Non-dysplastic Barrett's Mucosa Research Articles

Toward improved endoscopic surveillance with multidiameter single fiber reflectance spectroscopy in patients with Barrett's esophagus.

Patients with Barrett's esophagus are at an increased risk to develop esophageal cancer and, therefore, undergo regular endoscopic surveillance. Early detection of neoplasia enables endoscopic treatment, which improves outcomes. However, early Barrett's neoplasia is easily missed during endoscopic surveillance. This study investigates multidiameter single fiber reflectance spectroscopy (MDSFR) to improve Barrett's surveillance. Based on the concept of field cancerization, it may be possible to identify the presence of a neoplastic lesion from measurements elsewhere in the esophagus or even the oral cavity. In this study, MDSFR measurements are performed on non-dysplastic Barrett's mucosa, squamous mucosa, oral mucosa, and the neoplastic lesion (if present). Based on logistic regression analysis on the scattering parameters measured by MDSFR, a classifier is developed that can predict the presence of neoplasia elsewhere in the Barrett's segment from measurements on the non-dysplastic Barrett's mucosa (sensitivity 91%, specificity 71%, AUC = 0.77). Classifiers obtained from logistic regression analysis for the squamous and oral mucosa do not result in an AUC significantly different from 0.5.

Abstract 3600: Early detection of esophageal adenocarcinoma using near-infrared lectin-based imaging

Abstract Background: Long procedure times and sampling error frequently limit the efficacy of endoscopic surveillance for Barrett's esophagus (BE). Near-infrared (NIR) fluorescence imaging minimizes optical scattering and tissue autofluorescence. We assessed, in an ex vivo setting, the feasibility of using a topically applied NIR dye-labeled lectin for the detection of early neoplasia in BE. Methods: We recruited consecutive patients undergoing endoscopic mucosal resection (EMR) for BE-related early neoplasia. EMR specimens were freshly collected and sprayed at the bedside with a fluorescent lectin and then imaged ex vivo. A maximum of two punch biopsies were collected from each EMR under NIR light guidance. Fluorescence intensity from dysplastic and nondysplastic areas within EMRs were compared and from punch biopsies with different histological grades. Results: We analyzed 29 EMR specimens from 17 patients. Dysplastic regions showed significantly lower fluorescence across whole EMR specimens (P < 0.001). A 41% reduction in fluorescence was found for dysplastic compared to nondysplastic punch biopsies (P < 0.001), with a sensitivity and specificity for dysplasia detection of 80% and 82.9%, respectively. Conclusion: NIR imaging using fluorescently-labeled lectins can distinguish dysplastic from nondysplastic Barrett's mucosa ex vivo. We are currently planning a first-in-human study to validate this imaging platform. Citation Format: Andre A. Neves, Massimiliano Di Pietro, Maria O'Donovan, Dale J. Waterhouse, Sarah E. Bohndiek, Kevin M. Brindle, Rebecca C. Fitzgerald. Early detection of esophageal adenocarcinoma using near-infrared lectin-based imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3600.

RAF-kinase inhibitor protein (RKIP) downregulation in esophageal cancer and its metastases

Raf kinase inhibitor protein (RKIP) is an inhibitor of Raf-mediated activation of mitogen-activated protein (MAP) kinase (MEK)-MAP kinase and is considered as an important tumor suppressor. RKIP-expression was investigated retrospectively in 321 esophageal cancers [179 adenocarcinomas (ACs), 142 squamous cell carcinomas (SCCs)]. RKIP-expression was further investigated in 41 precursor lesions consisting of 14 cases of non-dysplastic Barrett's mucosa, 5 low grade dysplasias (LGD), and 12 high grade dysplasias (HGD) as well as, 4 cases with low grade and 6 cases with high-grade squamous cell dysplasia. Corresponding lymph node metastases were investigated in 140 patients, distant metastases in 29, and local recurrences in 12. High RKIP-expression was significantly more common in Barrett's mucosa without dysplasia and in LGD compared to HGD (p = 0.047, χ(2) test) and invasive AC (p < 0.001, χ(2) test). In 187 primary esophageal cancers (58.3 %) RKIP was downregulated (AC: 51.4 %; SCC: 66.9 %). RKIP status of primary tumors influenced RKIP expression in corresponding lymph node and distant metastases (p < 0.05, linear regression). Downregulation of RKIP was associated with shorter overall survival (OS) and disease free survival (DFS) in all tumors (p ≤ 0.05, Cox regression). In AC, downregulation of RKIP was an independent prognostic factor for OS and DFS (p ≤ 0.05, Cox regression), while in SCC it reached significance only in univariate analysis (p ≤ 0.05, log-rank test). In conclusion, downregulation of RKIP is associated with shorter survival in esophageal cancers, and RKIP status of tumor cells seems to be preserved at the formation of metastases. Inhibition of RKIP-downregulation might reduce the ability of esophageal cancers to establish disseminated disease.

Frühes Ösophaguskarzinom: Pro endoskopische Resektion

In several publications including more than 1,000 endoscopically treated patients it could be demonstrated that endoscopic treatment of early esophageal cancer is effective and safe. A combination of endoscopic resection (ER) of early Barrett's neoplasia followed by ablation of the remaining non-dysplastic Barrett's mucosa was able to significantly reduce the rate of recurrence and metachronous neoplasia. Long-term complete remission rates of more than 95% can be achieved. Compared to esophagectomy, endoscopic treatment has only a very low complication rate and almost no mortality. Therefore, ER is the treatment of choice and recommended by several international guidelines. Esophageal resection only plays a minor role in patients with early esophageal cancer.

Diagnostic Challenges in the Pathologic Evaluation of Barrett Esophagus

Abstract Context.—Barrett esophagus represents an unstable epithelium resulting from chronic gastroesophageal reflux disease. Patients with Barrett esophagus routinely undergo endoscopic examination to detect dysplasia and early carcinoma. Although appropriate classification of Barrett esophagus and neoplasia is usually straightforward, persistent esophageal inflammation may induce epithelial changes that mimic, or mask, dysplasia. Recent data also indicate that specific molecular changes occur in nondysplastic Barrett mucosa and herald the development of dysplasia and/or carcinoma. Objective.—To describe problematic aspects of biopsy interpretation in tissue samples of the gastroesophageal junction and distal esophagus, including the diagnostic criteria for Barrett esophagus, the importance of the gastric cardia, and pitfalls to the diagnosis of dysplasia. Ancillary studies that have recently emerged as potential adjuncts to the evaluation of patients with Barrett esophagus will be briefly discussed. Dat...

Diagnostic Challenges in the Pathologic Evaluation of Barrett Esophagus

Barrett esophagus represents an unstable epithelium resulting from chronic gastroesophageal reflux disease. Patients with Barrett esophagus routinely undergo endoscopic examination to detect dysplasia and early carcinoma. Although appropriate classification of Barrett esophagus and neoplasia is usually straightforward, persistent esophageal inflammation may induce epithelial changes that mimic, or mask, dysplasia. Recent data also indicate that specific molecular changes occur in nondysplastic Barrett mucosa and herald the development of dysplasia and/or carcinoma. To describe problematic aspects of biopsy interpretation in tissue samples of the gastroesophageal junction and distal esophagus, including the diagnostic criteria for Barrett esophagus, the importance of the gastric cardia, and pitfalls to the diagnosis of dysplasia. Ancillary studies that have recently emerged as potential adjuncts to the evaluation of patients with Barrett esophagus will be briefly discussed. A comprehensive review of the relevant literature indexed in PubMed (National Library of Medicine) was performed. Barrett esophagus is currently defined as the presence of intestinal metaplasia in samples obtained from an endoscopically evident abnormality in the distal esophagus. Diagnosis and grading of dysplasia in mucosal biopsies remain the most reliable method to assess risk for neoplastic progression, but its classification may be hindered by superimposed inflammatory changes and suffers from considerable interobserver variability. Therefore, immunohistochemical studies and molecular assessment for TP53, CDKN2A , and DNA content abnormalities have emerged as potential adjuncts to the detection of dysplasia.

High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy

Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. To investigate the expression of this candidate target in esophageal cancer, we evaluated expression of FAS protein in 22 cases of esophageal squamous cancer, 79 cases of esophageal adenocarcinoma, and 16 cases of Barrett's esophagus with high-grade dysplasia - a lesion thought to represent a pre-invasive precursor to esophageal cancer. Using immunohistochemistry, we found significantly higher levels of FAS expression in 77 % of the squamous cancers, 96% of the adenocarcinomas, and 94% of the Barrett's lesions with high-grade dysplasia, when compared to levels in normal esophageal epithelium and non-dysplastic Barrett mucosa. To evaluate the potential for inhibiting this enzyme as a treatment of esophageal cancer, we treated mice bearing xenografts of the Colo680N esophageal squamous cell carcinoma cell line using C93, a rationally designed molecule that inhibits FAS activity. In these experiments, C93 significantly inhibited the growth of orthotopic xenograft tumors without causing anorexia and weight loss in the treated animals. We conclude that, similar to several other common types of human cancer, FAS is expressed at very high levels in esophageal cancer, and growth of these cancers can be inhibited by pharmacological agents that target this enzyme. Moreover, this high expression of FAS is also seen in high-risk, pre-invasive lesions of the esophagus, leading us to propose considering FAS-inhibitors for purposes of esophageal cancer chemoprevention.

Platelet 12-lipoxygenase and stem cells in Barrett’s esophagus

Esophageal adenocarcinoma has shown a significant increase in incidence in recent years. It is thought that the development of gastroesophageal reflux disease (GERD), followed by columnar-lined esophagus and the development of dysplasia, leads to invasive adenocarcinoma. The exact pathogenesis of this process, the diagnosis and differentiation of the metaplastic and dysplastic esophageal lesions have yet to be determined. The purpose of this immunohistochemical study was to investigate the expression of pro-tumorigenic enzyme platelet 12-lipoxygenase (p12LOX) using two new available antibodies in non-dysplastic and dysplastic Barrett's esophagus. The stem cell markers nestin, CD117 and CD44, were then evaluated. The comparative group included GERD carditis, gastric intestinal metaplasia and colorectal adenoma. The overexpression of p12LOX detected by two specific antibodies in the non-dysplastic and dysplastic Barrett's mucosa clearly demonstrated that this enzyme plays an important role in the development of esophageal adenocarcinoma.

T1707 Tissue Proteomic Profile Accurately Classifies Non-Dysplastic Barrett's Mucosa, High Grade Columnar Dysplasia and Esophageal Adenocarcinoma

T1707 Tissue Proteomic Profile Accurately Classifies Non-Dysplastic Barrett's Mucosa, High Grade Columnar Dysplasia and Esophageal Adenocarcinoma

Characterization of tissue autofluorescence in Barrett's esophagus by confocal fluorescence microscopy

High grade dysplasia and early cancer in Barrett's esophagus can be distinguished in vivo by endoscopic autofluorescence point spectroscopy and imaging from non-dysplastic Barrett's mucosa. We used confocal fluorescence microscopy for ex vivo comparison of autofluorescence in non-dysplastic and dysplastic Barrett's esophagus. Unstained frozen sections were obtained from snap-frozen Barrett's esophagus biopsy samples and scanned with confocal fluorescence microscopy (458 nm excitation; 505-550 nm [green] and > 560 nm [red] emission). Digital micrographs were taken from areas with homogenous and specific histopathology. Visual inspection and statistical analysis were used to evaluate the image datasets. Dysplastic and non-dysplastic Barrett's esophagus epithelia fluoresced mainly in the green spectrum and the main sources of autofluorescence were the cytoplasm and lamina propria. High-grade dysplasia was differentiated from non-dysplastic Barrett's esophagus by microstructural tissue changes. However, there were no specific changes in either the locations or average intensities of intrinsic green and red autofluorescence at the epithelial level that could differentiate between dysplastic and non-dysplastic Barrett's esophagus epithelia, ex vivo. Detectable differences in autofluorescence between BE and dysplasia/cancer in vivo are probably not caused by specific changes in epithelial fluorophores but are likely due to other inherent changes (e.g. mucosal thickening and increased microvascularity) attenuating autofluorescence from the collagen-rich submucosa. Furthermore, confocal fluorescence microscopy provides 'histology-like' imaging of Barrett's tissues and may offer a unique opportunity to exploit microstructural tissue changes occurring during neoplastic transformation for in vivo detection of high-grade dysplasia in Barrett's patients using newly developed confocal fluorescence microendoscopy devices.

Evaluation of sensitivity and inter- and intra-observer variability in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus with enhanced magnification endoscopy

Objective. Magnification endoscopy with acetic acid or dye for diagnosis of Barrett's esophagus is presently undergoing clinical evaluation. Current studies report good accuracy in predicting specialized intestinal metaplasia. To date, however, there is no definitive information on the inter- and intra-observer variability of these methods applied to the diagnosis of normal and dysplastic Barrett's mucosa. Material and methods. Sixty patients with endoscopically suspected Barrett's esophagus were investigated prospectively with the zoom endoscope after contrast enhancement of the mucosa with 1.5% acetic acid. Two hundred and twenty-three enlarged and histologically investigated areas of gastric, cardiac, normal and dysplastic Barrett's mucosa were photodocumented and in randomized sequence presented to 4 endoscopists in a blinded manner (2 with and 2 without experience of zoom endoscopy for evaluation). The reference for the first evaluation (A1) was standard endoscopic photographs of the respective, histologically confirmed mucosal entity. In a second evaluation (A2), the pictures were again interpreted by the same blinded investigators, but this time a modified pit-pattern classification as proposed by Sharma et al. was employed as the evaluation reference. Results. The diagnostic sensitivity for specialized intestinal metaplasia and dysplasia in Barrett's esophagus calculated for the A1 evaluation ranged – investigator dependently – from 54.9% to 80.7% and for A2 from 42.2% to 81.5%. The inter- and intra-observer variability for the evaluation procedure A1 and A2 was high (all kappa values <0.4). In particular, the inexperienced investigators demonstrated high intra-observer variability and low sensitivity in comparison with the experienced investigators. Conclusions. The diagnosis of Barrett's mucosa using enhanced magnification endoscopy after acetic acid instillation is associated with a high level of interobserver variability. One reason is a frequent mismatch between cardiac mucosa and non-dysplastic Barrett's mucosa.

Concordant Loss of MTAP and p16/CDKN2A Expression in Gastroesophageal Carcinogenesis

The gene that encodes methylthioadenosine phosphorylase (MTAP), an enzyme involved in adenine and methionine salvage pathways, is located on chromosome 9p21 telomeric to the p16INK4A/CDKN2A tumor suppressor gene. Inactivation of the p16INK4A/CDKN2A gene occurs by three different mechanisms: hypermethylation of the gene promoter, intragenic mutation coupled with loss of the second allele, and homozygous deletion. Immunohistochemical labeling for the p16INK4A/CDKN2A gene product parallels gene status but does not elucidate the mechanism of gene inactivation. Since the MTAP gene is often co-deleted with p16INK4A/CDKN2A, concurrent immunolabeling for both proteins can identify cases with homozygous p16INK4A/CDKN2A gene deletion. MTAP loss itself has therapeutic implications since it may confer selective sensitivity to inhibitors of de novo purine biosynthesis, such as L-alanosine. Twelve tissue microarrays were constructed from 92 cases of Barrett-associated adenocarcinomas and precursor lesions and 112 cases of gastric adenocarcinoma and precursor lesions comprising 1161 individual cores. Multiple cores were arrayed from any given case, and when available, included the entire histologic spectrum of intestinal metaplasia-dysplasia-carcinoma. Tissue microarrays were labeled with monoclonal antibodies against MTAP protein (clone 6.9, Salmedix, Inc) and p16 (clone 16P07, Neomarkers). Complete loss of labeling was considered negative, while any labeling (p16: nuclear; MTAP: cytoplasmic and nuclear) was considered positive. Loss of MTAP labeling occurred exclusively in conjunction with loss of p16 labeling, confirming that the previous findings from this group that concurrent loss of MTAP and p16 labeling is a surrogate marker of 9p21 homozygous deletions. Complete loss of MTAP and p16 was seen in 4 of 25 (16%) patients with Barrett's esophagus, 4 of 18 (22%) with low-grade dysplasia, 5 of 39 (13%) with high-grade dysplasia, 17 of 78 (22%) with invasive adenocarcinoma, and 8 of 36 (22%) of metastases. There were 7 cases of esophageal adenocarcinoma with loss of both MTAP and p16 for which precursor lesions were available. In 6 on these 7 cases (85%), the precursor lesion(s) had loss of both MTAP and p16. Lack of MTAP and p16 expression was seen in 11 of 106 (10%) cases of gastric adenocarcinoma. All metaplastic (30 biopsies from 20 cases) and dysplastic (15 biopsies from 13 cases) gastric tissues had both intact MTAP and p16INK4A/CDKN2A gene products. No precursor lesions were available from the gastric cancers that had loss of both MTAP and p16. Two benign gastric hyperplastic polyps also had intact p16 and MTAP. Concurrent MTAP and p16 loss detected by immunohistochemistry can serve as a convenient surrogate for p16INK4A/CDKN2A gene homozygous deletion in archival tissues. Inactivation of p16INK4A/CDKN2A by homozygous deletion appears to be an early event in Barrett carcinogenesis, occurring in noninvasive precursor lesions, including nondysplastic Barrett mucosa, in subsets of cases. In the absence of MTAP, cells depend exclusively on the de novo synthesis pathway for production of adenosine. This loss of MTAP during 9p21 homozygous deletion might be exploited therapeutically using de novo purine synthesis antimetabolites to treat a subset of invasive gastroesophageal adenocarcinomas and esophageal precursor lesions.

Barrett Esophagus

To evaluate risk factors for dysplasia and adenocarcinoma development in nondysplastic Barrett mucosa. The risk for patients with Barrett esophagus to develop esophageal adenocarcinoma is low, and most patients undergoing surveillance will not develop malignancy. Identification of risk factors may allow for more rational surveillance programs in which patients are stratified according to their individual risk of progressing to dysplasia and invasive adenocarcinoma. The development of dysplasia and esophageal adenocarcinoma was studied during long-term endoscopic and histologic surveillance in 140 patients with Barrett esophagus free from dysplasia. Risk factors for progression to dysplasia and adenocarcinoma were evaluated. Median follow-up was 5.8 years. Forty-four patients (31.4%) developed low-grade dysplasia and 7 patients (5%) developed high-grade dysplasia or esophageal adenocarcinoma. Dysplasia development was significantly less common after antireflux surgery compared with conventional medical therapy. Low-grade dysplasia (relative risk = 5.5; 95% confidence interval, 1.1-28.6) and long duration of reflux symptoms (relative risk = 1.3; 95% confidence interval, 1.2-1.7) were independently associated with an increased risk of developing high-grade dysplasia or esophageal adenocarcinoma. Successful antireflux surgery protects the Barrett mucosa from developing high-grade dysplasia and esophageal adenocarcinoma, possibly by better control of reflux of gastric contents. Low-grade dysplasia is the only clinically useful risk factor that permits stratification of the surveillance intervals according to the risk of the individual patient.

Expression of CD44v5 and -v6 in Barrett's Carcinoma Is Not Increased Compared to That in Nondysplastic Barrett's Mucosa

Barrett's adenocarcinoma currently shows the highest increase in the incidence of all malignant tumors. Reliable molecular markers to identify Barrett's patients at risk are still missing. Our own results demonstrate that the expression of CD44v6 correlates with the development of dysplasia in colorectal neoplasms. Therefore, we examined the expression of CD44 variants v5 and v6 in normal esophageal mucosa, nondysplastic Barrett's mucosa, and Barrett's carcinoma. mRNA from biopsy specimens of patients with Barrett's esophagus ( n = 19) or Barrett's carcinoma ( n = 15) and patients without esophageal diseases (controls; n = 9) were extracted and used as templates for cDNA synthesis. CD44 variants were detected by RT–PCR with primers hybridizing with CD44 sequences up- and downstream of variable exons. CD44v6 expression was found in 36 of 56 biopsy specimens (64%) of nondysplastic Barrett's mucosa, in 100% of squamous epithelium, and in none of the gastric mucosa specimens. Eleven of 15 specimens (73%) of Barrett's carcinoma tested positive for v6 expression. The identification of v5 expression did not give additional information. There was no correlation between CD44v5 or -v6 expression and staging or grading of the tumors. Expression of CD44v5 and -v6 seems to be independent of the development of cancer in Barrett's mucosa.

Aberrant expression of minichromosome maintenance proteins 2 and 5, and Ki-67 in dysplastic squamous oesophageal epithelium and Barrett's mucosa.

Minichromosome maintenance (Mcm) proteins are essential for eukaryotic DNA replication, and their expression implies potential for cell proliferation. Expression is dysregulated in dysplastic states but data for oesophageal squamous mucosa and Barrett's mucosa have not been published. To test the hypothesis that Mcm proteins are downregulated together with the proliferation marker Ki-67 in differentiating epithelial compartments of non-dysplastic squamous and Barrett's epithelium, and that this process does not occur in dysplastic mucosae. METHODS AND CASES: Forty five patients with Barrett's oesophagus included 20 with glandular dysplasia (10 low grade, eight high grade, two both, and four with invasive adenocarcinoma). Twenty five other patients included 12 with oesophageal squamous dysplasia (three low grade, six high grade, three both, and four with invasive squamous carcinoma). Formalin fixed paraffin embedded tissue sections from biopsy series and resections were immunostained using antibodies to Mcm2, Mcm5, and Ki-67. Percentage of nuclei positive for Mcm2, Mcm5, and Ki-67 was estimated and scored from 0 to 6 as: 0, none +; 1, <10%+; 2, 10-30%+; 3, 30-70%+; 4, 70-90%+; 5, >90%+; 6, all+. Four separate epithelial strata were scored: in squamous epithelium the basal layer and thirds to the surface, in Barrett's mucosa the luminal surface, upper and lower crypt, and deep glands. In non-dysplastic squamous epithelium and Barrett's mucosa, high level expression of Mcm2, Mcm5, and Ki-67 proteins was largely confined to the proliferative compartments and downregulated in differentiated compartments. Expression persisted up to the mucosal surface in dysplastic squamous epithelium and Barrett's mucosa. Persistent expression of Mcm2, Mcm5, and Ki-67 proteins in luminal compartments of dysplastic oesophageal squamous epithelium and dysplastic Barrett's mucosa may be diagnostic markers and imply disruption of cell cycle control and differentiation in these dysplastic epithelia.

P53 Gene Mutation and Protein Accumulation during Neoplastic Progression in Barrett's Esophagus

The aim of the present study was to characterize expression and mutation of p53 during the neoplastic progression from Barrett's esophagus to adenocarcinoma and to test the reliability of immunohistochemistry for p53 overexpression as an indicator of p53 mutation in this context. The association of both gene mutation and protein accumulation with clinicopathological findings and survival was also studied. A total of 77 samples from 30 esophagectomy specimens with Barrett's esophagus and adenocarcinoma of patients in longitudinal clinical follow-up were analyzed. Different lesions (intestinal metaplasia, dysplasia, and adenocarcinoma) as well as normal squamous-cell esophageal epithelia were sampled from formalin-fixed, paraffin-embedded tissues by microdissection. Mutations in p53 Exons 5 to 9 were detected by polymerase chain reaction–single-strand conformation polymorphisms (PCR-SSCP) and confirmed by direct DNA sequencing. Nuclear accumulation of p53 protein was analyzed immunohistochemically from tissue sections adjacent to those used for microdissection. p53 gene mutations were found in 17 and p53 protein accumulation were found in 20 tumor samples. Of the 17 adenocarcinomas with a p53 mutation, 16 stained positive for p53 protein. p53 mutations were detected significantly more frequently in high-grade dysplastic than in low-grade dysplastic lesions (77% versus 29%, P < 0.01). In contrast, nuclear accumulation of p53 was detected in 85% of high-grade and 71% of low-grade dysplastic lesions. In eight cases with p53 mutation, the mutation identified in the tumors was also detected in premalignant lesions, mainly in high-grade dysplasia. In four cases of p53-mutated tumors, clones with different p53 mutations were detected in premalignant lesions. Neither p53 mutations nor p53 protein accumulations were found in metaplastic lesions. In summary, we found that p53 mutations occurred mainly during the transition from low-grade to high-grade dysplasia in the neoplastic progression of Barrett's esophagus but not in the nondysplastic Barrett's mucosa. Mutational analysis of p53 by PCR-SSCP and p53 accumulation by immunohistochemistry were mostly concordant in adenocarcinoma and high-grade dysplastic lesions but frequently discordant in low-grade dysplastic lesions. No correlation between p53 gene mutation or p53 accumulation and clinicopathological findings was observed in this study.

Clinicopathologic and molecular analysis of high-grade dysplasia and early adenocarcinoma in short- versus long-segment Barrett esophagus

Barrett esophagus, especially dysplastic Barrett mucosa, has been regarded as a preneoplastic lesion for esophageal adenocarcinoma. However, the etiology and pathogenesis of dysplasia and early adenocarcinoma in short- (SSBE) and long- (LSBE) segment Barrett esophagus have not been studied in detail. The aims of this study were to clarify clinicopathologic and genetic differences between high-grade dysplasia (HGD) and early adenocarcinoma in SSBE versus LSBE. We analyzed the clinicopathologic features from 47 patients (19 SSBE [<3 cm] and 28 LSBE [≥3 cm]) with esophagectomy for HGD/T1 adenocarcinoma. Allelic losses on chromosomes 3p (FIHT), 5q (APC), 9p (p16), and 17p (p53) were compared in 12 HGD and 9 T1 tumors from 19 cases of SSBE and in 23 HGD and 15 T1 tumors from 28 cases of LSBE. Patients with SSBE were more likely to be smokers than were patients with LSBE (94.7% v 57.1%; P =.004). HGD or T1 tumors arising from SSBE were less likely to show adjoining nondysplastic Barrett mucosa than those from LSBE (73.6% v 100%; P =.02). LSBE more frequently showed a circumferential pattern of Barrett mucosa than did SSBE (96.4% v 47.3%; P =.0002). Chromosomal allelic losses on 3p, 5q, 9p, and 17p were detected in 19% (4 of 21), 43% (15 of 35), 40% (14 of 35), and 48% (16 of 33) of HGD, respectively, and 26% (5 of 19), 35% (8 of 23), 35% (8 of 23), and 57% (13 of 23) of T1 tumor, respectively. There were no significant differences in allelic loss of 3p, 5q, 9p, or 17p in HGD or T1 tumors from SSBE versus LSBE. These results suggest that both HGD and early adenocarcinoma in SSBE and LSBE may occur through similar genetic alterations, whereas there are some clinicopathologic differences between SSBE and LSBE. HUM PATHOL Copyright © 2001 by W.B. Saunders Company

Argon plasma coagulation in the treatment of Barrett's high-grade dysplasia and in situ adenocarcinoma.

Endoscopic therapy of high-grade dysplasia (HGD) and superficial adenocarcinoma associated with Barrett's esophagus (BE), using Nd:YAG laser, KTP laser, or photodynamic therapy (PDT), has been reported to be effective in a curative role. Argon plasma coagulation (APC) appears to be effective in the eradication of nondysplastic Barrett's mucosa, but no results are available in the management of early neoplasms complicating BE. We report our initial experience in the application of APC in this indication. Ten patients (mean age 74.2) with histologically proven HGD (n = 7) or in situ adenocarcinoma (n = 3) associated with BE (mean length 6 cm) and unfit for surgery were treated using APC and high-dose omeprazole (40 mg daily) until squamous re-epithelialization or complete eradication of the initially apparent lesions. Endoscopic follow-up was maintained at every 3 months. Complete eradication of HGD and in situ adenocarcinoma was achieved after a mean number of 3.3+/-1.5 APC sessions in 8/10 patients (80%). The eight patients with complete clearance of the neoplastic areas did not show any evidence of local recurrence during a median follow-up of 24 months (range 12-36 months). One patient with initial HGD had persistence of HGD 30 months after initial diagnosis, and one patient progressed to invasive adenocarcinoma after failure of APC and PDT. APC is safe and effective in the management of HGD and in situ adenocarcinoma associated with BE, and might represent an interesting alternative in selected patients who are not candidates for surgery.

Chromosomal numerical aberrations are frequent in oesophageal and gastric adenocarcinomas: a study using in-situ hybridization.

(i) To investigate and compare the numerical aberrations of chromosomes 7, 8, 11, 17 and Y in a series of 60 adenocarcinomas of the oesophagus, gastric cardia and gastric antrum; and (ii) to specify the sequence of chromosomal aberrations occurring during the neoplastic progression of Barrett's oesophagus. Chromosomal in-situ hybridization was performed on deparaffinized tissue sections from 20 Barrett's adenocarcinomas, 20 adenocarcinomas of the cardia and 20 adenocarcinomas of the antrum, with centromeric alpha satellite DNA probes specific for chromosomes 7, 8, 11, 17 and Y, labelled with digoxigenin. Signals were detected by immunoperoxidase staining. The copy number for each chromosome was counted in 200 tumour cells nuclei and 100 lymphocytes as controls. In parallel, the DNA content of the nuclear suspensions was measured by flow cytometry. Numerical abnormalities of the five chromosomes (loss of the Y chromosome, monosomy, trisomy, and tetrasomy) were frequently observed in the three groups of adenocarcinomas (from 40% to 65% of the cases). Sixty per cent to 75% of oesophagus and gastric adenocarcinomas were DNA-aneuploid. Chromosomal aberrations progressively increased with advancing degrees of dysplasia in Barrett's mucosa, with an increasing frequency of trisomy and loss of the Y chromosome from non-dysplastic Barrett's mucosa to invasive adenocarcinoma, and with monosomy and tetrasomy present only in invasive cancers. Our study confirms the high frequency of chromosomal numerical aberrations in oesophageal and gastric adenocarcinomas, without differences between adenocarcinomas of the gastric cardia and antrum. We have shown that these alterations occur early during the neoplastic transformation of Barrett's mucosa.

4915 Long-term results of photodynamic therapy for barrett's esophagus.

Many mucosal ablative techniques have been used to treat Barrett's esophagus but their long-term effects are unknown. Aim: To determine the longterm results of patients with Barrett's esophagus treated by photodynamic therapy (PDT). Methods: Patients with documented Barrett's esophagus confirmed by two experienced GI pathologists were entered into a photodynamic therapy trial. PDT was performed by administering intravenous hematoporphyrin derivative (HpD) at a dose of 1.75-4 mg/kg followed in 48 hours by endoscopy and photoradiation at a dose of 175-200 J/cm fiber using a 2.5 cm cylindrical diffusing fiber. Patients were treated with omperazole 40 mg a day for maintenance therapy. Patients have been prospectively followed with endoscopy performed with biopsies taken in 4 quadrants every centimeter throughout the length of the esophagus that was formerly occupied by Barrett s mucosa. Biopsies were also taken extensively from the squamocolumnar junction. Surveillance was performed at 3-6 month intervals dependent on the degree of dysplasia. We assessed patients who have had a minimum of 1 year of follow-up after PDT. Results: A total of 78 patients (63 males) with a mean age 61±1 years have been treated with PDT for Barrett's esophagus and followed for a mean of 34±2 months. The initial Barrett's segment was 7±1 cm in length that significantly decreased to 2±1 cm after an average 2 of treatments (p<0.01). The initial histology of the group included 29 (37%) with high grade dysplasia, 3 (4%) patients with superficial cancer within Barrett's esophagus, 31 (40%) with low grade dysplasia, and 11 (14%) patients without dysplasia. After PDT, the histology improved significantly (p<0.05) to normal squamous mucosa in 23 (29%), non-dysplastic Barrett's mucosa in 34 (44%), low grade dysplasia in 18 (23%), high grade dysplasia in 1 (1%), and superficial cancer in 2 (3%). The cancers all occurred in patients who had high grade dysplasia that could not be eliminated. Strictures developed in 14 patients (18%) that were all managed endoscopically and 13 patients (17%) had cutaneous photosensitivity. Conclusions: After a mean of three years of follow-up, PDT was able to eliminate Barrett's mucosa in 29% of patients. There was a significant decrease Barrett's length and improvement in histology. PDT appears to provide durable regression of Barrett's esophagus. Many mucosal ablative techniques have been used to treat Barrett's esophagus but their long-term effects are unknown. Aim: To determine the longterm results of patients with Barrett's esophagus treated by photodynamic therapy (PDT). Methods: Patients with documented Barrett's esophagus confirmed by two experienced GI pathologists were entered into a photodynamic therapy trial. PDT was performed by administering intravenous hematoporphyrin derivative (HpD) at a dose of 1.75-4 mg/kg followed in 48 hours by endoscopy and photoradiation at a dose of 175-200 J/cm fiber using a 2.5 cm cylindrical diffusing fiber. Patients were treated with omperazole 40 mg a day for maintenance therapy. Patients have been prospectively followed with endoscopy performed with biopsies taken in 4 quadrants every centimeter throughout the length of the esophagus that was formerly occupied by Barrett s mucosa. Biopsies were also taken extensively from the squamocolumnar junction. Surveillance was performed at 3-6 month intervals dependent on the degree of dysplasia. We assessed patients who have had a minimum of 1 year of follow-up after PDT. Results: A total of 78 patients (63 males) with a mean age 61±1 years have been treated with PDT for Barrett's esophagus and followed for a mean of 34±2 months. The initial Barrett's segment was 7±1 cm in length that significantly decreased to 2±1 cm after an average 2 of treatments (p<0.01). The initial histology of the group included 29 (37%) with high grade dysplasia, 3 (4%) patients with superficial cancer within Barrett's esophagus, 31 (40%) with low grade dysplasia, and 11 (14%) patients without dysplasia. After PDT, the histology improved significantly (p<0.05) to normal squamous mucosa in 23 (29%), non-dysplastic Barrett's mucosa in 34 (44%), low grade dysplasia in 18 (23%), high grade dysplasia in 1 (1%), and superficial cancer in 2 (3%). The cancers all occurred in patients who had high grade dysplasia that could not be eliminated. Strictures developed in 14 patients (18%) that were all managed endoscopically and 13 patients (17%) had cutaneous photosensitivity. Conclusions: After a mean of three years of follow-up, PDT was able to eliminate Barrett's mucosa in 29% of patients. There was a significant decrease Barrett's length and improvement in histology. PDT appears to provide durable regression of Barrett's esophagus.