Non-goblet cell population of Barrett's esophagus: an immunohistochemical demonstration of intestinal differentiation

Barrett's esophagus develops with the following 2 distinct types of lining mucosa: with and without specialized intestinal metaplasia (SIM). Goblet cells found only in SIM areas identify an intestinal phenotype, recognized as the histological hallmark diagnosing Barrett's metaplasia, and selecting high-risk patients for endoscopic surveillance. The columnar non-goblet cells are the major component of the heterogeneous Barrett's metaplastic cell population and are present in areas either with or without SIM. Their significance in the differentiation of columnar-lined esophagus, and their relationship to malignancy, is still unclear. This immunohistochemical study used two markers of enterocytic differentiation, to explore the intestinal phenotype of the non-goblet cell population of Barrett's epithelium and Barrett's-associated adenocarcinoma cells. Sucrase-isomaltase (SI) and dipeptidilpeptidase IV (DPP) immunoexpression was assessed in paraffin-embedded samples of 12 surgical specimens containing Barrett's esophageal mucosa in association with adenocarcinoma/high grade dysplasia. Ileal mucosa and mucosa from normal gastric and esophageal segments of the surgical specimen were used as positive and negative controls, respectively. SI and DPP were expressed by the neoplastic cells and the columnar non-goblet, being negative in goblet cells. The localization of the enzymes was predominantly apical for SI and cytoplasmatic for DPP. There was immunoreactivity for SI in 58.3% of the carcinomas and in 66.6% of Barrett's mucosa, with equal frequency in areas with and without SIM. DPP was identified in 66.6% of the carcinomas, in 50% of the cases of Barrett's metaplasia with SIM, and in 75% of those without SIM. The columnar non-goblet cell components of Barrett's metaplasia contain small intestine enzymes in the areas either with or without SIM, which suggests that they identify an "incomplete form" of intestinal metaplasia. The demonstration that the two enzymes, SI and DPP, are produced by the columnar non-goblet cell metaplastic population and by the neoplastic cells of the associated adenocarcinoma, indicates that, in addition to the goblet cells, the non-goblet elements may also be involved in the malignant transformation of Barrett's esophagus.     

Endoscopic versus histological diagnosis of Barrett's esophagus: a cross-sectional survey

CONTEXT : Barrett's esophagus is a common pathological condition in patients with gastro-esophageal reflux disease. OBJECTIVE : The aim of this study was to compare endoscopic diagnosis versus histological confirmation. DESIGN : Cross-sectional. SETTING: Cancer Institute of the Imam Khomeini Hospital. MATERIAL AND METHODS : A total of 50 patients with a history of gastro-esophageal reflux were recruited and underwent upper endoscopy at this cross-sectional survey. Four-quadrant biopsy was taken from all suspected areas of intestinal metaplasia. Sections of blocks were stained with Mixed Alcian Blue (PH 2.5)/PAS and haematoxylin-eosin stainings for the diagnosis of intestinal metaplasia (complete vs. incomplete types) and goblet cell / columnar cell / dysplasia, respectively. Main outcome measure : The presence of Helicobacter pylori was assessed by Giemsa staining. RESULTS : There were 44 cases of short-segment Barrett's esophagus and 6 of long-segment Barretts esophagus by endoscopy. When examined by histologic examination, 12 patients with short-segment Barrett's esophagus and 4 with long-segment Barrett's esophagus had intestinal metaplasia. Haematoxylin-eosin staining diagnosed 12 cases of intestinal metaplasia, whereas mixed alcian blue/PAS was used to diagnose 16 cases (κ = 80%, p < 0.001). The positive predictive value in the diagnosis of goblet cell metaplasia and columnar cell metaplasia was 32% and 66%, respectively. Helicobacter pylori infection was observed in 10 cases of those with columnar cell metaplasia without goblet cells, while none of the patients with intestinal metaplasia were infected. CONCLUSION : Our findings suggest that biopsy taking is necessary in all patients with gastro-esophageal reflux disease, whose results suggest columnar cell lining in distal esophagus in endoscopy.     

Mucin histochemistry of heterotopic gastric mucosa of the upper esophagus in adults: possible pathogenic implications

The mucin profile of 24 endoscopic biopsies of heterotopic gastric mucosa (HGM) of the upper esophagus in adults and a control group of ten cases of Meckel's diverticula containing heterotopic gastric mucosa were studied with two combined histochemical methods: alcian blue pH 2.5/PAS and high iron diamine/alcian blue pH 2.5. The clinical and light microscopic features of the 24 HGM cases were also reviewed. In addition to overall secretion of neutral mucins by the 24 HGM cases, mucin histochemistry showed prominent secretion of acidic mucins in 19 of 24 HGM cases (79%), with sulphomucins in 11 of 24 HGM cases (45.8%). This mucin profile of HGM was unlike that of either normal gastric mucosa or heterotopic gastric mucosa in Meckel's diverticula. Moreover, a comparison between the mucin profile and clinical features of HGM and Barrett's esophagus showed certain similarities. The data suggest a physiopathologic link between HGM and Barrett's esophagus.     

Gastric-type mucin and TFF-peptide expression in Barrett's oesophagus is disturbed during increased expression of MUC2

AIMS: Barrett's oesophagus constitutes metaplastic epithelium, often diagnosed by mucin histochemistry. We determined the mucins and trefoil factor family (TFF)-peptides that were expressed in Barrett's oesophagus, in order to study changes in protein expression in early stages of Barrett's oesophagus development. METHODS AND RESULTS: Biopsy specimens of 71 Barrett's oesophagus patients were collected, and sections were stained for secretory mucins by histochemistry. Immunohistochemistry was performed for secretory mucins (MUC2, MUC5AC, MUC5B, MUC6), TFFs (TFF1, TFF2, TFF3), and proliferation (Ki67). Protein expression in the tissue was measured semiquantitatively. MUC5AC and TFF1 showed high levels and strong colocalization in the surface epithelium, whereas MUC6, MUC5B and TFF3 were found in the deeper glandular structures. TFF2 was found in both surface and glandular epithelium. The co-ordinate expression patterns of these six markers were similar to gastric antrum epithelium. MUC2 expression was ubiquitously associated with goblet cells within intestinal metaplasia, occurring in 68% of patients, and was correlated with increasing proliferation in the epithelium. CONCLUSIONS: Virtually all cells in Barrett's oesophagus epithelium displayed a secretory phenotype, demonstrating a co-ordinate gastric-type MUC and TFF expression. When MUC2 expression was more pronounced, the expression patterns of the other MUCs and the TFFs were increasingly disturbed. MUC2 expression may constitute a marker for early change in the phenotype of Barrett's oesophagus as a precancerous lesion.     

Barrett-Ösophagus

Whereas attention in the past has been focused on goblet cells as the primary marker for Barrett’s esophagus (BE), the recent change in the definition now includes the non-goblet cell columnar cell-lined esophagus. In the present study the histological features of neoplasia of the lower esophagus and esophago-gastric junction in a German cohort were examined using immunohistochemical staining for MUC, CD10, intestinal and gastric type major tight junction proteins (claudins). Experimental studies using rat duodenogastric content reflux models have also been performed and data show that most neoplastic lesions of the esophageal glands in humans express gastric mucin phenotypes. Cardiac type mucosa was the main histological type in the surrounding mucosa of neoplastic lesions; however, most cardiac type mucosa has intestinal type tight junction proteins. BE with goblet cells has been reported to originate from stem cells located in the basal layer of esophageal squamous cell epithelium in previous models. However, the cardiac type mucosa seems to develop from the site of the stomach and not from the basal layer of esophageal squamous cell epithelium according to our model.     

Mucin histochemical analysis in the interpretation of Barrett's esophagus. Results of a multicenter study. The Operative Group for the Study of Esophageal Precancer.

A multicentric study of Barrett's esophagus (BE) was started in November 1987 to evaluate (1) the prevalence of BE among subjects undergoing upper gastrointestinal endoscopic examination; (2) the pathologic features of BE; and (3) the correlation between BE and early malignant changes. In 157 of 330 patients who underwent multiple standardized biopsies, BE was confirmed with histologic evaluation. Specialized intestinal-type BE was observed in 84 patients. By applying Alcian blue (pH 2.5)-periodate oxidation-Schiff, high-iron diamine-Alcian blue (pH 2.5), and periodate borohydride-saponification-periodate oxidation-Schiff techniques, the intestinal type of BE was subclassified into colonic and ileal types, both complete and incomplete. Fifty cases had incomplete colonic metaplasia with sulphomucins in the columnar cells and 64 had complete colonic intestinal metaplasia, 49 of them containing O-acetylated sialomucins in the goblet cells. These patients are being included in a short-term follow-up. Dysplasia (six low grade, two high grade) was observed in eight patients in areas of intestinal colonic-type epithelium; in these patients, a complete loss of O-acetylated sialomucins in the dysplastic areas and a remarkable reduction of these mucins in the surrounding tissue were observed. The reduction of O-acetylated sialomucins might indicate relative tissue immaturity, which could represent an early sign of neoplastic dedifferentiation. Therefore, the relevance of O-acetylated sialomucin content in BE, first demonstrated in intestinal type, is now evident, although its biologic importance is being studied.     

Mucins in Barrett's esophagus: a histochemical study

To define the mucin secretion of Barrett's esophagus, 132 biopsy specimens from 37 patients were studied with histochemical stains for mucins. Columnar mucous cells contained largely neutral mucins, but scattered cells in over 70% of the biopsies also produced sialomucins and sulfomucins. Goblet cells contained sialomucins, sulfomucins, or both. The distribution and relative proportions of mucins varied considerably among biopsies and among patients. Barrett's esophagus histochemically represents a heterogeneous, partially differentiated epithelium analogous to incomplete intestinal metaplasia of gastric mucosa.     

Mucin expression and proliferating cell index of esophageal Barrett's adenocarcinoma

Barrett's esophagus is a premalignant condition associated with gastroesophageal reflux disease, and consists of mucosa with a metaplastic columnar epithelium (specialized columnar epithelium). In this study, we examined the expression of mucin and the Ki-67 labeling index (LI) in 15 cases of esophageal Barrett's adenocarcinoma, and clarified the significance of incomplete intestinal metaplasia of Barrett's mucosa as a premalignant lesion. Gastric mucin (MUC5AC, HGM, and/or MUC6) was detected in 93.3% of the adenocarcinomas, while MUC2 and CD10 (markers of intestinal phenotypes) were detected in 73.3% and 46.2%, respectively. The Ki-67 LI was 34.1% in Barrett's adenocarcinoma. In all cases, gastric mucin was found in the non-neoplastic Barrett's mucosa around the adenocarcinoma. MUC2 was detected in 86.7% of proximal non-neoplastic mucosa and 100% of distal non-neoplastic mucosa, while CD10 was found in 20.0% of proximal non-neoplastic mucosa and 40.0% of distal non-neoplastic mucosa of Barrett's adenocarcinoma. In conclusion, Barrett's esophageal mucosa with intestinal metaplasia and a high Ki-67 LI is suggested to be more important as a premalignant lesion, and predominantly found in the proximal rather than distal region of Barrett's esophagus.     

Chromosomal analysis of Barrett's cells: demonstration of instability and detection of the metaplastic lineage involved.

Barrett's esophagus is lined by columnar and goblets cells with gastric and intestinal characteristics. Despite the association between goblet elements and malignancy, it was not demonstrated that other columnar cells lineages are not related to neoplasia. Chromosomal abnormalities were described in metaplasia adjacent to Barrett's neoplasia, but it is unknown which metaplastic lineages are involved. This work assessed the frequency and the type of chromosomal abnormalities in Barrett's esophagus without neoplasia and performed the identification of the metaplastic cells carrying chromosomal gains. Barrett's esophagus biopsies were collected and processed for short-term cell culture and cytogenetic analysis. Combined immunofluorescence/fluorescence in situ hybridization was performed in cases exhibiting chromosomal gains by using antisera against intestinal (MUC2) and gastric (MUC5AC and MUC6) apomucins and chromosome pericentromeric alpha satellite DNA probes for the chromosomes involved. Each case was scored for the number of spots (0, 1, 2, >2) in 200 nonoverlapping nuclei. Columnar and goblet cells were separately assessed. Short-term cell cultures were achieved in 40/60 cases (67%). There were clonal abnormalities in 27/40 cases (68%) and tetraploid (4n) clones in 10/40 (25%). Structural alterations were detected in 14/40 (35%) with recurrent breakpoints at 1q21, 15q15 and 15q22. Numerical changes (trisomies 7 and 18 and loss of Y) occurred in 16/40 (40%). Gains of chromosomes 7 and 18 were more frequent in columnar than in goblet cells (9.8% vs 0.7% (P<0.05)) and (7.9 vs 1.9% (P<0.05)) respectively. These alterations were detected in cells exhibiting gastric as well as intestinal features and were more frequent in cells without apomucin production. Conclusions: (1) chromosomal instability is a common finding in Barrett's esophagus without neoplasia. (2) The two metaplastic populations are committed, chromosomal gains being more frequent in columnar nongoblet than in goblet cells. (3) The two metaplastic phenotypes, gastric and intestinal, are equally involved.     

Significance of acid-mucin-positive nongoblet columnar cells in the distal esophagus and gastroesophageal junction

Acidic mucin-positive nongoblet columnar cells (NGCC) have recently been observed in the surface epithelium of the gastroesophageal junction (GEJ) and distal esophagus in resections from patients with traditional long segment (>3 cm) Barrett's esophagus (BE). However, the significance of finding acidic mucin-positive NGCC in the surface epithelium of biopsy specimens from the distal esophagus/GEJ region in the absence of goblet cells (GC) remains unknown. Therefore, to determine the significance of mucin histochemical changes in the distal esophagus/GEJ region, we analyzed and compared the types, prevalence, and distribution of neutral and acidic mucins in biopsy specimens obtained from 2 groups of patients: those with (32 patients) and those without (107 patients) GC identified in this area. Various mucin histochemical stains (PAS-Ab pH 2.5, HID-Ab pH 2.5, PB/KOH/PAS) were used to identify neutral mucins, acidic mucins (sialomucins and sulphomucins), and o-acetylated sialomucins. The results were compared between the 2 patient groups and correlated with the clinical, endoscopic, and pathologic features. Compared with patients without GC, patients with GC had a significantly higher male/female ratio and a higher proportion of patients with greater than 3 cm of columnar epithelium within the esophagus. Acidic mucin (sialomucin and sulphomucin)-positive NGCC in the surface, foveolar, and glandular epithelium did not show any correlation with any of the clinical, endoscopic, or pathologic features, such as esophagitis, carditis, antritis, Helicobacter pylori infection, or length of columnar epithelium in the distal esophagus. However, acidic mucin-positive NGCC correlated strongly with the presence of GC (P < .001). For example, sialomucin-positive NGCC were present in 28 of 32 (88%) patients with GC compared with 31 of 107 (29%) patients without GC (P < .001). Similarly, sulphomucin-positive NGCC were present in 20 of 32 (62%) patients with GC, compared with 11 of 107 (10%) patients without GC (P < .001). Of the non-GC cases, all biopsy specimens that stained positively for sulphomucin in surface NGCC (11 specimens), except one, showed staining restricted to the surface of multilayered epithelium, a distinctive type of epithelium that shows morphological, ultrastructural, and cytochemical features of both squamous and columnar epithelium. Sialomucin positivity in surface NGCC from the distal esophagus/GEJ region is a sensitive (sensitivity 88%), but nonspecific (specificity 71%), indicator of GC metaplasia. In contrast, sulphomucin expression in NGCC from the same anatomic area is a less sensitive (sensitivity 62%), but more specific (specificity = 90%) marker for the presence of metaplastic epithelium, of either the GC or the multilayered epithelial cell type and thus may represent an early or incomplete form of intestinal metaplasia.     

Incomplete intestinal metaplasia in the diagnosis of columnar lined esophagus (Barrett's esophagus)

To investigate the distribution and specificity of intestinal metaplasia (IM) in columnar lined esophagus (CLE), the authors reviewed biopsies of the hiatal hernia pouch (HHP) and esophagus from 17 patients with CLE (84 biopsies) and 10 controls (25 biopsies). The proximal margin of the gastric folds was used as an endoscopic landmark, corresponding to the gastroesophageal muscular junction (GEMJ). No biopsies obtained above the GEMJ in control patients showed columnar mucosa. No goblet cell metaplasia was seen in 21 biopsies of the HHP from patients with CLE or in 13 corresponding biopsies from controls. In contrast, alcian blue (AB) stains showed diffuse acid mucins in 3 of 21 biopsies of the HHP from patients with CLE and in 10 of 13 corresponding biopsies from controls, demonstrating that goblet cell metaplasia clearly distinguishes biopsies of CLE from the HHP (P less than 0.01), whereas small amounts of diffuse acid mucin on AB stains do not. IM evidenced by goblet cell metaplasia was frequently seen in biopsies only 2-3 cm above the GEMJ, and CLE was limited to that area in three patients, suggesting that the distal esophagus cannot be dismissed as a site for metaplastic and possibly premalignant mucosa. Adenocarcinoma was diagnosed during the course of the study in one patient with only 5 cm of columnar mucosa above the GEMJ.     

Esophageal adenocarcinoma arising in cervical inlet patch with synchronous Barrett's esophagus‐related dysplasia

Esophageal adenocarcinomas usually develop in Barrett's esophagus, typically through the metaplasia–dysplasia–carcinoma sequence, but adenocarcinomas can occur from heterotopic gastric mucosa in cervical esophagus (inlet patch). This report describes the first case of synchronous presentation of adenocarcinoma arising from cervical inlet patch and Barrett's esophagus‐related dysplasia in a 76‐year‐old man. Surveillance CT detected a 3‐cm polypoid mass in the cervical esophagus. Endoscopic biopsies confirmed a diagnosis of adenocarcinoma of the cervical esophagus. Barrett's esophagus was present also in the lower esophagus. Histologic examination of the surgically resected specimen revealed the polypoid mass as composed of tubular adenocarcinoma, and was associated with non‐neoplastic columnar mucosa representing pre‐existing inlet patch. Another isolated cervical inlet patch with intestinal metaplasia was also recognized. In the lower esophagus, high‐grade dysplasia was noted within the Barrett's esophagus. Immunohistochemically, the adenocarcinoma associated with inlet patch had intestinal immunophenotype (CDX2‐, CD10‐ and MUC2‐positive), whereas the Barrett's esophagus‐related high‐grade dysplasia showed mixed immunophenotype (MUC5AC‐ and MUC6‐positive, with scattered MUC2‐positive goblet cells). Previous studies and our findings suggest that intestinal metaplasia might predispose to the development of adenocarcinoma in the inlet patch. Therefore, endoscopists and pathologists should be aware of rare malignant transformation of inlet patches, especially those with intestinal metaplasia.     

Specialized metaplastic columnar epithelium in Barrett's esophagus. A comparative transmission electron microscopic study

Barrett's esophagus develops as a complication of regurgitant esophagitis and predisposes patients to the development of dysplasia and esophageal adenocarcinoma. Prior ultrastructural studies have suggested that Barrett's epithelium is a mucous secretory epithelium that shares some morphologic features with the intestine. The origin and development of Barrett's epithelium and the cellular abnormalities accompanying its neoplastic progression are poorly understood. In an attempt to better understand the histogenesis of the mucus-producing cells that predominate in Barrett's epithelium, these cells were studied by transmission electron microscopy and compared with other upper gastrointestinal epithelia: esophageal glands, normal gastric surface, pit, and cardiac gland regions, gastric intestinal metaplasia, and normal jejunal villous tip and crypt regions. A total of 134 mucosal biopsies from the stomach and esophagus of 28 patients with Barrett's esophagus and 37 biopsies from 14 other control patients were studied. Barrett's specialized metaplastic surface cells display a spectrum of ultrastructural features among three main surface columnar epithelial cell types: mucous cells resembling those seen in the normal gastric surface epithelium or resembling mucous neck cells normally seen in the gastric pits; goblet cells similar to those seen in the jejunum; and "pseudoabsorptive" cells with features of both gastric mucous secretory cells and jejunal absorptive cells. Cytoplasmic organelles of Barrett's specialized metaplastic, normal gastric mucous neck, and normal gastric surface mucous epithelial cells, including rough endoplasmic reticulum, glycogen aggregates, Golgi apparatus, and mucous secretory granules, have common ultrastructural features associated with mucus synthesis. The morphologic heterogeneity of Barrett's specialized metaplastic cells and common ultrastructural features associated with normal mucus biosynthesis suggest that they develop from a gastrointestinal stem cell that retains the capacity for a wide range of normal and abnormal differentiation in the esophagus. The identity of this undifferentiated cell, which may reside in normal proximal gastric or esophageal mucosa, remains unknown. However, the gastric mucous neck cell has properties that suggest it could be the progenitor cell for Barrett's esophagus because it is a stem cell that has ultrastructural similarities to Barrett's specialized metaplastic epithelial cells and it is located in intact gastric mucosa adjacent to where Barrett's esophagus forms.     

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.     

Functional Anatomy of the Syrinx of the Chukar Partridge (Galliformes: Alectoris chukar) as a Model for Phonation Research

The phonation process of vertebrates is influenced by the material characteristics of the participating structures, ranging from molecular to macroscopic dimensions. Good animal models for phonation research are still lacking. Due to easy availability and relatively simple structure, the syrinx of birds might serve as a good animal model for this purpose. Our aim was therefore to determine structural features of the syrinx and obtain insights into its mucus layer characteristics. Epithelium and glands were analyzed using histological, histochemical, and immunohistochemical methods and conclusions were drawn on the use of the syrinx as a model for phonation research by comparing the epithelium and its mucus characteristics to human laryngeal secretions. Ten adult partridges were analyzed. The tympanum of the syrinx developed from the last two tracheal cartilages, whereas the caudal part of the syrinx was formed from eight pieces of bronchial cartilages. The tracheal and bronchial epithelia and the pessulus of the syrinx were lined by pseudo‐stratified columnar epithelium in which goblet cells and intraepithelial glands were localized. Collagen fibers were distributed in the lamina propria of all parts of the syringeal mucosa. Elastic fibers in the membranes of the syrinx showed evident distribution. All glandular epithelial cells and goblet cells were positive for neutral, acidic and carboxylated mucins were dominant in particular. Epithelium and glands revealed positive reactivity with antibodies to the mucins MUC1, MUC2, and MUC5AC. Of these, MUC2 and MUC5AC were dominant. The syrinx of partridge can serve as a good ex vivo model for phonation research. Anat Rec, 298:602–617, 2015. © 2014 Wiley Periodicals, Inc.     

Ovarian mucinous tumor of gastric and intestinal type associated with Peutz-Jeghers syndrome: in situ hybridization study of apomucin gene transcripts

Occurrence of mucinous tumors is favored by Peutz-Jeghers syndrome (PJS). A case of bilateral ovarian mucinous tumor associated with ovarian mature teratoma occurring in a 22-year-old woman with PJS was reported. Tumor cells included 5 cell types: tall columnar mucinous pale cells with neutral mucins; goblet cells with acidic nonsulfated mucins; non mucinous columnar cells; mucinous cuboidal cells lining small glands; endocrine cells. Expression of the MUC2, MUC3, MUC5AC and MUC6 genes was demonstrated by in situ hybridization according to cell type. Some atypia and numerous mitotic figures were observed in basal glands. Diagnosis was ovarian borderline mucinous tumor with gastric and intestinal phenotype associated with PJS.     

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.     

Notch signaling pathway and Cdx2 expression in the development of Barrett's esophagus

Cdx2 expression in esophageal stem cells induced by reflux bile acids may be an important factor for development of Barrett's esophagus, whereas Notch signaling is a molecular signaling pathway that plays an important role in the determination of cell differentiation. ATOH1 (a factor associated with Notch signaling) plays an important role in differentiation of stem cells into goblet cells. However, the relationship between the Notch signaling pathway and Cdx2 expression in the development of Barrett's esophagus has not been explored. The aim of this study was to investigate the interrelationship between Notch signaling and Cdx2 in esophageal epithelial cells. The expressions of Cdx2, MUC2, and intracellular signaling molecules related to Notch signaling (Notch1, Hes1, and ATOH1) were examined using real-time polymerase chain reaction (PCR) and immunohistochemical staining with biopsy specimens obtained from esophageal intestinal metaplasia (IM) with goblet cells (IM?) and columnar epithelium not accompanied by goblet cells (IM?). For in vitro experiments, we employed human esophageal epithelial cell lines (OE33, OE19, and Het-1A). After forced Cdx2 expression by applying a Cdx2 expression vector to the cells, changes in the expressions of Notch1, Hes1, ATOH1, Cdx2, and MUC2 were analyzed by real-time PCR and western blot analysis. Changes in expressions of Notch1, Hes1, ATOH1, Cdx2, and MUC2 in cells were analyzed following stimulation with bile acids in the presence or absence of Cdx2 blocking with Cdx2-siRNA. Suppressed Hes1 and enhanced ATOH1 and MUC2 expressions were identified in IM? specimens. Forced expression of Cdx2 in cells suppressed Hes1, and enhanced ATOH1 and MUC2 expressions, whereas bile acids suppressed Hes1, and enhanced ATOH1, Cdx2, and MUC2 expressions. On the other hand, these effects were blocked by siRNA-based Cdx2 downregulation. Enhanced expression of Cdx2 by stimulation with bile acids may induce intestinal differentiation of esophageal columnar cells by interaction with the Notch signaling pathway.