DNA ploidy abnormalities in basal and superficial regions of the crypts in Barrett's esophagus and associated neoplastic lesions

The purpose of this study was to define the zonal DNA content distribution in the basal versus the superficial crypt cells in Barrett's esophagus (BE) and related neoplastic lesions. One hundred and five tissue sections of BE patients and 12 gastric tissue section as controls were stained with hematoxylin-eosin and Feulgen and high-fidelity DNA histograms were generated from whole crypts (n=117) and also separately from the basal and superficial portions of the crypts (n=71). Three parameters were analyzed: (1) peak DNA index (DI), classified into diploidy (DI=0.9-1.1) or aneuploidy (DI>1.1), the latter of which was further divided into 3 types: mild (DI=1.1-1.3), moderate (DI=1.3-1.8), and severe (DI>1.8). (2) Heterogeneity index (HI), representing groups of cells with different DNA content. (3) Percentage of cells with DI exceeding 5N rate (5N-ER). In full crypts, compared with gastric controls, the prevalence of DNA aneuploidy increased significantly (P<0.01) from nondysplastic BE to basal crypt dysplasia (BCD), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinoma (AC). Nondysplastic BE, BCD, and LGD had mostly mild aneuploidy, and the majority of HGD and AC had either moderate or severe aneuploidy. In addition, both HI and 5N-ER increased progressively from BCD and LGD to HGD and AC (P<0.01). When analyzed separately, the superficial crypt cells were diploid in nondysplastic BE and BCD, but were aneuploid in 50% of LGD and 100% of HGD cases. In contrast, basal crypt cells were aneuploid in 37% of nondysplastic BE, 50% of BCD, 73% of LGD, and 100% of HGD cases. A similar progressive increase in the HI and 5N-ER values in basal crypt cells was observed with dysplastic progression. The changes in DNA ploidy profiles of basal crypt cells in BCD and LGD were remarkably similar. These results suggest that with neoplastic progression, dysplastic changes in BE begin in the basal crypt cells and then extend further up the crypts, and BCD represents a true early form of dysplasia limited to the crypt bases.     

Barrett's esophagus: pathologic considerations and implications for treatment

Barrett's esophagus (BE) is a complication of chronic reflux that results in the replacement of esophageal squamous epithelium with columnar epithelium. BE is endoscopically recognized and pathologically confirmed. The presence of goblet cells is diagnostic. The pathologist must also determine if dysplasia or invasive cancer is present. Acceptable terms for dysplasia are no dysplasia, indefinite for dysplasia, low-grade dysplasia (LGD), or high-grade dysplasia (HGD). It can be difficult to differentiate HGD from intramucosal cancer (IMC) in an endoscopic biopsy specimen. Treatment based on this differentiation is problematic. Indications for treatment of BE are similar to those of patients without BE. Treatment will not cause clinically significant regression of BE or prevent progression to cancer. Cancer development following successful antireflux surgery is uncommon.     

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.     

Diagnostic variation and outcome for high-grade gastric epithelial dysplasia

HYPOTHESIS: High-grade dysplasia (HGD) of the gastric epithelium is associated with high prevalence of invasive carcinoma, and distinction by endoscopic biopsy is difficult. DESIGN: Cohort study, 1996 to 2003. SETTING: Tertiary care center. PATIENTS: Consecutive sample of 22 patients with initial diagnosis of gastric HGD by endoscopic biopsy. Biopsy specimens were separately reviewed by 3 experienced pathologists. Clinical management was individually decided. MAIN OUTCOME MEASURES: Strength of interpathologist agreement (kappa) and final pathological diagnosis. RESULTS: The diagnosis was revised to intramucosal carcinoma in 14% to 32% of patients or suspicious for invasive carcinoma in 23% to 41%. The strength of agreement between any 2 pathologists for distinguishing between dysplasia and invasive carcinoma was fair (kappa = 0.35-0.36). A diagnosis of intramucosal carcinoma or suspicious for invasive carcinoma by 2 pathologists correlated strongly with subsequent detection of invasive carcinoma. Three patients underwent gastrectomy for HGD, and invasive carcinoma was detected in all (2 patients, T1 N0; 1 patient, T2 N0). Six patients had invasive carcinoma on endoscopic surveillance at a median of 15 months (range, 3-34 months) after diagnosis of HGD and underwent endoscopic mucosal resection (2 patients, T1 NX), gastrectomy (2 patients, T1 N0), or no resection (2 patients). Another patient had metastatic gastric adenocarcinoma despite having a diagnosis of only HGD by endoscopy. Seven patients (32%) died of unrelated causes, without invasive carcinoma, at a median of 19 months (range, 1-38 months). Three patients were alive with persistent HGD at 26 to 61 months. Two patients had no dysplasia on follow-up. CONCLUSIONS: Experienced pathologists often disagreed in distinguishing invasive carcinoma from HGD in gastric biopsy specimens. One third of patients with gastric HGD died of causes unrelated to cancer. Invasive carcinoma was detected in 67% of the remainder.     

Expert pathology review and endoscopic mucosal resection alters the diagnosis of patients referred to undergo therapy for Barrett’s esophagus

Background

Endoscopic therapy has emerged as an alternative to surgical esophagectomy for the management of Barrett’s esophagus (BE)-associated neoplasia. Accurate pretreatment staging is essential to ensure an appropriate choice of therapy and optimal long-term outcomes. This study aimed to assess the frequency with which expert histopathologic review of biopsies combined with endoscopic mucosal resection (EMR) would alter the pretreatment diagnosis of BE-associated neoplasia.

Methods

Patients referred to the Vanderbilt Barrett’s Esophagus Endoscopic Treatment Program (V-BEET) were retrospectively identified. Demographic, histopathologic, and endoscopic data were extracted from the medical record.

Results

For this study, 29 subjects referred for endoscopic staging of BE fulfilled the entry criteria. The referral diagnosis was low-grade dysplasia (LGD) in 3 % (1/29), high-grade dysplasia (HGD) in 62 % (18/29), intramucosal adenocarcinoma (T1a) adenocarcinoma in 17 % (5/29), and invasive adenocarcinoma in 17 % (5/29) of the subjects. Expert histopathologic review of available referral biopsy specimens altered the diagnosis in 33 % (5/15) of the cases. Further diagnostic staging with EMR showed BE without dysplasia in 10 % (3/29), LGD in 14 % (4/29), HGD in 34 % (10/29), T1a adenocarcinoma in 28 % (8/29), and invasive adenocarcinoma in 14 % (4/29) of the patients. The combination of expert histopathologic review and EMR altered the initial diagnosis for 55 % (16/29) of the subjects, with 56 % (9/16) upstaged to more advanced disease and 44 % (7/16) downstaged to less advanced disease.

Conclusions

The practice of combined expert histopathologic review and EMR alters the pretreatment diagnosis for the majority of patients with BE-associated neoplasia. Caution is advised for those embarking on endoscopic or surgical treatment for BE-associated neoplasia in the absence of these staging methods.     

Efficacy of Nissen fundoplication versus medical therapy in the regression of low-grade dysplasia in patients with Barrett esophagus: a prospective study

OBJECTIVE: The aim of this study is to compare the effect of medical and surgical treatment on the history of patients with Barrett esophagus (BE) and histologic evidence of low-grade dysplasia (LGD). SUMMARY BACKGROUND DATA: BE is a complication of severe gastroesophageal reflux. It is considered a major risk factor for esophageal adenocarcinoma, which may develop through stages from nondysplastic metaplasia to dysplasia (LGD and high-grade dysplasia). Presently, there are no recommended therapeutic guidelines for patients with LGD. METHODS: Between 1998 through 2003, 6592 patients underwent upper endoscopy; 327 of 6592 (5%) patients had BE, and 35 of 327 (10.7%) had LGD. Nineteen patients with LGD were treated with high-dose proton pump inhibitors, and 16 patients underwent laparoscopic Nissen fundoplication. Endoscopic and histologic follow-up was available in all patients after 18 months. We used multiple logistic regression to examine the effect of the 2 treatments on regression of LGD. RESULTS: LGD was predominant in men (male-to-female ratio: 1.7:1). Mean age was 58 +/- 13.5 years. Sixty percent of patients had no endoscopic evidence of esophagitis. A regression from LGD to BE was observed in 12 of 19 (63.2%) patients in the medical group and in 15 of 16 (93.8%) patients in the surgical group (statistically significant difference). Differences between the 2 groups were statistically significant (P = 0.03). CONCLUSION: The results of our study suggest that surgical treatment may be more effective than medical therapy to modify the natural history of LGD in patients with BE, perhaps because it not only controls acid but also biliopancreatic reflux into the esophagus.     

Prediction of adenocarcinoma in esophagectomy specimens based upon analysis of preresection biopsies of Barrett esophagus with at least high-grade dysplasia: a comparison of 2 systems

Distinguishing Barrett esophagus with high-grade dysplasia (BE-HGD) from intramucosal and submucosal adenocarcinomas on biopsies is challenging, yet important, in the choice of therapy. The current study evaluates preresection biopsies from patients who underwent esophagectomy for at least BE-HGD, to compare the recently published histologic categories by the University of Michigan (UM) and Cleveland Clinic (CC), correlate preresection and final resection diagnosis, and identify histologic features in biopsies that might be predictive of adenocarcinoma on esophagectomy. A total of 112 cases with a consensus biopsy diagnosis (agreement by ≥4 of 7 gastrointestinal pathologists) were statistically analyzed to identify histologic features that predicted adenocarcinoma on resection. Applying the UM criteria to the biopsy series showed excellent agreement with the CC system (κ=0.86) and significant correlation between preoperative and esophagectomy diagnoses (P<0.001). The likelihood of finding carcinoma on resection was significantly higher with the category of HGD with marked glandular distortion cannot exclude intramucosal adenocarcinoma [CC; odd ratio (OR), 2.8; P=0.046] or HGD suspicious for adenocarcinoma (UM; OR, 4.3; P=0.008), compared to HGD alone. The presence of "never-ending" glands (OR, 3.7; P=0.008), sheet-like growth (P<0.001), angulated glands (OR, 8.5; P<0.001), ≥3 dilated glands with intraluminal debris (OR, 2.6; P=0.05), and >1 focus of single-cell infiltration into the lamina propria (OR, 8.9; P<0.001) increased the odds of finding carcinoma on resection. The latter 2 variables remained independent predictors of adenocarcinoma in multivariable analysis. In conclusion, the CC and UM systems show excellent agreement and define histologic categories that can improve prediction of adenocarcinoma on resection.     

Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett's esophagus cohort

Little is known regarding the significance of esophageal biopsies that show dysplasia-like atypia limited to the bases of the crypts, without involvement of the surface epithelium in Barrett's esophagus (BE). The aim of this study was to evaluate the clinical, pathologic, immunohistochemical, and molecular characteristics of basal crypt dysplasia-like atypia (BCDA) with surface maturation in surveillance endoscopic mucosal biopsies to gain insight into its biologic significance. The Seattle Barrett's Esophagus Project is a prospective cohort study in which patients and their biopsies have been evaluated prospectively for clinical, pathologic, and molecular markers. As part of continued surveillance of the cohort, 206 consecutive BE patients were evaluated prospectively for BCDA between July 1, 2001 and August 13, 2003; 15 patients had BCDA (prevalence rate = 7.3%). These 15 patients were evaluated for clinical, pathologic, and immunohistochemical (p53 and MIB-1) features during the study period (2001-2003) as well as associations with clinical, pathologic, and molecular markers [17p(TP53) loss of heterozygosity (LOH), 9p(p16) LOH, tetraploidy, and aneuploidy] that were detected previously in the same patients in the cohort study (1983-2001). All BE patients with BCDA (male-to female ratio, 12:3; mean age, 72 years; mean length of BE, 7.0 cm; mean duration of BE, 95.1 months), except 2 (87%), had dysplasia or adenocarcinoma detected in biopsies either prior to or concurrent to the one that contained BCDA. In contrast, only 112 of 191 (59%) controls had neoplasia during the same time period (59%, P = 0.05). The difference between BCDA and controls was particularly significant with regard to the association with high-grade dysplasia (P = 0.004). Compared with adjacent nonatypical and nondysplastic (metaplastic) BE, areas of BCDA showed a significantly elevated prevalence rate of p53 positivity (60% vs. 13%, P<0.02) and a significantly elevated total crypt and basal crypt MIB-1 proliferation rate (P<0.001). Indeed, the MIB-1 proliferation rate in the basal portion of the crypts in BCDA was similar to that detected in conventional low- or high-grade dysplasia. Patients with BCDA showed a significantly increased rate of 17p(TP53) LOH (P = 0.016), aneuploidy (P = 0.004), and a trend in increased 9p(p16) LOH (P = 0.08), compared with control patients without BCDA. The clinical, pathologic, immunohistochemical, and molecular abnormalities were similar in BCDA cases that were considered low-grade versus those considered high-grade by histologic evaluation, except that high-grade cases tended to be older (79 years vs. 68 years, P = 0.06). BCDA with surface maturation, in mucosal biopsies from patients with BE, is an uncommon but significant pathologic change that shows a variety of proliferative and molecular abnormalities and has a high association with conventional dysplasia and/or adenocarcinoma. Based on these findings, BCDA warrants further investigation as a possible subtype of true dysplasia despite the morphologic appearance of surface maturation.     

Outcomes of dysplasia arising in Barrett's esophagus: a dynamic view

BACKGROUND: The management of dysplasia arising in Barrett's esophagus is controversial. STUDY DESIGN: Twenty patients (group 1, prompt attitude) underwent operation as soon as high-grade dysplasia (HGD) was discovered (n = 8) or just after either the presence of HGD was confirmed (n = 9) or invasive carcinoma (IC) was found (n = 3) in a second set of biopsy samples taken soon after HGD had been discovered. In contrast, esophagectomy in 13 patients (group 2, expectant attitude) was performed only because HGD persisted (n = 4) or turned into IC (n = 4) at endoscopic followup (7 to 23 months) (subgroup 2a, n = 8) or because HGD (n = 2) or low-grade dysplasia (LGD) (n = 3) was disregarded until dysphagia and IC developed (12 to 70 months) (subgroup 2b, n = 5). Skeletonizing en-bloc esophagectomy was performed in 29 patients and four patients (three with HGD and one with mucosal IC in the resected specimen) underwent vagus-sparing esophagectomy. RESULTS: Invasive carcinoma was found in 11 of 24 patients (45.8%) supposed to have only HGD (in repeat biopsies in 3 patients from group 1 and in the resected specimen in eight of 21 patients (38%) operated on for HGD. Metastatic lymph nodes were found in the resected specimen of seven patients (group 1: one of 20 or 5%, versus subgroup 2a: two of eight or 25%, versus subgroup 2b: four of five or 80%; p = 0.001). Unlike none of the 26 patients (0%) with an intramural process, five of the seven patients (71.4%) with an extramural process (one had had disregarded LGD) developed neoplastic recurrence at followup (p < 0.0001). Cancer-related survival in the long term was 100% in group 1 versus 52.5% in group 2 (p = 0.0094). CONCLUSIONS: Invasive carcinoma is present in almost one half of patients with HGD within a Barrett's area. Promptness in the decision regarding an esophageal resection as soon as HGD is found is much safer than expectant observation. Not enrolling a patient with LGD in an endoscopic surveillance program can lead to the development of extramural IC with poor outcomes.     

Temporally and spectrally resolved fluorescence spectroscopy for the detection of high grade dysplasia in Barrett's esophagus

BACKGROUND AND OBJECTIVES: Temporal and spectral fluorescence spectroscopy can identify adenomatous colonic polyps accurately. In this study, these techniques were examined as a potential means of improving the surveillance of high grade dysplasia (HGD) in Barrett's esophagus (BE). STUDY DESIGN/MATERIALS AND METHODS: Using excitation wavelengths of 337 and 400 nm, 148 fluorescence spectra, and 108 transient decay profiles (at 550 +/- 20 nm) were obtained endoscopically in 37 patients. Corresponding biopsies were collected and classified as carcinoma, HGD, or low risk tissue (LRT) [non-dysplastic BE, indefinite for dysplasia (IFD), and low grade dysplasia (LGD)]. Diagnostic algorithms were developed retrospectively using linear discriminant analysis (LDA) to separate LRT from HGD. RESULTS: LDA produced diagnostic algorithms based solely on spectral data. Moderate levels of sensitivity (Se) and specificity (Sp) were obtained for both 337 nm (Se = 74%, Sp = 67%) and 400 nm (Se = 74%, Sp = 85%) excitation. CONCLUSIONS: In the diagnosis of HGD in BE, steady-state fluorescence was more effective than time-resolved data, and excitation at 400 nm excitation was more effective than 337 nm. While fluorescence-targeted biopsy is approaching clinical usefulness, increased sensitivity to dysplastic changes-possibly through modification of system parameters-is needed to improve accuracy levels.     

Metallothionein: early marker in the carcinogenesis of ulcerative colitis-associated colorectal carcinoma

Metallothioneins (MTs) are zinc-binding proteins whose overexpression may lead to sequestration of zinc ions and consequently to functional inactivation of the p53 tumor suppressor gene. The aim of the study was to investigate the potential role of MTs in the carcinogenesis of ulcerative colitis (UC) as well as possible effects on p53 function. The monoclonal antibodies E9 (anti-MT), DO-7, and 1801 (anti-p53) and the polyclonal antibody CM-1 (anti-p53) were used to stain formalin-fixed, paraffin-embedded colon specimens obtained from 14 patients with UC-associated colorectal carcinoma (CAC), 13 with high-grade dysplasia (HGD), 10 with low-grade dysplasia (LGD), and 30 with UC without dysplasia or carcinoma. Statistical significance (p <0.05) was assessed using Fisher's exact test. Positive MT staining (> 20% of tumor, dysplastic, or epithelial cells) was found in most UC and LGD but in only a small percentage of HGD and CAC (p <0.01 for CAC vs. UC and LGD vs. HGD). Positive p53 immunoreactivity was observed predominantly in HGD and CAC but not in LGD and UC (p <0.01 for CAC vs. UC and HGD vs. LGD). In histologically normal tissue neighboring CAC, significant MT expression was found in six of seven specimens with simultaneous lack of p53 expression. MT overexpression may represent an important early step in the development of CAC independent of p53 expression and should be investigated in the long term as an independent cancer risk factor in UC.     

Barrett's oesophagus: endoscopic diagnosis and follow-up

Barrett's oesophagus (BO), or replacement of the squamous mucosa by a specialized intestinal metaplasia due to gastro-oesophageal reflux disease (GORD), predisposes to adenocarcinoma. It is estimated that 6 to 12% of patients undergoing GI endoscopy have short BO (< 3 cm), and 1% have a long BO. Macroscopic diagnosis of BO is sometimes difficult and, in case of doubt, endoscopy should be redone after a period of efficient anti-secretory treatment. Diagnosis of BO is histological and should be confirmed by biopsies. The incidence of adenocarcinoma is globally estimated at 0.5% patient by year of follow-up, and exists for both short and long BO. Due to this low incidence, screening for BO is only justified in patients at high risk for adenocarcinoma (male gender, age > 50 ans, old GORD in a young patient). Low-grade dysplasia (LGD) then high-grade dysplasia (HGD) precedes adenocarcinoma. Histological diagnosis of LGD is difficult: the main cause of confusion is inflammation so diagnosis of LGD must be confirmed after a 3-month high-dose anti-secretory treatment. Diagnosis of HGD is easier but multiple biopsies are needed to determine the focal or multifocal disposition of HGD. The benefit of follow-up of BO is debated. Aged patients should be followed only if dysplasia is present. When dysplasia is absent, an endoscopic control with biopsies is desirable within 3 to 5 years. In case of dysplasia, the latter must be confirmed by another examination of biopsies, particularly in case of suspicion of HGD and after antisecretory treatment. In case of LGD, endoscopy with biopsies should be redone 6 months later to screen for HGD, then every year if LGD is confirmed. In case of HGD, the 5-year risk of cancer is 60% so surgical or endoscopic treatment is usually proposed. If HGD follow-up is decided, it should be performed on a 3- to 6-month basis.     

食管鳞状细胞癌及癌前病变组织中多个染色体区域微卫星杂合性缺失的研究

目的 探讨与食管癌早期癌变的发生、发展密切相关的分子变化,寻找早期诊断的分子标记.方法 采用PCR荧光测序仪凝胶电泳分别检测34例食管癌患者手术切除的鳞状细胞癌(SCC)组织、癌前病变组织及匹配的外周血样本中16个微卫星位标的杂合性缺失状况.将轻、中度不典型增生定义为低级别不典型增生(LGD),将重度不典型增生归为高级别不典型增生(HGD).比较不同病理形态组织中16个位标的杂合缺失率.结果 16个位标的总体缺失率随组织形态的严重程度而升高,LGD中缺失率(9.8%)低于HGD(48.6%)和SCC(58.5%,P＜0.01).有8个位标,即D3S1597、D3S2452、D3S1285、D4S174、D5S2501、D9S125、D13S153和D17S786,在LGD中已呈现杂合性缺失;另发现4例患者的HGD和SCC样本分别在D3S2452、D4S174、D9S125及D17S261处出现了杂合性缺失的逆转.结论 食管鳞状上皮从不典型增生至癌变的过程中需要一系列分子变化的积累;针对某些位标的杂合性缺失分析将有助于食管癌的早期诊断;食管癌的发生可能存在遗传异质性.     

Emerging Concepts for the Endoscopic Management of Superficial Esophageal Adenocarcinoma

Journal of Gastrointestinal Surgery - Endoscopic therapy has revolutionized the treatment of Barrett’s esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma by allowing...     

Correlation between dysplasia and mutations of six tumor suppressor genes in Barrett's esophagus

BACKGROUND: Barrett's esophagus (BE) may progress to adenocarcinoma through dysplastic progression. Classification of dysplasia in BE has significant interobserver variability. Our objective was to determine whether genetic alterations in BE correlate with degrees of histologic dysplasia. METHODS: Fixed tissue from 37 patients with BE and adenocarcinoma was studied for six tumor suppressor genes. Tissues were microdissected and analyzed for loss of heterozygosity. Microdissection of individual crypts showing metaplasia and dysplasia were performed and analyzed for 23 of the 37 patients whose tumors were heterozygous for at least four of the six genes studied. RESULTS: Frequency of alterations for MXI1, hOGG1, p53, MTS1, DCC, and APC were 7 of 32 (22%), 12 of 35 (34%), 12 of 26 (46%), 17 of 30 (57%), 17 of 27 (63%), and 23 of 36 (64%), respectively. Analysis of BE demonstrated that crypts with metaplasia, low-grade dysplasia, and high-grade dysplasia strongly correlated with alterations in tumor suppressor genes (p < 0.0001). CONCLUSIONS: This pilot study demonstrates that genetic analysis can be performed on individual crypts in patients with BE, and that alterations may facilitate objective classification of the severity of dysplasia.     

The frequency of advanced adenoma in consulting patients: a nationwide survey in Iceland (2003–2006)

Aim To assess the frequency of advanced colorectal adenomas in consulting patients in Iceland. Method The histological configuration of colorectal adenomas (CRA) found in 3603 patients was classified into tubular (TA), villous (VA) and serrated (SA) and the degree of neoplastic severity into low‐grade dysplasia (LGD), high‐grade dysplasia (HGD), carcinoma in situ (CIS), intramucosal carcinoma (IMC) and submucosal carcinoma (SMC). Advanced CRA were those showing HGD, CIS, IMC and/or SMCs. In patients with two or more adenomas, the adenoma with the highest degree of epithelial neoplasia was selected to record cases. Results Between 2003 and 2006 a total of 19 424 endoscopic examinations (13 572 colonoscopies and 5852 sigmoidoscopies) were performed in Iceland (mean, 4856 endoscopies per year). At histology a mean of 759.3 CRA per year were found. Thus, CRA were found in 15.6% of the colorectal endoscopies performed per year. Out of the 3037 CRA studied, 67% were TA, 29% VA and the remaining 4% SA. LGD was present in 79%, HGD in 15%, CIS in 2.4%, IMC in 1.9% and SMC in 1.9%. Consequently, out of 3037 CRA investigated, 652 (21.5%) were advanced CRA; 71% of these showed HGD, 11% CIS, 9% IMC and 9% SMC. Two‐thirds of the 652 advanced CRA were advanced VA, and more than three‐quarters of 58 advanced CRA with SMC, were advanced VA. Conclusion Advanced VA displaying intraepithelial neoplasia (HGD and CIS) showed a propensity to evolve into invasive carcinoma. Accordingly, VA displaying HGD and CIS might be regarded as biological markers for predicting colorectal cancer risk. This is the first study in which the frequency of CRA and advanced CRA detected in consulting patients is reported on a nationwide basis.     

Minimally invasive esophagectomy for Barrett's esophagus with high-grade dysplasia

BACKGROUND: Barrett's esophagus with high-grade dysplasia (BE/HGD) is associated with invasive carcinoma in 30% to 70% of cases. Esophagectomy is the treatment of choice for patients with BE/HGD but esophagectomy can be associated with high morbidity and mortality. The aim of our study was to report our preliminary experience in applying minimally invasive surgical techniques to esophagectomy for BE/HGD. METHODS: From August 1996 to February 1999, 12 consecutive patients underwent minimally invasive esophagectomy for biopsy-proven BE/HGD. Our consort consisted of 7 men and 5 women; average age was 64 years (range, 40-78 years). All patients underwent a complete laparoscopic or combined laparoscopic and thoracoscopic resection of the esophagus with cervical anastomosis. RESULTS: Mean operative time was 7.8 +/- 2.1 hours, mean intensive care unit stay was 2.6 +/- 2.2 days, and mean length of hospital stay was 8.3 +/- 4.7 days. Five patients (42%) had carcinoma in situ or carcinoma identified on pathologic specimen. Analyses of all resected lymph nodes in the 12 patients were negative for metastatic disease. There were 6 major complications in 5 patients: 1 patient had a small bowel perforation requiring operative repair, 2 patients needed prolonged ventilatory support for respiratory insufficiency, and 3 patients had delayed gastric emptying requiring revision of the pyloromyotomy. The single minor complication in this series was a jejunostomy tube-site infection. There were no conversions to laparotomy or thoracotomy. All patients were alive and free of metastatic disease at a mean follow-up of 12.6 months. CONCLUSIONS: Minimally invasive esophagectomy is a feasible and safe alternative to conventional open esophagectomy for patients with BE/HGD.     

Association of manganese superoxide dismutase expression with progression of carcinogenesis in Barrett esophagus

HYPOTHESIS: The down-regulation of manganese superoxide dismutase (MnSOD) expression plays a role in the progression of Barrett esophagus (BE). DESIGN: An evaluation of 92 esophageal samples, including 17 patients with normal esophagus, 22 with intestinal metaplasia, 22 with indefinite/low-grade dysplasia, 16 with high-grade dysplasia (HGD), and 15 with esophageal adenocarcinoma were evaluated for MnSOD expression. We evaluated MnSOD expression using immunohistochemistry and graded it separately on a 2-category ordinal scale in relation to the mucosa and submucosa that ranged from 0 (no staining) to 3 (strong staining). The total grading score of MnSOD immunoreactivity was the addition of mucosa and submucosa intensity, from 0 (no immunoreactivity in any of the anatomic sites) to a maximum score of 6 (strong staining reaction in both of the histoanatomic sites). SETTING: Study subjects were recruited from the Barrett's Esophageal Registry at the University of Louisville, Louisville, KY. MAIN OUTCOME MEASURE: Manganese superoxide dismutase expression in established groups of progressive BE. RESULTS: Ninety-two samples were evaluated for MnSOD expression. The expression of MnSOD was found to be significantly reduced in samples with specialized intestinal metaplasia (mean score, 1.8), low-grade dysplasia (mean, 2.2), high-grade dysplasia (mean, 2.4), and esophageal adenocarcinoma (mean, 2.4) when compared with normal esophagus (mean, 3.9; P = .002). Manganese superoxide dismutase expression was similar for esophageal adenocarcinoma and high-grade dysplasia. CONCLUSIONS: Manganese superoxide dismutase expression is significantly reduced in patients with BE with high-grade dysplasia and esophageal adenocarcinoma. Manganese superoxide dismutase is related to the progression of BE and may represent one of the primary factors in oxidative stress protection. Further evaluation within genotypic expression and the role of antioxidants is needed in the effective screening and treatment of BE.     

Endoscopic Treatment of High-Grade Dysplasia and Early Esophageal Cancer

Background

The emergence of novel endoscopic modalities has challenged the role of surgery for patients with Barrett’s esophagus (BE) and high-grade dysplasia (HGD) or early esophageal adenocarcinoma.

Aim

The aim of this study was to review the available evidence of the endoscopic treatment of HGD and early esopahgeal adenocarcinoma.

Results

For most patients with BE and HGD, endoscopic ablative therapy is the preferred treatment strategy. Patients with intramucosal adenocarcinoma (T1a) should be treated with endoscopic mucosal resection (EMR) followed by ablative therapy, in order to eradicate the remaining intestinal metaplasia. The best approach to treatment of adenocarcinoma with submucosal invasion (T1b) remains elusive. Endoscopic resection may be suitable for low-risk T1b tumors (well differentiated, without lymphovascular invasion and with superficial submucosal invasion); however, further data are necessary to better risk stratify this group. Careful endoscopic surveillance is recommended following complete eradication of intestinal metaplasia to detect recurrent disease.

Conclusion

Patients with BE and HGD should undergo endoscopic ablative therapy. Patients with T1a adenocarcinoma should be treated with EMR and subsequent ablation of the entire BE segment. Low-risk T1b tumors may be suitable for endoscopic resection.

     

Esophageal preservation in esophageal high-grade dysplasia and intramucosal adenocarcinoma

The management of esophageal high-grade dysplasia (HGD) and intramucosal adenocarcinoma remains controversial. Because lymph node involvement is unlikely in this setting, interest in the treatment strategies for esophageal preservation has grown. Esophageal preservation indicates any endoluminal procedure that is used in an attempt to completely eradicate disease while preserving the anatomic structure of the esophagus. The goal of esophagus-preserving approaches is to provide definitive therapy while avoiding the morbidity of esophagectomy. This article describes the patient selection and the status of currently available esophagus-preserving options, and discusses the strategy for treating HGD and intramusocal adenocarcinoma.