these conditions. One hundred thirty-four routinely processed biopsy and/or resection specimens from 134 patients with BE [M/F ratio: 5.7, mean age: 67 y (36 negative (intestinal metaplasia only), 14 indefinite for dysplasia (IND), 16 low-grade dysplasia (LGD), 32 high-grade dysplasia (HGD), and 36 invasive adenocarcinoma (ACA)] and 74 specimens from 74 patients with inflammatory bowel disease (IBD) [56 with ulcerative colitis, 18 with Crohn's disease, M/F ratio: 1.8, mean age: 55 y (17 negative, 7 IND, 26 LGD, 10 HGD, and 14 ACA)] were immunostained with a monoclonal AMACR antibody (p504S). The degree of cytoplasmic staining in all cases was evaluated in a blinded fashion according to the following grading system: 0, negative (0% cells positive); 1+, 1% to 10% cells positive; 2+, 10% to 50% cells positive; or 3+, >50% cells positive. In patients with BE, AMACR was not expressed in any negative foci (0%) but was significantly increased (P<0.0001) in foci of LGD (38%), HGD (81%), and ACA (72%). Three of 14 (21%) IND foci from 3 BE patients were only focally positive (grade 1: 7%, 2: 14%). However, 1 of these 3 patients had follow-up information available and had developed ACA subsequently. Similarly, in patients with IBD, AMACR was not expressed in any foci considered negative for dysplasia, but was significantly increased (P<0.0001) in foci of LGD (96%), HGD (80%), and ACA (71%). Only 1/7 (14%) IND focus from 1 patient was focally positive (grade 1). The sensitivity for the detection of LGD and HGD in BE and IBD was 38% and 81%, and 96% and 80%, respectively, for the 2 types of disorders. The specificity was 100% for both BE and IBD. AMACR is involved in the neoplastic progression in BE and IBD. The high degree of specificity of AMACR for dysplasia/carcinoma in BE and IBD suggests that it may be useful to detect neoplastic epithelium in these conditions.

Endoscopic Ultrasonography (EUS) and Endoscopic Mucosal Resection (EMR) for Staging and Treatment of High-Grade Dysplasia (HGD) and Early Adenocarcinoma (EAC) in Barrett's Esophagus (BE)

Aim: Endoscopic therapy can be curative for BE and HGD (Tis) or EAC confined to the mucosa (T1m). The risk of lymph node metastasis increases with the depth of mucosal invasion, and rises rapidly with submucosal invasion (T1sm). EUS has provided the highest accuracy for clinical staging of depth of invasion, but remains imperfect. We tested a staging strategy of an initial EUS, followed by EMR in patients with ≤T1m on EUS. Methods: We staged patients with HGD or EAC with high-frequency EUS (20 MHz). Patients with EUS stage of ≥T1sm were referred to surgery. Patients with EUS stage ≤T1m had cap-assisted EMR of focal lesions in long-segment BE or of all short segment BE. EMR specimens were evaluated by histology: m1 = tumor above the basement membrane (HGD); m2 = tumor invading the lamina propria; m3 = tumor invading the muscularis mucosae; sm = tumor invading the submucosa. Results: A total of 50 patients (40 M, 10 F), mean age 70 years (range 36-87 years) with HGD and possible EAC in BE were evaluated with EUS. In 8 patients, EUS indicated ≥T1sm. EUS was accurate compared to surgical pathology in 7/8 cases, but over-staged 1 patient with T1m disease. EMR was carried out in the remaining 42 patients (20 focal lesions, 22 short segment BE). EMR staging results compared with initial endoscopic biopsy diagnosis are shown in the table below. EMR was carried out as an outpatient procedure without serious complication. Subsequent treatment was based on EMR results and clinical status. In the 22 patients with m1 (HGD) on EMR, 1 had esophagectomy, and 21 had endoscopic follow-up, including 6 who received additional endoscopic therapy (EMR, photodynamic therapy, or argon plasma coagulation). None of the 21 developed metastatic cancer over a mean of 15.4 ± 9.0 months. In the 20 patients with EAC on EMR, 6 had esophagectomy, including 5/6 with sm invasion. In 12/14 patients, additional endoscopic therapy was carried out, and 1 patient received combined radiation and chemotherapy. None of the 14 developed metastatic cancer over a mean of 19.7 ± 8.9 months. Conclusions: Staging patients with HGD and EAC in BE can be performed accurately with EUS followed by EMR. Invasion of the deep mucosa and the submucosa can be definitively established. In medium-term follow-up, endoscopic therapy has been successful in patients with HGD and cancer limited to the mucosa.

Endoscopic Mucosal Resection for High-Grade Dysplasia and Intramucosal Carcinoma Occurring in Barrett's Esophagus

Introduction: Patients with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (AC). High-grade dysplasia (HGD) is considered the final step toward AC, and esophagectomy is advised. Endoscopic mucosal resection (EMR) could become an alternative to surgery. The limited available data are encouraging. Aim: To evaluate the effectiveness and safety of selective EMR in patients with HGD and/or intramucosal cancer (IMC) occurring in BE patients. Methods: Between October 1998 and July 2003, 38 consecutive patients (mean age 62.5 ± 1.5 years) with HGD (34) and/or IMC (4) in BE underwent EMR. All patients had endoscopically detectable mucosal abnormalities. Long segment BE (>30 mm, LSBE) was present in 18 patients. In 3 patients with short segment BE (SSBE: 15%), HGD was detected in a normal appearing BE. The latter patients were included with the aim of completely removing BE. EUS was performed to assess the depth of the lesion and the status of mediastinal lymph nodes. The median diameter of lesions was 13.5 mm (range 3-40). EMR was carried out by using the cap method (EMRC), after submucosal injection of a diluted epinephrine solution (1:60.000). During the EMR, patients were sedated with propofol. Follow-up was scheduled at 3, 6 months, and then every 6 months thereafter. Results: The average size of EMR was 20.0 ± 9.5 × 14.0 ± 6.4 mm. The results of the histopathologic assessment post-EMR were: 5 LGD (13.2%), 26 HGD (68.4%), 2 IMC (5.3%), and 5 AC with submucosal infiltration (13.2%). EMR changed the pre-treatment diagnosis in 10 patients (26.3%). Three patients with invasive AC underwent surgery, but the histopathologic assessment of the surgical specimen did not show residual disease and lymph node involvement. The remaining 2 patients with AC are cancer free at 8 and 10 months. Among the 26 HGD, one recurrence occurred after 19 months, and a new EMR was performed. Three months later, a further control was negative. Post-EMR bleeding occurred in 4 patients (10.5%), and hemoclips were placed in 2 of them. After a median follow-up of 14.2 months (range 3-55.8), all patients remained in remission. Conclusions: EMRC is effective and safe to treat HGD and/or IMC within BE. Moreover, it is a valuable staging method. EMRC can completely remove BE in patients with SSBE. The complication rate is negligible even in large resections. Careful surveillance is recommended for early detection of residual and metachronous lesions.

Section I: Epidemiological review

The incidence of esophageal adenocarcinoma has increased tremendously in the United States and other Western countries over the past 30 years while the incidence of esophageal squamous cell carcinoma has remained unchanged. The rate of increase in incidence is higher than for any other cancer. The reasons for this are multifactorial. Despite this, esophageal cancer remains a relatively uncommon malignancy. Barrett's esophagus (BE) is the most important risk factor for the development of esophageal adenocarcinoma and is believed to be the precursor lesion for most. The risk of developing esophageal adenocarcinoma from known BE is estimated to be 0.5% per patient year. Persistent high-grade dysplasia in BE is a sensitive indicator for the development of esophageal adenocarcinoma. However, only a minority of patients with BE are ever diagnosed and, therefore, surveillance endoscopy in Barrett's patients has failed to affect the incidence of esophageal adenocarcinoma. The relationship of Helicobacter pylori to esophageal adenocarcinoma is complex, but nonsteroidal antiinflammatory drugs may confer protection against the development of this cancer. Fortunately, improved survival is being seen with both squamous cell esophageal carcinoma and esophageal adenocarcinoma. Additional study is required to better determine the risk factors for the development of esophageal cancer, and epidemiologic understanding will prove important in developing methods of detection and therapeutic intervention for this disease. © 2003 Elsevier Inc. All rights reserved.