糜烂性食管炎、Barrett食管及食管腺癌中SOX2、CDX2的表达及其临床意义

目的探讨CDX2、SOX2在糜烂性食管炎、Barrett食管的3种不同组织类型(胃底型、贲门型、肠化生型)及食管腺癌(esophageal adenocarcinoma,EAC)中的表达及意义。方法采用免疫组化Eli Vision两步法检测CDX2和SOX2在35例贲门组、23例胃底组、14例肠化组、10例糜烂性食管炎组、7例EAC组、10例正常食管下段黏膜中的表达情况。结果 CDX2在肠化组及EAC组中的阳性率均为85.7%,显著高于其他四组(P0.05);CDX2阳性率在贲门组(11.4%)、胃底组(0)、糜烂性食管炎组(0)及正常食管组(0)中的差异无显著性(P0.05)。CDX2在贲门组(75%)及EAC组(66.7%)以(+)为主,差异无统计学意义(P0.05),与肠化组(91.7%)以()为主显著不同(P0.05)。SOX2在Barrett食管三组中的阳性率均为100%,显著高于EAC组(28.6%)(P0.05)。SOX2以(++)表达方式在胃底组(95.7%)及贲门组(74.3%)中差异无统计学意义(P0.05);显著高于肠化组(50%)和EAC组(50%)(P0.05)。SOX2和CDX2的表达在肠化型Barrett食管中呈负相关(P0.05),在贲门组、胃底组、EAC组中无明显相关(P0.05)。结论短段贲门型Barrett食管中CDX2的阳性率不高,可能只是一种柱状上皮化生,与EAC的关系不大;CDX2在鳞状上皮向特殊肠上皮化生转化过程中发挥重要作用,SOX2的沉默促进EAC发生。     

Carcinoma with Multidirectional Differentiation Arising in Barrett's Esophagus

Four cases of esophageal carcinoma arising in metaplastic Barrett's epithelium are presented in which multidirectional differentiation was demonstrated by light and/or electron microscopy and immunohistochemistry. All tumors and adjacent mucosa produced both neutral and acidic mucins, as well as one or more hormones indigenous to the gut, including gastrin, bombesin, substance P, somatostatin, and serotonin. Gastrin and somatostatin were the peptides most frequently identified in the tumors, while somatostatin and serotonin predominated in Barrett's epithelium. Ultrastructurally, neurosecretory-type granules, 80-250 nm in diameter, were present in 2 cases; squamous features also were present in one of these cases. One patient displayed hypertrophic osteoarthropathy, which disappeared after the tumor was resected.

These cases represent the majority of the Barrett-associated carcinomas in our material. Compared to the “pure” esophageal adenocarcinomas not included in this report, these tumors behaved more aggressively, with wider local involvement and nodal and systemic metastases at the time of presentation.

The incidence of multidifferentiation in esophageal carcinomas is not known nor is its possible significance, particularly with regard to tumors arising in metaplastic epithelium. This group may merit further study to detect true differences, if any, between these esophageal carcinomas and their apparently more common counterparts.     

Ultrasound-guided fine-needle aspiration diagnosis of adenocarcinoma of esophagus with signet-ring cell features arising in Barrett's esophagus: A case report

We report a rarely documented case of adenocarcinoma of esophagus with signet-ring cell features arising in a Barrett's esophagus. This was diagnosed by employing combined endosonography and fine-needle aspiration cytology. The patient had progressive dysphagia and a poorly circumscribed mass involving the distal esophagus and gastroesophageal junction. An incisional biopsy was performed which showed Barrett's esophagus with highly atypical glands suspicious for adenocarcinoma. Following that, an ultrasound-guided endoscopic fine-needle aspiration revealed a cellular specimen with multiple groups and singly dispersed atypical glandular cells with a predominance of signet-ring features. These findings represented an adenocarcinoma with signet-ring cell features arising in Barrett's esophagus. Diagn. Cytopathol. 1998;19:51–54. © 1998 Wiley-Liss, Inc.     

Claudin expression in Barrett's esophagus and adenocarcinoma

Claudins (CLDNs) are key molecules in cell adhesion, polarity, and control of paracellular solute transport. Several studies suggested that changes in claudin pattern have a role in cancer development. This study aimed to detect alterations in CLDN 1, 2, 3, 4, and 7 expression patterns in Barrett's esophagus (BE) and adenocarcinoma (ACC) compared with that in foveolar epithelium (FOV), normal squamous epithelium (SQ), and squamous cell carcinoma (SQCC). One hundred twenty five surgically or endoscopically removed, paraffin-embedded cases were studied by immunohistochemistry and analyzed statistically. BE, ACC, and FOV were dissected from 30 paraffin-embedded samples for further mRNA expression analysis. CLDN 7 was the dominating type in all epithelia and carcinomas, but its expression did not differ in normal and altered tissues. CLDN 1 expression was significantly increased in SQCC compared with that in SQ. CLDNs 3 and 4 were significantly elevated both in BE and ACC compared with that in FOV. CLDN 2 expression increased significantly in ACCs compared with that in BE. This is the first report proving similarities and differences regarding claudin expression pattern in BE and ACC compared with that in FOV and SQ. Our data prove a close link in CLDN pattern between BE and ACC, adding further evidence that BE is an alteration preceding esophageal ACC.     

Coexistence of choriocarcinoma and hepatoid adenocarcinoma in the stomach

The case is presented of a 46 year old woman who had a gastric tumor with components of choriocarcinoma, hepatoid adenocarcinoma and common types of adenocarcinoma. Although two histologic types of tumor producing carcinoplacental or carcinofetal proteins were contained within the tumor, immunohistochemical analyses, especially of placental alkaline phosphatase, clearly showed that each component was present separately within the same tumor. It was only hepatoid adenocarcinoma cells that permeated the lymph and blood vessels. After the recurrence, the serum level of alpha-fetoprotein (AFP) markedly elevated, but that of human chorlonlc gonadotropin β-subunit (hCG-β) was always within normal range. These findings Indicate that in the present case the hepatoid adenocarcinoma component was more aggressive in growth than the choriocarcinoma component.     

Hepatoid adenocarcinoma of the gallbladder: Case report and review of the literature

A rare case of hepatoid adenocarcinoma (HAC) of the gallbladder occurred in a 72-year-old man who presented with abdominal pain and was admitted to hospital. Ultrasonography and computed tomography revealed a mass in the gallbladder, multiple nodules in the liver and enlargement of the lymph nodes. He was diagnosed as having a gallbladder carcinoma with multiple liver and lymph node metastases. Cholecystectomy and partial hepatectomy was performed. Histologically, most of the mass in the gallbladder was composed of cells with eosinophilic cyto-plasm arranged in a trabecular pattern, which resembled hepatocellular carcinoma, but there was a component of well-differentiated adenocarcinoma in the mucosa. Immunohistochemically these hepatoid tumor cells were positive for Hepatocyte (Hepatocyte Paraffin 1: Hep Par1), which is considered highly sensitive and highly specific for hepatocyte differentiation. Based on these findings, this case was diagnosed as hepatoid adenocarcinoma of the gallbladder, which is generally a vary rare neoplasm in the literature, but should be included in the differential diagnosis of a mass in the gallbladder.     

Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma

Barrett's esophagus, a pre-malignant condition that can lead to esophageal adenocarcinoma, is characterized by histological changes in the normal squamous epithelium of the esophagus. Numerous molecular changes occur during the multistage conversion of Barrett's metaplasia to dysplasia and frank adenocarcinoma. Epigenetic changes, especially changes in DNA methylation are widespread during this process. Aberrant DNA methylation has been shown to occur at promoters of tumor suppressor genes, adhesion molecules and DNA repair genes during Barrett's esophagus. These epigenetic alterations can be used as molecular biomarkers for risk stratification and early detection of esophageal adenocarcinoma. We also show that genome wide analysis of methylation surprisingly reveals that global hypomethylation and not hypermethylation is the dominant change during Barrett's metaplasia. The transformation of Barrett's esophagus to frank adenocarcinoma is in turn characterized by much smaller wave of selective promoter hypermethylation. These studies reveal many novel, potential targets for new therapies and illustrate the utility of incorporating these epigenetic changes as biomarkers during endoscopic surveillance interval for patients with Barrett's esophagus.     

LOH at the sites of the DCC, APC, and TP53 tumor suppressor genes occurs in Barrett's metaplasia and dysplasia adjacent to adenocarcinoma of the esophagus

Barrett's esophagus carries a 30- to 100-fold increased risk of adenocarcinoma, which is thought to develop via a metaplasia-dysplasia-carcinoma progression. A common genetic abnormality detected in Barrett's adenocarcinoma is loss of heterozygosity (LOH) at the sites of known or putative tumor suppressor genes, of which there are at least 9 associated with esophageal adenocarcinoma. The aim of this study was to identify at which histological stage of carcinogenesis LOH at these sites occur. Microdissection of multiple paraffin-embedded tissue blocks from 17 esophagogastrectomy specimens of adenocarcinoma arising in Barrett's esophagus yielded areas of metaplasia, low-, intermediate- and high-grade dysplasia, and carcinoma. LOH analysis of microdissected tissues was performed using a double polymerase chain reaction technique with 11 microsatellite primers shown previously to have LOH in at least 30% of esophageal adenocarcinomas. Identical LOH was detected in premalignant and malignant tissues in 4 of 17 patients, and was located at 5q21-q22 (D5S346 primer), 17p11.1-p12 (TCF2 primer), 17p13.1 (TP53 primer), 18q21.1 (detected in colon cancer tumor suppressor gene [DCC] primer), and 18q23-qter (D18S70 primer). These results suggest that LOH at the sites of the DCC, adenomatous polyposis coli (APC), and TP53 tumor suppressor genes occur before the development of adenocarcinoma in Barrett's esophagus, and so merit further study as potential biomarkers of neoplastic progression in patients with Barrett's esophagus undergoing endoscopic and histological surveillance.     

Esophageal adenocarcinoma that probably originated in the esophageal gland duct: A case report

A case of primary esophageal adenocarcinoma in a 64-year-old man is reported. An ulcerating tumor was located in the middle intrathoracic esophagus. Histopathological examination revealed a moderately differentiated adenocarcinoma, which had invaded down to the adventitia. The cancerous tubuli were lined by flattened cuboidal cells with eosinophilic cytoplasm, which were analogous with the esophageal gland ducts and syringoma of the skin. The carcinoma was spread widely in the lamina propria mucosae without intraepithelial neoplastic elements. An immunohistochemical profile of individual cytokeratins and other epithelial markers in the carcinoma was similar to that of the esophageal gland ducts. Barrett's metaplastic epithelium or ectopic gastric mucosa was not found around the tumor. It is strongly suggested that this unique carcinoma is derived from the esophageal gland ducts.     

Cytological features of hepatoid adenocarcinoma of the gallbladder: A case report with immunocytochemical analyzes

Hepatoid adenocarcinoma is defined as an extrahepatic malignant neoplasm showing morphological and immunohistochemical resemblance of hepatocellular carcinoma. The occurrence of this type of tumor in the gallbladder is extremely rare. In this study, we report the first cytological case of hepatoid adenocarcinoma of the gallbladder. An 80‐year‐old Japanese female was found to have a tumorous lesion in the gallbladder. Papanicolaou smear of the ascites demonstrated a few epithelial cell clusters composed of round to oval neoplastic cells with distinct cell border and large centrally‐located nuclei. Tumor touch smear of the resected tumor revealed the presence of two distinct neoplastic components. The first component was composed of clusters or sheets of epithelial cells with distinct cell border, relatively rich clear cytoplasm, and centrally‐located nuclei, as seen in the ascites specimen. The other component was composed of tall columnar cells with large basally‐oriented nuclei, and glandular formation was noted as well. Immunocytochemical analyzes of the touch smear material demonstrated that the former component was positive for HepPar1, thus it was considered as a hepatoid adenocarcinoma, and the latter component deemed as a typical adenocarcinoma. Histopathological and immunohistochemical examination of the resected gallbladder tumor confirmed a diagnosis of hepatoid adenocarcinoma. The characteristic cytological features of hepatoid adenocarcinoma are the presence of sheets or clusters of neoplastic cells with distinct cell border and centrally‐located nuclei. Immunocytochemical analysis for HepPar1 may help its diagnosis. Demonstration of hepatoid adenocarcinoma is important in the cytological specimen because this type of tumor shows an aggressive clinical course.     

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.     

Cyclooxygenase-2 is expressed frequently and early in Barrett's oesophagus and associated adenocarcinoma

AIMS: To establish the prevalence of cyclooxygenase-2 (COX-2) expression in a large series of resected Barrett's adenocarcinoma and associated preneoplastic lesions and to correlate this expression with clinicopathological data and prognosis. METHODS: COX-2 expression was assessed by immunohistochemistry in resected surgical specimens of 66 Barrett's adenocarcinomas and 32 cases of Barrett's mucosa (with dysplasia in 17 cases). RESULTS: Epithelial expression of COX-2 protein was increased in Barrett's mucosa compared with normal oesophagus. Epithelial expression of COX-2 was found in 91% of Barrett's specialized mucosa negative for dysplasia, 94% of Barrett's mucosa with dysplasia, and 97% of Barrett's adenocarcinoma. COX-2 expression was significantly higher in the well-differentiated adenocarcinomas when compared with the poorly differentiated tumours. There was no significant correlation between COX-2 expression and the other pathological features of the tumours. Survival analysis showed no significant prognostic value for COX-2. CONCLUSION: Our results confirm up-regulation of COX-2 in Barrett's oesophagus-metaplastic and dysplastic-and in Barrett's adenocarcinoma. Increased COX-2 expression did not differ during the progression from Barrett's oesophagus negative for dysplasia to Barrett's adenocarcinoma and is related to adenocarcinoma whose histology is well differentiated. This suggests that enhanced expression of COX-2 may occur early during Barrett's-associated neoplastic transformation.     

Mucin core polypeptide expression in the progression of neoplasia in Barrett's esophagus

We have previously demonstrated a specific pattern of mucin (MUC) core polypeptide expression in Barrett's esophagus (BE) characterized by MUC1 and MUC6 positivity in goblet cells in a proportion of cases. The aim of this study was to determine the pattern of MUC expression associated with the development and progression of dysplasia in BE. Endoscopic mucosal biopsies from 35 patients with BE (10 with no dysplasia, 6 with indefinite for dysplasia, 12 with low-grade dysplasia [LGD], and 7 biopsies with high-grade dysplasia [HGD]) were immunostained (ABC method) with antibodies against MUC1, MUC2, MUC3, MUC5AC, and MUC6. The extent and pattern of staining for each marker was evaluated in intestinalized Barrett's epithelium and in the various grades of dysplasia. For cases with dysplasia, staining was evaluated separately in nondysplastic epithelium adjacent to (<1 cm) and distant from (>2 cm) areas of dysplasia. In nondysplastic BE, MUC1, MUC2, MUC3, MUC5AC, and MUC6 stained 40%, 100%, 100%, 100%, and 90% of cases, respectively, in goblet or nongoblet columnar epithelium. With the progression of dysplasia (from metaplasia to indefinite, LGD and HGD), there was a significant decrease in expression of MUC1, MUC2, and MUC3, and alterations in the staining patterns of MUC5 and MUC6. In fact, MUC1 and MUC3 were entirely absent from all cases of HGD. Interestingly, BE-associated adenocarcinomas showed an MUC phenotype distinct from that of HGD, with expression of MUC1 and MUC3 in 47% and 67% of cases, and expression of MUC1 in a membranous pattern. There was no significant difference in MUC staining in nondysplastic BE between patients with and without dysplasia. Alterations in MUC expression occur in the progression of dysplasia in BE. However, none of these markers helps identify a subgroup of patients at increased risk for neoplasia.     

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.     

Cyclooxygenase-2 expression and cell proliferation are increased in MUC2-positive area of columnar-lined esophagus

Columnar-lined esophagus is composed of intestinal type and gastric type epithelium. Only the specialized or intestinal type columnar epithelium is susceptible to the development of esophageal adenocarcinoma. The aim of the present paper was to evaluate the expression of cyclooxygenase (COX) and microsomal prostaglandin E synthase (mPGES) in gastric-type and intestinal-type metaplasia in columnar-lined esophagus and compare these with cell proliferation. Biopsy specimens of 30 columnar-lined esophagus patients were collected, and immunohistochemistry was performed for secretory mucins (MUC2, MUC5AC), COX, mPGES and cell proliferation (Ki-67). The MUC2-positive area had higher COX-2 expression and cell proliferation than the MUC5AC-positive area. There was a close correlation between COX-2 expression and cell proliferation. In contrast, the expression of COX-1, mPGES-1 and -2 was similar between intestinal metaplasia and gastric metaplasia. In conclusion, intestinal-type columnar-lined esophagus possesses COX-2 expression and a higher proliferation potential, suggesting that esophageal adenocarcinoma may arise from specialized columnar-lined esophagus.     

Carcinoma with Multidirectional Differentiation Arising in Barrett's Esophagus

Four cases of esophageal carcinoma arising in metaplastic Barrett's epithelium are presented in which multidirectional differentiation was demonstrated by light and/or electron microscopy and immunohistochemistry. All tumors and adjacent mucosa produced both neutral and acidic mucins, as well as one or more hormones indigenous to the gut, including gastrin, bombesin, substance P, somatostatin, and serotonin. Gastrin and somatostatin were the peptides most frequently identified in the tumors, while somatostatin and serotonin predominated in Barrett's epithelium. Ultrastructurally, neurosecretory-type granules, 80–250 nm in diameter, were present in 2 cases; squamous features also were present in one of these cases. One patient displayed hypertrophic osteoarthropathy, which disappeared after the tumor was resected.

These cases represent the majority of the Barrett-associated carcinomas in our material. Compared to the “pure” esophageal adenocarcinomas not included in this report, these tumors behaved more aggressively, with wider local involvement and nodal and systemic metastases at the time of presentation.

The incidence of multidifferentiation in esophageal carcinomas is not known nor is its possible significance, particularly with regard to tumors arising in metaplastic epithelium. This group may merit further study to detect true differences, if any, between these esophageal carcinomas and their apparently more common counterparts.     

Ski/SnoN expression in the sequence metaplasia-dysplasia-adenocarcinoma of Barrett's esophagus

Barrett's esophagus (BE) is a precancerous condition. However, the mechanisms underlying the transformation from metaplastic to dysplastic to adenocarcinomatous epithelium are still poorly understood. As loss of transforming growth factor-beta growth inhibition is considered a hallmark of several human neoplasms, we evaluated the expression of Ski and SnoN (proteins that antagonize transforming growth factor-beta signaling through physical interaction with Smad complex and by recruiting histone deacetylases), as markers of the transforming growth factor-beta signaling pathway, in BE with and without dysplasia. Biopsy samples from 37 patients (26 men, aged 60 +/- 8 years) with histologically proven BE were evaluated; 10 patients had concomitant low-grade dysplasia, 7 high-grade dysplasia (HGD), and 6 HGD associated with adenocarcinoma. Ski and SnoN expression was assessed immunohistochemically. Neither Ski nor SnoN was expressed in normal esophageal epithelium, but both were strongly expressed in BE tissue, with intense cytoplasmic positivity. Expression of these proteins decreased markedly in dysplastic areas in patients with low-grade dysplasia and was absent in those with HGD or HGD/adenocarcinoma. Ski and SnoN proteins are overexpressed in BE and may be involved in abnormal signaling elicited by transforming growth factor-beta in this epithelium, enhancing the tumorigenesis process. These observations might help to elucidate the molecular mechanisms involved in the BE tumorigenesis process.     

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.     

Carcinosarcoma in Barrett's oesophagus: A case report with immunohistological examination

A case of a carcinosarcoma which developed in a Barrett's oesophagus is presented. The tumour consisted of an adenocarcinoma and a spindle cell sarcoma. Immunohistological examinations demonstrated vimentin positivity in the sarcomatous portion with a negative reaction for keratin. Immunohistological and histological findings did not rule out the possibility of a double or collision tumour in this case.     

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.