同一个体食管和贲门双源癌前病变组织中Rb的表达

目的 探讨同一个体食管鳞状上皮不典型增生(esophageal epithelial dysplasia,EDYS)和贲门腺上皮不典型增生(gastric cardia dysplasia,GDYS)组织中Rb蛋白表达的变化特征及其意义.方法 采用免疫组化ABC法和组织病理学方法,分析河南食管癌高发区30例同一个体同时发生EDYS和GDYS组织中Rb蛋白的表达情况.结果 Rb在EDYS组织中阳性率为70%(21/30),GDYS组织阳性率为80%(24/30),两者阳性率差异无统计学意义(χ~2=0.800,P>0.05);同一个体EDYS和GDYS组织Rb表达有明显一致性(Kappa=0.561,P<0.01),25例(83%,25/30)同时出现EDYS和GDYS组织Rb表达的一致性改变,一致阳性率为67%(20/30),一致阴性率为17%(5/30);EDYS和GDYS组织中Rb的表达相关(P<0.01).结论 Rb在同一个体EDYS和GDYS组织中存在较高的表达一致性改变,进一步提示食管鳞癌和贲门腺癌可能具有相似的发病因素和分子机制.     

p16 gene mutations in Barrett's esophagus in gastric metaplasia - intestinal metaplasia - dysplasia - adenocarcinoma sequence

PurposeBarrett's associated esophageal adenocarcinoma (ADC) is one of the malignancies of most rapidly increasing incidence. The aim of the study was to assess p16 tumor suppressor gene alterations in the ADC premalignant conditions.Material &; MethodsIn the present study two p16 gene mutations (A148T and I49S) analysis with PCR- RFLP method have been performed in oesophageal biopsy specimen in 33 patients with Barrett's gastric metaplasia (GM), 27 - with Barrett's intestinal metaplasia (IM), 8 - with dysplasia and 11 - with ADC.ResultsWe have detected the I49S mutation in 12% (4/33) patients with GM, 18% (5/27) with IM, 50% – with dysplasia (4/8) and in 27% (3/11) – with ADC. The A148T mutation were found in 3% (1/33) patients with GM, 22% (6/27) – IM, 25% (2/8) – dysplasia and 27% patients with ADC (3/11). The frequency of the A148S mutation was rising in GM – IM – dysplasia - ADC sequence and was significantly lower in GM compared to all other grades taken together (p=0.0256). The frequency of the I49S mutation was rising in GM – IM – dysplasia sequence, to drop in ADC cases. There were no significant differences in frequency of the I49S mutation between studied groups.ConclusionsThese findings are consistent with the hypothesis on the role of the p16 mutations in early phase of Barrett's epithelium progression to ADC. The presence of p16 mutations in esophageal metaplastic columnar epithelium without goblet cells suggest that this pathology may have malignancy potential.     

Distinction between intestinal metaplasia in the cardia and in Barrett's esophagus: the role of histology and immunohistochemistry

Intestinal metaplasia in Barrett's esophagus (BIM) is a precancerous condition, whereas the carcinogenic potential of intestinal metaplasia of the cardia (CIM) is uncertain. Although clinically important, histological distinction between both conditions by endoscopic biopsies is considered problematic. In the present study, 4-mm samples of BIM (n=31) and CIM (n=9) were selected from esophagectomy specimens that had been resected for esophageal cancer. Slides were coded and stained with hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (PAS), cytokeratins (CK) 7 and 20, and CD10, which labels the intestinal brush border. The predictive value of these stains for the recognition of BIM and CIM was evaluated independently by two senior pathologists. With the use of H&E-stained slides exclusively, BIM samples were categorized correctly in 93.5% and 83.9% of cases (pathologists 1 and 2, respectively), and CIM samples, in 100% and 88.9% of cases. Alcian blue-PAS-positive goblet cells were identified by both investigators in all BIM and CIM samples. BIM-typical CK 7 and 20 immunostaining pattern was identified in 90.3%/83.9% of BIM but only in 11.1%/11.1% of CIM. CD10-positive brush border was present in 32.3%/25.8% of BIM and in 88.9%/88.9% of CIM. When HE-stained slides and immunohistologically stained slides were used together for tissue recognition, BIM were categorized correctly in 90.3%/80.6% of cases, and CIM, in 88.9%/88.9% of cases. In conclusion, BIM and CIM can be usually distinguished on the basis of HE sections. CK 7 and CK 20 expression pattern analysis discriminates correctly between BIM and CIM in the majority of cases. CD10-positive intestinal brush border is present in the majority of CIM but only in a minority of BIM. However, immunohistochemical investigations could not improve the diagnostic accuracy of HE histology alone.     

Combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus

Hepatoid adenocarcinoma arising in the esophagus is extremely rare. To date, there are only 3 cases in the world English literature. We report the fourth case here. A 76-year-old Japanese man was admitted to our hospital because of the deterioration of nephritic syndrome. He presented with chest burn, and the endoscopic examination of upper digestive tract disclosed the tumor in the lower esophagus. The subtotal esophagectomy was undertaken because of esophageal cancer. The postoperative histologic examination showed the finding of combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus. Immunohistochemically, hepatoid adenocarcinoma cells were positive for a-fetoprotein, hepatocyte, a1-antitrypsin, a1-antichymotrypsin, and CDX2, but negative for MUC5AC and MUC6. Esophageal hepatoid adenocarcinoma seems to be closely associated with Barrett esophagus and show the intestinal phenotype rather than gastric phenotype.     

Expression of survivin, p53, and caspase 3 in Barrett's esophagus carcinogenesis

The regulation of apoptosis, as a distinctive form of programmed cell death, in multistep Barrett's esophagus (BE) carcinogenesis is poorly understood. The aim of this study was to investigate, in the intestinal metaplasia-dysplasia-carcinoma sequence, the role of survivin, an inhibitor of apoptosis; the p53 protein, a tumor suppressor gene involved in cell cycle control; and caspase 3, a protease-inducing apoptosis and inhibited by survivin. Immunohistochemical expression was tested in 40 cases of BE, including 11 low-grade and 19 high-grade dysplasias (HGD), and samples were obtained from 40 surgical specimens of esophagectomy performed for HGD or Barrett's adenocarcinoma. To define the deregulation time of the proteins, overexpression was evaluated in relation to the proliferative and/or maturative compartment. In BE, cytoplasmic expression of survivin and caspase 3 (100% of cases) was significantly higher than expression of p53 (25%). The latter increased with increasing grade of dysplasia. In BE, the expression of survivin, p53, and caspase 3 mainly involved the proliferative compartment, whereas in LGD and HGD, the 3 proteins were coexpressed in both proliferative and maturative compartments. These results indicate that survivin overexpression is an early event in the proliferative compartment of BE, preceding both p53 accumulation and dysplastic changes. Cytoplasmic survivin location may indicate an initial antiapoptotic, more than proliferative, role in the early phases of Barrett carcinogenesis. Expression of caspase 3 in BE and dysplasia may be ascribed to accumulation of the nonactivated form, as the antibody used detects both cleaved and uncleaved caspase 3.     

CDX2和Villin在胃黏膜病变中的表达及其临床病理意义

目的:探讨CDX2和Villin在胃黏膜病变中的表达及其临床病理意义和诊断作用.方法:收集2015年1月至2017年5月本院胃黏膜活检标本90例,其中慢性胃炎21例,慢性胃病伴肠上皮化生22例,胃上皮内瘤变25例,胃癌22例.采用免疫组织化学方法检测CDX2和Villin蛋白在胃黏膜活检组织中的表达.结果:CDX2及Villin在慢性胃病伴肠上皮化生组、胃上皮内瘤变组及胃癌组均有高表达,其阳性率显著高于慢性胃炎组,差异有统计学意义(P<0.01);CDX2与Villin的表达存在正相关(P<0.01).结论:CDX2和Villin异常表达于胃黏膜肠上皮化生、胃上皮内瘤变及胃癌组织中,提示两者可能在胃癌(特别是肠型胃癌)的发生中起重要意义,同时在胃黏膜活检中诊断胃癌及癌前病变(尤其是形态学难以确定)时,两者联合检测可以作为辅助诊断的依据.     

Barrett's esophagus: a comprehensive review and update

Barrett's esophagus (BE) is a known precursor to esophageal adenocarcinoma. In the United States, a prevalence of up to 25% is reported in high risk populations and it is identified in about 5% of patients with gastroesophageal reflux disease (GERD). The diagnosis of BE requires endoscopically identifying columnar (“salmon colored”) mucosa, taking biopsies from targeted areas and then confirming histologically. The American College of Gastroenterologists updated its criteria in 2016, introducing a length requirement. This brief review addresses diagnosis of BE and its various associated challenges; identifying dysplasia, grading it, and management.     

Gene amplification of ERBB2 and EGFR in adenocarcinoma in situ and intramucosal adenocarcinoma of Barrett's esophagus

We examined 11 cases of carcinoma arising from Barrett's esophagus consisting of two adenocarcinomas in situ (ACIS), two intramucosal adenocarcinomas, and seven overt invasive adenocarcinomas. Overexpression of p53 (implying a mutation of the p53 gene), ERBB2, and EGFR was measured by immunohistochemistry, and gene amplification of ERBB2 and EGFR was measured by fluorescence in situ hybridization (FISH). In all cases of ACIS and the intramucosal adenocarcinomas, almost all cancer cells overexpressed p53, however the populations overexpressing ERBB2 and EGFR varied in different cases: in one ACIS, ERBB2 was coexpressed in all the cancer cells, in the other ACIS and one intramucosal adenocarcinoma, ERBB2 was overexpressed in about 50% and only 10% of the p53‐positive cells respectively. EGFR was co‐expressed in 20% in the other intramucosal adenocarcinoma. Protein overexpression of ERBB2 or EGFR corresponded to the amplification of their respective genes on a cell by cell basis. These gene amplifications, however, were not found in the seven invasive adenocarcinomas. Thus we speculate that the gene amplification occurred late in the dysplasia‐carcinoma sequence probably after the mutation of p53. Furthermore, new clonal expansion accompanied by tumor invasion might have extinguished the originally amplified genes in these tumors.     

内镜下氩离子凝固术联合雷贝拉唑治疗Barrett食管的疗效分析

目的探讨内镜下氩离子凝固术联合雷贝拉唑治疗Barrett食管疗效。方法选择经电子胃镜检查及病理组织学检查确诊为Barrett食管患者181例,随机分成3组,A组（56例）为单纯雷贝拉唑治疗组;B组（60例）为单纯内镜下氩离子凝固术治疗组;C组（65例）为内镜下氩离子凝固术联合雷贝拉唑治疗组。所有入选患者在首次治疗的3、6、12个月内随访复查内镜及病理组织学检查。结果 A、B、C三组在首次治疗的3、6、12个月内随访,A组总有效率分别为5.4%、4.9%、3.1%;B组总有效率分别为85.0%、82.4%、85.4%;C组总有效率分别为90.8%、92.5%、91.5%。以上两两组间比较均有统计学意义（P〈0.05）。结论内镜下氩离子凝固术联合雷贝拉唑治疗Barrett食管是安全有效的,值得临床推广与应用。     

Barrett's dysplasia and the Vienna classification: reproducibility, prediction of progression and impact of consensus reporting and p53 immunohistochemistry

Aims:  The Vienna classification is used to classify dysplasia in Barrett's oesophagus (BO), but reproducibility and value of diagnosis of lower grades in particular are often questioned. The aim was to test the diagnostic variability and correlation with patient outcome and to attempt to define histological features causing discrepant diagnoses, as well as to test the impact of adding p53 immunohistochemistry on reproducibility and prediction of outcome.
Methods and results:  One hundred and forty-three patients with 154 sets of biopsy specimens originally diagnosed with Barrett's dysplasia were retrieved from the pathology records of Nottingham University Hospital. Thirty-two Barrett's patients without dysplasia were added. Anonymized slides were graded independently by five pathologists without and with p53-stained slides. Interobserver variation, correlation with outcome and diagnostic accuracy were determined. Weighted κ scores between pairs of pathologists showed substantial agreement and improved after p53 immunohistochemistry. Agreement with the original diagnosis was substantially lower. Fourteen of 34 low-grade dysplasias (LGD) and 27 of 30 high-grade dysplasias on consensus progressed within 10 years compared with 18/94 and 28/39 of original diagnoses. Progression correlated with p53 positivity.
Conclusion:  The Vienna classification is useful and reproducible in BO. Consensus diagnosis by gastrointestinal pathologists produces high specificity and predictive value, even for LGD. p53 immunohistochemistry assists in diagnosis in difficult cases and predicts progression.     

Expression of MUC1 and MUC2 mucin gene products in Barrett's metaplasia, dysplasia and adenocarcinoma: an immunopathological study with clinical correlation

AIMS: Changes in the histochemical characteristics of the surface epithelial mucins is the hallmark of Barrett's metaplasia. The study investigated the pattern of expression of MUC1 and MUC2 mucin gene products in Barrett's metaplasia, dysplasia and adenocarcinoma as possible indicators of increased malignant potential. METHODS AND RESULTS: Tissue sections from 51 patients with Barrett's intestinal metaplasia, nine with dysplasia (three indefinite) and 28 resected adenocarcinomas were stained with monoclonal antibodies to MUC1 and MUC2. The majority of the patients were men (70/88, 80%) who were treated over a period of 3 years. None of the patients with dysplasia or carcinoma were under surveillance at the time of presentation. All 51 biopsies with Barrett's metaplasia expressed MUC2 and MUC1 was consistently absent. Neither MUC1 or MUC2 were expressed in the dysplastic epithelium whether in its pure form (6/6) or when associated with carcinoma (26/28) (P < 0.005). Three biopsies which were initially classified as high-grade dysplasia expressed MUC1 and these turned out to be carcinomas on further investigations. MUC1 was also expressed in 12/28 (43%) of the adenocarcinomas and majority of these were poorly differentiated stage 3 tumours (P < 0.05). MUC2 was only positive in mucin-secreting carcinomas (4/28; 14%) irrespective of the tumour stage. CONCLUSION: Despite the large number of patients with Barrett's metaplasia and carcinoma, very few patients presented with dysplasia, implying that Barrett's oesophagus is a silent disease in the community presenting late as carcinoma. The study has demonstrated aberrant expression of MUC2 (an intestinal mucin) in Barrett's metaplasia and this expression is lost when the cells become dysplastic. The lack of MUC1 in dysplastic epithelium and its expression in carcinoma could be utilized as a marker which could differentiate dysplasia from carcinoma in mucosal biopsies. Furthermore, expression of MUC1 in advanced stage oesophageal cancers (as in breast cancer) suggests an unfavourable prognosis.     

Activation of Wnt signalling promotes development of dysplasia in Barrett's oesophagus

Barrett's oesophagus is a precursor of oesophageal adenocarcinoma, via intestinal metaplasia and dysplasia. Risk of cancer increases substantially with dysplasia, particularly high-grade dysplasia. Thus, there is a clinical need to identify and treat patients with early-stage disease (metaplasia and low-grade dysplasia) that are at high risk of cancer. Activated Wnt signalling is critical for normal intestinal development and homeostasis, but less so for oesophageal development. Therefore, we asked whether abnormally increased Wnt signalling contributes to the development of Barrett's oesophagus (intestinal metaplasia) and/or dysplasia. Forty patients with Barrett's metaplasia, dysplasia or adenocarcinoma underwent endoscopy and biopsy. Mice with tamoxifen- and β-naphthoflavone-induced expression of activated β-catenin were used to up-regulate Wnt signalling in mouse oesophagus. Immunohistochemistry of β-catenin, Ki67, a panel of Wnt target genes, and markers of intestinal metaplasia was performed on human and mouse tissues. In human tissues, expression of nuclear activated β-catenin was found in dysplasia, particularly high grade. Barrett's metaplasia did not show high levels of activated β-catenin. Up-regulation of Ki67 and Wnt target genes was also mostly associated with high-grade dysplasia. Aberrant activation of Wnt signalling in mouse oesophagus caused marked tissue disorganization with features of dysplasia, but only selected molecular indicators of metaplasia. Based on these results in human tissues and a mouse model, we conclude that abnormal activation of Wnt signalling likely plays only a minor role in initiation of Barrett's metaplasia but a more critical role in progression to dysplasia.     

Two distinct pathways of carcinogenesis in primary sclerosing cholangitis

Zen Y, Quaglia A, Heaton N, Rela M & Portmann B
(2011) Histopathology  59 , 1100–1110
Two distinct pathways of carcinogenesis in primary sclerosing cholangitis Aims: To identify clinicopathological characteristics of cholangiocarcinoma and premalignant lesions arising in patients with primary sclerosing cholangitis (PSC). Methods and results: This study consisted of 25 patients with PSC and bile duct neoplasia [16 with cholangiocarcinoma and nine with biliary intra‐epithelial neoplasia (BilIN) equivalent to biliary dysplasia]. Tumour cell morphology, growth patterns, history of inflammatory bowel disease and postoperative survival were recorded. Immunohistochemistry for CK7, CK20, MUC1, MUC2, MUC5AC, MUC6 and CDX2 was performed to characterize cell phenotypes. Cholangiocarcinoma and BilIN were classified into intestinal (n = 14) and non‐intestinal classical (n = 11) types. Intestinal‐type lesions showed histological features resembling intestinal dysplasia or adenocarcinoma. Intestinal‐type cholangiocarcinoma commonly showed intraductal papillary proliferation and mucinous nodule formation. Intestinal‐type lesions often had an intestinal immunophenotype that was not detected in classical‐type lesions: CK20, 50% versus 0% (P = 0.007); MUC2, 86% versus 0% (P < 0.001); CDX2, 54% versus 0% (P = 0.003). Less commonly, intestinal‐type cholangiocarcinoma showed perineural invasion (P = 0.003). Patients with intestinal‐type cholangiocarcinoma had a more favourable cancer‐specific prognosis than those with classical‐type cholangiocarcinoma (P = 0.043). Conclusions: Bile ducts in PSC show two distinct dysplasia–carcinoma sequences as evidenced by differences in cell morphology, growth patterns, immunophenotypes and grade of malignancy.     

A classification of gastric dysplasia

Epithelial dysplasia was studied in 53 surgical specimens of gastric carcinoma and eight gastric adenomas. A spectrum of dysplasia was observed, but there were two principal types. Type I resembled the epithelium lining colonic adenomas whereas type II was composed of eosinophilic cells with basally sited vesicular nuclei. These findings are compared with reports on heterogeneity within both gastric dysplasia and dysplasia in other areas of the gastrointestinal tract. A link is demonstrated between incomplete intestinal metaplasia, type II dysplasia and the more poorly differentiated cancers of intestinal type.     

Lymphatic anastomoses between the distal esophagus and gastric cardia in dogs

The intramural lymphatic system draining the distal esophagus and gastric cardia was studied on 35 mongrel dogs, using a dye injection procedure. When the dye was injected into the esophageal or gastric mucosa within 2 cm of the esophago-gastric junction (EGJ), a mesh of lympho-capillary networks was observed advancing inferiorly or superiorly across the EGJ. The intramural lymphatics of the distal esophagus and gastric cardia anastomose, especially in the central part of the muscularis mucosae. On transmission electron microscopy, lumina filled with dye were proved to be lymphatic capillaries by demonstrating open gaps and overlapping or inter-digitating endothelial cell processes. Some lympho-capillaries containing dye were also observed beneath the esophageal epithelium. If the situation be extrapolated to human anatomy, the results suggest that lymphatic neoplastic metastases may occur even in early cases of carcinoma of the distal esophagus or gastric cardia.     

Role of cytology in the diagnosis of Barrett's esophagus and associated neoplasia

We studied 327 consecutive paired esophageal biopsies and brushing specimens obtained during the same endoscopic session to evaluate the role of cytology for the diagnosis of Barrett's esophagus (BE) and/or surveillance for associated dysplasia. A diagnosis of BE was based on the cytologic presence of goblet cells. Cases were reviewed and categorized into: 1) benign esophageal lesions (125 cases), with 48 cases of Candida (32 cases diagnosed by both techniques and 16 diagnosed only by cytology), 3 cases of herpes simplex with only 1 case diagnosed by cytology, and 74 cases of inflammation and/or repair; 2) benign BE (141 cases), with 74 cases (52%) diagnosed by both techniques, 11 cases by cytology only (8%), and 56 cases (40%) by histology only; 3) low-grade dysplasia (LGD, 30 cases), with 5 cases (17%) diagnosed with both specimens, one case (3%) by cytology only, and 24 cases (80%) by histology only; 4) high-grade dysplasia (HGD, 10 cases), with 8 cases (80%) diagnosed with both specimens, 1 case (10%) by cytology, and 1 case (10%) by histology; and 5) carcinomas (23 cases), with 20 cases (87%) diagnosed with both specimens, 2 cases (9%) by cytology only, and 1 case (4%) by histology only. Our results support the high degree of diagnostic accuracy of cytology for the diagnosis of Barrett's-associated HGD and/or carcinoma, and moderate sensitivity for BE.     

Tubal metaplasia: A cytologic study with comparison to other neoplastic and non-neoplastic conditions of the endocervix

Tubal metaplasia of the endocervix (TME), a condition that may be con/used morphologically with glandular neoplasia, is frequently found in cone or hysterectomy specimens. To determine the frequency of detecting TME in cytologic smears, we retrospectively reviewed 28 Papanicolaou (Pap) smears from 22 women (mean age 39.1 yr; range 25-60 yr) with histologically proven TME. Our criteria for TME were the presence of two cell types in addition to endocervical secretory cells, i.e., peg cells (cells with dark and granular cytoplasm and elongate nuclei) and ciliated cells. All women had cervical cytology specimens obtained with an endocervical brush shortly before the procedures in which TME was diagnosed, and five also had at least one post-procedure smear. Of 20 smears with an adequate, non-neoplastic endocervical component, TME was found in 2 (10%). In these two, TME cells constituted 10% and < 5% of all the glandular cells, respectively, and the percentage of ciliated cells in the TME was approximately 25% and 75%. In conclusion, TME was noted infrequently (10%) on the cervical cytosmears of women with histologically-proven TME. This result corresponds to the histologic finding that TME typically involves the upper endocervix and glandular epithelium, with only 13% of the women having TME on the surface of the lower endocervix. Atypical glandular cells on cervical cytology are a problem for clinicians and pathologists alike. The differential diagnosis of such atypia, including TME, cells of the lower uterine segment, squamous intraepithelial lesion in glands and glandular neoplasia, is discussed.     

Differences in genetic instability and cellular phenotype among Barrett's, cardiac, and gastric intestinal metaplasia in a Japanese population with Helicobacter pylori

Aims:  Intestinal metaplasia is considered to be a precursor lesion in both Barrett's and intestinal-type gastric cancer. The aim was to clarify the differences in molecular pathology between specialized intestinal metaplasia (SIM) in Barrett's oesophagus (BO), cardiac (CIM) and gastric intestinal metaplasia (GIM).
Methods and results:  Eighty-eight SIM cases with BO, 30 CIM cases and 52 GIM cases in patients with or without Helicobacter pylori infectionwere analysed for genetic instability and Das-1. Microsatellite instability and a loss of heterozygosity were evaluated at five microsatellite loci. The incidence of genetic instability was 55.7% in SIM, 40.0% in CIM and 23.1% in GIM, revealing a significant difference between SIM and GIM ( P  < 0.0005). For each microsatellite marker analysed, there were obvious differences in frequency among the three conditions. Das-1 reactivity was significantly higher in SIM than in CIM or GIM ( P  < 0.0001, both). Interestingly, both genetic instability and Das-1 reactivity in SIM showed a significantly higher incidence in patients with H. pylori infection than in those without ( P  < 0.005 and P  < 0.01, respectively).
Conclusions:  SIM is distinct from CIM and GIM, and the pathogenesis of SIM, like that of GIM, is associated to some degree with H. pylori infection in a Japanese population.