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This disorder is at the forefront of research in gastrointestinal pathology. It develops in the setting of long-standing reflux esophagitis or GERD, occurring in up to 10-20% of patients with symptomatic disease. The symptoms are similar to patients with GERD. The clinical appearance, as seen by the endoscopist, is replacement of the pale whitish esophageal squamous mucosa with red, velvety mucosa. Under the microscope, this red mucosa is metaplastic columnar epithelium, of the type similar to the small intestine. This phenomenon is known as intestinal metaplasia. It occurs as a protective and adaptive mechanism of the esophageal mucosa as the squamous cells differentiate into columnar epithelium which is more resistant to gastric acid injury. Patients may be aysmptomatic or exhibit symptoms of GERD.


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SYNONYMS Barrett's esophagus
INCIDENCE 10-20% of all patients with GERD
Dysplasia in Barrett's varies from 14-40%
Rarely in children
SEX (MALE:FEMALE) 4:1 (white males)
GEOGRAPHIC DISTRIBUTION Parallels GERD, common in N. America and Europe
Uncommon in Japan and China
Heavy cigarette smoking  
Heavy alcohol abuse  


Chronic gastresophageal reflux (GERD) Reflux associated conditions such as scleroderma will also predispose
Esophageal bile reflux Associated with postgastrectomy state
Esophageal injury following lye ingestion  



Expression of apoptosis-related proteins in Barrett's metaplasia-dysplasia-carcinoma sequence: A switch to a more resistant phenotype.

Van Der Woude CJ, Jansen PL, Tiebosch AT, Beuving A, Homan M, Kleibeuker JH, Moshage H.

Departments of Gastroenterology and Pathology, University Hospital Groningen, The Netherlands.

Hum Pathol 2002 Jul;33(7):686-92 Abstract quote

Barrett's esophagus, or colomnar-lined esophagus (CLE), is a premalignant disorder in which the stratified squamous epithelium is replaced by metaplastic epithelium. To gain more insight into the process of carcinogenesis in CLE, we studied several factors involved in the apoptotic pathway in biopsies with gastric metaplasia (GM), intestinal metaplasia (IM), dysplasia, and/or adenocarcinoma.

Immunohistochemistry was performed for Fas, Bcl-2, Bax, Bcl-xl, inducible nitric oxide synthase (iNOS), and cyclooxagenase 2 (COX-2). Fas staining was positive in the epithelium of all biopsies from patients with CLE but negative in normal gastric mucosa. Fas staining was positive in all tumor cells of the 8 cases containing adenocarcinoma. Bcl-2 was positive in lamina propria immune cells of all specimens.

Bax staining was positive in the epithelium of all biopsies, including tumor cells. Bcl-xl was positive in dysplasia and tumor cells, but negative in 8 of 17 biopsies containing IM. iNOS was positive in 20 of 21 biopsies with IM and in 4 of 8 dysplasia biopsies. COX-2 was positive in 7 of 8 adenocarcinomas. We conclude that the apoptotic balance in the transformation from IM to adenocarcinoma switches to an antiapoptotic phenotype because of increased Bcl-xl expression and decreased Bax expression. Fas can be used as a marker for the differentiation of gastric mucosa and metaplasia in the esophagus. iNOS is highly positive in CLE-associated intestinal metaplasia. COX-2 is negative in nonmalignant CLE.

Therefore, pharmacologic inhibition of COX-2 activity is unlikely to be effective in the preventing CLE-associated adenocarcinoma. There was no clear correlation between iNOS expression and activation of proapoptotic and antiapoptotic genes.

p53 May be acquisition of several mutations which leads to cancer
Evaluation of p53 mutations in premalignant esophageal lesions and esophageal adenocarcinoma using laser capture microdissection.

Djalilvand A, Pal R, Goldman H, Antonioli D, Kocher O.

1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2004 Nov;17(11):1323-7. Abstract quote  

p53 mutations have been implicated in the development of esophageal malignancies.

The purpose of this study was to assess more accurately the incidence and types of p53 mutations in Barrett's esophagus (BE) with and without dysplasia and in esophageal adenocarcinoma, using pure preparations of epithelial cells obtained by laser capture microdissection (LCM). Assays were performed on paraffin-embedded tissue samples of normal antrum and premalignant and malignant esophageal samples from 57 patients, including 16 controls, 10 with BE metaplasia alone, 20 with BE-associated dysplasia, and 11 with BE-associated adenocarcinoma. All tissues were processed for LCM. DNA was extracted from isolated cells, and polymerase chain reaction (PCR) was performed using oligonucleutide primers for exons 5-8 of p53. PCR products were processed for DNA sequencing. p53 sequence abnormalities were identified in 2/16 cases of normal antrum and regenerative/chemical gastritis, 1/10 cases of BE, 1/20 cases of BE with dysplasia, and 2/11 cases of adenocarcinomas.

The abnormalities occurred in exons 7 and 8 in the form of point mutations. Our results, using LCM, show that p53 gene mutations are relatively rare in esophageal preneoplastic and neoplastic conditions. Only point mutations were detected, but no deletions/insertions were identified.

Chromosomal gains and genomic loss of p53 and p16 genes in Barrett's esophagus detected by fluorescence in situ hybridization of cytology specimens.

Fahmy M, Skacel M, Gramlich TL, Brainard JA, Rice TW, Goldblum JR, Connor JT, Casey G, Legator MS, Tubbs RR, Falk GW.

Department of Anatomic and Clinical Pathology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Mod Pathol. 2004 May;17(5):588-96. Abstract quote

Endoscopic brush cytology is a promising surveillance technique for Barrett's esophagus. Ancillary markers are sought to increase the sensitivity of cytology and allow identification of patients at increased risk for disease progression.

To determine if there are specific genetic changes in Barrett's esophagus with associated high-grade dysplasia/intramucosal adenocarcinoma compared to those without dysplasia, we performed fluorescence in situ hybridization (FISH) on cytologic specimens using probes to chromosomes and genomic regions previously described as altered in this disease. We studied archival brush cytology slides from 40 Barrett's esophagus patients: 21 with biopsy-proven high-grade dysplasia/carcinoma and 19 with no dysplasia and a minimum 5 years of negative follow-up. Centromeric enumeration probes (CEP) for chromosomes 6, 7, 11, and 12, and locus-specific probes (LSI) for 9p21 (p16 gene), and 17p13.1 (p53 gene) loci along with their corresponding CEP (9 and 17, respectively) were used in this study. A positive FISH result was defined as the presence of cells with >2 CEP signals or with a loss of the LSI signals relative to their corresponding CEP. p53 locus loss and/or aneusomy of chromosomes 6, 7, 11, and 12 abnormalities could be detected by FISH in routinely processed endoscopic brush cytology specimens from 95% of biopsy-positive cases with a specificity of 100%.

Interestingly, all five cases with cytologic changes classified as indefinite for dysplasia from patients with a positive biopsy showed changes by FISH. Loss of the p16 locus was seen commonly in patients both with and without dysplasia/carcinoma. Selected biomarkers from this study merit further investigation to determine their potential to detect genetic changes in patients with Barrett's esophagus prior to the development of high-grade dysplasia.

Frequent c-myc Amplification in High-Grade Dysplasia and Adenocarcinoma in Barrett Esophagus

Mario Sarbia, MD, Jawed Arjumand, MD, Marietta Wolter, PhD, Guido Reifenberger, MD, Hansjörg Heep, MD, and Helmut E. Gabbert, MD

Am J Clin Pathol 2001;115:835-840 Abstract

Barrett esophagus (BE) is a condition in which the normal squamous epithelium of the esophagus is replaced by a metaplastic columnar epithelium. BE is a premalignant lesion that represents the initial step in a metaplasia-dysplasia-carcinoma sequence.

In the present study, amplification of the proto-oncogene c-myc was determined by means of differential polymerase chain reaction analysis of metaplastic specialized epithelium, low-grade dysplasia, high-grade dysplasia, and invasive adenocarcinoma obtained by microscopic dissection of 43 esophagectomy specimens. Amplification of c-myc was found in none of 29 specialized epithelial specimens, none of 23 low-grade dysplasia specimens, 6 of 24 high-grade dysplasia specimens, and 17 of 39 adenocarcinoma specimens.

Our data indicate that amplification of c-myc is a late event in the metaplasia-dysplasia-carcinoma sequence in BE. Furthermore, determination of c-myc amplification may help identify high-risk patients who would benefit from intensified endoscopic surveillance or from immediate treatment.

p53 Gene Mutation and Protein Accumulation during Neoplastic Progression in Barrett’s Esophagus

Yan-Song Bian, etal.

Mod Pathol 2001;14:397-403 Abstract quote

The aim of the present study was to characterize expression and mutation of p53 during the neoplastic progression from Barrett’s esophagus to adenocarcinoma and to test the reliability of immunohistochemistry for p53 overexpression as an indicator of p53 mutation in this context. The association of both gene mutation and protein accumulation with clinicopathological findings and survival was also studied.

A total of 77 samples from 30 esophagectomy specimens with Barrett’s esophagus and adenocarcinoma of patients in longitudinal clinical follow-up were analyzed. Different lesions (intestinal metaplasia, dysplasia, and adenocarcinoma) as well as normal squamous-cell esophageal epithelia were sampled from formalin-fixed, paraffin-embedded tissues by microdissection.

Mutations in p53 Exons 5 to 9 were detected by polymerase chain reaction–single-strand conformation polymorphisms (PCR-SSCP) and confirmed by direct DNA sequencing. Nuclear accumulation of p53 protein was analyzed immunohistochemically from tissue sections adjacent to those used for microdissection. p53 gene mutations were found in 17 and p53 protein accumulation were found in 20 tumor samples. Of the 17 adenocarcinomas with a p53 mutation, 16 stained positive for p53 protein. p53 mutations were detected significantly more frequently in high-grade dysplastic than in low-grade dysplastic lesions (77% versus 29%, P < 0.01). In contrast, nuclear accumulation of p53 was detected in 85% of high-grade and 71% of low-grade dysplastic lesions. In eight cases with p53 mutation, the mutation identified in the tumors was also detected in premalignant lesions, mainly in high-grade dysplasia. In four cases of p53-mutated tumors, clones with different p53 mutations were detected in premalignant lesions. Neither p53 mutations nor p53 protein accumulations were found in metaplastic lesions.

In summary, we found that p53 mutations occurred mainly during the transition from low-grade to high-grade dysplasia in the neoplastic progression of Barrett’s esophagus but not in the nondysplastic Barrett’s mucosa. Mutational analysis of p53 by PCR-SSCP and p53 accumulation by immunohistochemistry were mostly concordant in adenocarcinoma and high-grade dysplastic lesions but frequently discordant in low-grade dysplastic lesions. No correlation between p53 gene mutation or p53 accumulation and clinicopathological findings was observed in this study.

Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders

Jonathan N. Glickman, MD, PhD
Annie Yang, BS
Aliakbar Shahsafaei, MSc
Frank McKeon, PhD
Robert D. Odze, MD, FRCP

Hum Pathol 2001;32:1157-116 Abstract quote

p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression has never been evaluated in the human gastrointestinal tract.

The aim of this study was to evaluate the expression of p63 in the esophagus and related metaplastic and neoplastic disorders to gain insight into the pathogenesis of these processes. Of particular interest was the expression of p63 in Barrett esophagus (BE) and in BE-associated multilayered epithelium. Multilayered epithelium has been postulated to represent an early precursor to the development of BE primarily because it shares morphologic and immunophenotypic features of both squamous and columnar epithelium, and has been shown prospectively to be highly associated with BE. Routinely processed mucosal biopsy or resection specimens that contained normal esophageal squamous epithelium (n = 20), squamous dysplasia (n = 4), squamous cell carcinoma (n = 7), BE (n = 10), BE-associated multilayered epithelium (n = 13), esophageal mucosal gland ducts (n = 10), BE-associated dysplasia (n = 12), and BE-associated adenocarcinoma (n = 7) were immunostained for p63 to determine the extent and location of staining. p63 staining was compared with the staining patterns observed for p53, Ki 67 (proliferation marker), and cytokeratins (CKs) 13 (squamous marker), 14 (basal squamous marker), 8/18 (columnar marker), and 19 (basal/columnar marker). Expression of p63 messenger RNA (mRNA) isoforms was also analyzed by reverse-transcription polymerase chain reaction of freshly isolated tissues.

In the normal esophagus, p63 was expressed in the basal and suprabasal layers of the squamous epithelium and in basal cells that line the mucosal gland ducts but was negative in all other epithelia of the gastrointestinal tract, including the stomach, small intestine, and colon. Similarly, p63 was not expressed in BE, but it, was present in the basal layer of multilayered epithelium in 9 of 13 cases (69%). p63-positive cells in multilayered epithelium and in the mucosal gland duct epithelium were positive for CK8/18 (100%) and CK13 (67% and 30%, respectively) and negative for CK14 (0%), in contrast to p63-positive cells in squamous epithelium, which were positive for CK14 and CK13 (100%) but negative for CK8/18.

In neoplastic tissues, p63 was diffusely expressed in all cases of esophageal squamous cell dysplasia and carcinoma but was negative in all cases of esophageal and colorectal adenocarcinoma. The N isoform of p63 mRNA predominated in all benign and neoplastic squamous tissues examined. p63 may represent a marker of 2 distinct epithelial progenitor cells (basal squamous epithelium and gland duct epithelium) in the esophagus. P63 is upregulated in squamous neoplastic conditions and in this manner may play a role in squamous carcinogenesis.

These data also indicate that multilayered epithelium is phenotypically similar to, and may share a lineage relationship with, mucosal gland duct epithelium.

Gene Amplification and Protein Overexpression of c-erb-b2 in Barrett Carcinoma and Its Precursor Lesions

Helene Geddert, MD, etal

Am J Clin Pathol 2002;118:60-66 Abstract quote

We examined 39 samples of metaplastic specialized epithelium (SE), 27 of low-grade dysplasia (LGD), 27 of high-grade dysplasia (HGD), and 46 of adenocarcinoma (CA) derived from Barrett esophagus for c-erb-b2 gene amplification using differential polymerase chain reaction and for overexpression of c-erb-b2 protein using immunohistochemical analysis.

Amplification of the c-erb-b2 gene was as follows: SE, 0.0%; LGD, 0.0%; HGD, 11.1%; and CA, 13.6%; and protein overexpression was as follows: SE, 0.0%; LGD, 7.4%; HGD, 18.5%; and CA, 21.7%. In 8 (89%) of 9 samples, c-erb-b2 gene amplification correlated with protein overexpression. The reverse was true in 8 (47%) of 17 samples: c-erb-b2 protein overexpression was proved with simultaneous gene amplification.

Amplification of c-erb-b2 is a late event in the carcinogenesis of Barrett esophagus. In contrast, protein overexpression appears more often and earlier. Besides gene amplification, other mechanisms to induce protein overexpression must exist.

The genesis of Barrett esophagus: has a histologic transition from gastroesophageal reflux disease-damaged epithelium to columnar metaplasia ever been seen in humans?

Riddell RH.

Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Arch Pathol Lab Med. 2005 Feb;129(2):164-9. Abstract quote

Has a histologic transition from gastroesophageal reflux disease-damaged epithelium to columnar metaplasia ever been seen in humans? The answer to this question seems to be that it has but that we either do not readily recognize it or it is not readily recognizable with regular light microscopy.

There are at least 3 possible mechanisms for the genesis of Barrett esophagus. The first is ulceration at the gastroesophageal junction with subsequent repair by an epithelium that differentiates into Barrett epithelium. The second is metaplasia through multilayered epithelium. The third is creeping columnar metaplasia at the Z-line proximally followed by intestinalization. These 3 hypotheses may not be mutually exclusive, and all may be operative, depending on the local circumstances, amount of inflammation, erosion, ulcers, healing, acid and alkaline reflux, and use of proton pump inhibitors.

Any of the epithelial types involved could be stable and not progress. They might even be reversible, which may also in part explain the mosaic of epithelial types that typify Barrett esophagus, and may be modified by any of the molecular mechanisms that turn protein transcription on and off (eg, promoter methylation, mutations). These mechanisms ultimately may also be involved in the genesis of neoplastic transformation.

Phenotypic Characteristics of a Distinctive Multilayered Epithelium Suggests That It Is a Precursor in the Development of Barrett's Esophagus

Jonathan N. Glickman,etal.

Am J Surg Pathol 2001;25:569-578 Abstract quote

A distinctive type of multilayered epithelium (ME) has been described at the neo-squamocolumnar junction and within columnar mucosa in patients with Barrett's esophagus (BE). This epithelium has morphologic and ultrastructural features of both squamous and columnar epithelium.

Multilayered epithelium may represent an early or intermediate stage of columnar metaplasia; therefore, we performed this study to determine the morphologic and biologic characteristics of this epithelium and to gain insight into its derivation.

Esophageal mucosal biopsies containing ME from 17 patients with BE were evaluated morphologically, stained with a variety of mucin histochemical stains; and also immunostained with antibodies against cytokeratins (CK) 13 (squamous epithelium marker); 14 (basal squamous epithelium marker) 7, 8/18, 19, and 20 (columnar epithelium markers), MIB-1 (proliferation marker); villin (intestinal brush border protein); and TGF, EGFR, pS2, and hSP (enteric proliferation/differentiation regulatory peptides). The results were compared with normal esophageal squamous epithelium, normal gastric cardia epithelium, specialized-type intestinal epithelium (BE), and esophageal mucosal and submucosal gland duct epithelium.

Multilayered epithelium expressed a pattern of mucin production (neutral mucin, sialomucin, and sulfomucin in 88%, 100%, and 71% of cases, respectively) and cytokeratin expression (CK 13 and 19 in the basal ``squamoid'' cells, CK 7, 8/18, 19, and 20 in the superficial ``columnar'' cells) similar to that of columnar epithelium in BE, and showed a high capacity for cellular proliferation (Ki-67-positive in 88% of cases) and differentiation (TGF, EGFR, pS2 and villin-positive in 100%, 100%, 93%, and 66% of cases, respectively). The mucosal gland duct epithelium showed a similar phenotypic pattern and, in one case, was seen to give rise to ME at the surface of the mucosa.

These data provide evidence in support of the hypothesis that ME represents an early or intermediate stage in the development of esophageal columnar metaplasia (BE). The mucosal gland duct epithelium may contain progenitor cells that can give rise to ME.

Distribution and Significance of Epithelial Types in Columnar-Lined Esophagus

Parakrama T. Chandrasoma, M.D.; Roger Der, M.D.; Patricia Dalton, M.D.; Greg Kobayashi, M.D.; Yanling Ma, M.D.; Jeffrey Peters, M.D.; Tom Demeester, M.D.

From the Departments of Surgical Pathology and Foregut Surgery, Keck School of Medicine at the University of Southern California, Los Angeles, California, U.S.A.

Am J Surg Pathol 2001;25:1188-1193 Abstract quote

An abnormal columnar-lined esophagus (CLE) is characterized by the presence of cardiac mucosa (CM), oxynto-cardiac mucosa (OCM), and intestinal metaplastic epithelium (IM) between gastric oxyntic mucosa and esophageal squamous epithelium.

Thirty-two patients with CLE measuring 2–16 cm long had 5–37 biopsies per patient that showed CM, OCM, or IM for a total of 424 biopsies. Detailed mapping of the distribution of epithelial types within the CLE showed a distinct zonation of epithelial types; CM was present throughout the CLE, whereas OCM and IM tended to occur in the distal and proximal part of the CLE, respectively. All 32 patients (64 of 68 biopsies) showed IM at the most proximal level, compared with 22 of 32 patients (40 of 102 biopsies) in the most distal level biopsies. The density of goblet cells was highest in the most proximal level. The differences in prevalence and density of goblet cells between most proximal and most distal level biopsies were highly significant. These data suggest that for a given number of biopsies within the CLE, the likelihood of finding IM is greatest when the biopsies are concentrated in the most proximal area of the CLE. We suggest that glandular transformation of squamous epithelium results in CM, which evolves into OCM and IM by development of specialized parietal cells and goblet cells, respectively. The severity and nature of reflux cause these epithelial transformations in a constant and predictable manner.

Recognition of these changes permits the development of morphologic definitions of reflux disease and the characterization of the sequence of epithelial changes that represent the reflux–adenocarcinoma sequence.


Modification of insulin-like growth factor 1 receptor, c-Src, and Bcl-XL protein expression during the progression of barrett's neoplasia.

Iravani S, Zhang HQ, Yuan ZQ, Cheng JQ, Karl RC, Jove R, Coppola D.

Hum Pathol. 2003 Oct;34(10):975-82. Abstract quote  

Oncogenes, growth factors, cell surface receptors, and cell-cycle and apoptotic regulatory proteins have been implicated in the growth regulation and progression of Barrett's-associated neoplasia. Among these, insulin-like growth factor 1 receptor (IGF1-R) and c-Src are reported to be key regulators of mitogenesis and tumorigenesis. In addition, c-Src may exert its transforming capability by inducing increased expression of IGF1-R on the neoplastic cells. Bcl-X(L), a member of the Bcl-2 family, blocks apoptosis and has been reported to increase in Barrett's-associated neoplasia.

To study the modifications in IGF1-R, c-Src, and Bcl-X(L) protein expression during the progression of Barrett's-associated neoplasia, we analyzed 34 resected gastroesophagectomy specimens by immunohistochemistry using antibodies to human IGF1-R, c-Src, and Bcl-X(L). In these cases, we found 22 intestinal (Barrett's) metaplasias (IMs), 25 low-grade dysplasias (LGDs), 28 high-grade dysplasias (HGDs), 34 invasive adenocarcinomas (CAs), and 19 lymph node metastases. High IGF1-R cytoplasmic staining was present in 14 of 19 (74%) node metastases, in 28 of 34 (82%) CAs, in 18 of 28 (64%) HGDs, in 13 of 25 (52%) LGDs, and in 5 of 22 (23%) IMs. Strong and diffuse c-Src expression was identified in 17 of 19 (89%) node metastases, in 29 of 34 (85%) Cas, in 26 of 28 (93%) HGDs, in 18 of 25 (72%) LGDs, and in 9 of 22 (41%) IMs. Bcl-X(L) cytoplasmic staining was evident in 12 of 19 (63%) node metastases, in 20 of 34 (59%) Cas, in 20 of 28 (71%) HGDs, in 15 of 25 (60%) LGDs, and in 6 of 22 (27%) IMs. In 11 cases, c-Src activity was measured by kinase assay and reflected the immunohistochemical results.

Our data indicate that expression levels of IGF1-R, c-Src, and Bcl-X(L) proteins are coordinately elevated in Barrett's-associated neoplasia. These findings indicate important roles of these growth regulatory proteins in the malignant progression of Barrett's-associated neoplasia.

Barrett's esophagus is characterized by expression of gastric-type mucins (MUC5AC, MUC6) and TFF peptides (TFF1 and TFF2), but the risk of carcinoma development may be indicated by the intestinal-type mucin, MUC2.

Warson C, Van De Bovenkamp JH, Korteland-Van Male AM, Buller HA, Einerhand AW, Ectors NL, Dekker J.

Gastrointestinal Pathology Unit, Catholic University Leuven, Leuven, Belgium and the Department of Pediatrics and Sophia Children's Hospital, Erasmus University, Rotterdam, The Netherlands.

Hum Pathol 2002 Jun;33(6):660-8 Abstract quote

Barrett's esophagus (BE) consists of metaplastic epithelium of the esophagus, generally diagnosed by mucin histochemistry.

We aimed to determine which mucins were expressed in BE, and to relate their expression to BE pathology. Archival biopsies of 4 patient groups were selected, based on standard histochemistry: BE without inflammation, BE with inflammation, ulcerating BE, and BE with dysplasia. Sections were stained by immunohistochemistry for secretory mucins (MUC2, MUC5AC, MUC5B, and MUC6), the proliferation marker Ki-67, and mucin-associated trefoil factor family (TFF) peptides (TFF1, TFF2, and TFF3). MUC5AC and TFF2 were expressed at similar high levels in each clinical group. Intestinal metaplasia (IM), detected both histochemically and by the intestinal mucin MUC2, was lowest in inflamed BE. The expression of the intestinal-type TFF3 did not differ among the groups. Ulcerating BE was distinguished by very low expression of MUC6 and MUC5B, but very high expression of TFF1. Proliferation was not different among the groups. In the total group of BE patients, H. pylori infection of the stomach correlated with decreased TFF2 expression in the BE epithelium.

We conclude that BE is best characterized by the specific expression of the gastric-type markers, MUC5AC, MUC6, TFF1, and TFF2. Ulcerating BE constitutes the most distinguished group with respect to mucin and TFF expression. Of the intestinal markers, MUC2 is very specific for IM in BE, whereas TFF3 is not a marker for IM. The low occurrence of IM in inflamed BE suggests that these patients may have the lowest risk of developing carcinoma.


Long segment Extends 3 cm or more up the esophagus
Short segment Extends less than 3 cm up the esophagus
Most cases associated with sliding hiatal hernia The squamocolumnar jucntion is displaced with the pink mucosa extending proximally, residual white squamous islands may be present

Are ulcers a marker for invasive carcinoma in Barrett's esophagus? Data from a diagnostic variability study with clinical follow-up.

Montgomery E, Bronner MP, Greenson JK, Haber MM, Hart J, Lamps LW, Lauwers GY, Lazenby AJ, Lewin DN, Robert ME, Washington K, Goldblum JR.

Department of Pathology, The Johns Hopkins University, Baltimore, Maryland 21205, USA.


Am J Gastroenterol 2002 Jan;97(1):27-31 Abstract quote

OBJECTIVES: We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers.

METHODS: A group of pathologist participants were asked to contribute patients' initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients.

RESULTS: There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients.

CONCLUSION: If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.


Evaluation of Initial and Deeper Sections of Esophageal Biopsy Specimens for Detection of Intestinal Metaplasia

Yoginder K. Chitkara, MD, and Catherine L. Eyre, HT(ASCP)
Am J Clin Pathol 2005;123:886-888 Abstract quote

There are wide variations in the preparation of histologic sections from endoscopic esophageal biopsy specimens.

We evaluated serial step sections from 261 esophageal or gastroesophageal junction biopsies at 4 levels to determine the first level at which goblet cell metaplasia (GCM) was detected. Deeper step sections of 152 paraffin blocks also were obtained to determine whether additional sections are useful in detecting GCM not seen in initial levels. GCM was identified in 95.3% of blocks in 3 levels. GCM was seen at level 4 in 12 blocks (4.7%). In the blocks that did not reveal intestinal metaplasia in the initial 4 levels, deeper sections disclosed GCM in only 1 (0.8%) of 120 blocks. However, deeper sections revealed initially undetected GCM in 4 of 32 blocks from patients with a history of documented Barrett esophagus.

We conclude that 4 levels of step sections are adequate in routine processing of esophageal biopsy specimens for demonstration of GCM. Deeper sections may be obtained for patients with known Barrett esophagus to better evaluate for dysplasia or find additional foci of GCM.
Specialized epithelium Intestinal metaplastic epithelium with goblet cells and columnar cells
Goblet cells contain acid mucins with mixtures of sialomucins and sulfomucins

The pathologist's most important task after diagnosing Barrett's esophagus is identifying dysplasia.

There is a well characterized risk of dysplastic Barrett's epithelium progressing to adenocarcinoma. Most experts in the area assert that dysplasia should only be diagnosed if the atypical cells extend to the mucosal surface. Dysplastic cells simply do not have the ability to mature normally. Transit time for an epithelial cell to move from the base of a gland to the mucosal surface in the stomach is only 2-6 days, thus it would thus be unusual at any one moment in time for all of the dysplastic cells to be captured at the bottom of the mucosa.

The grading system for dysplasia is most commonly a five-tiered system: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, and intramucosal adenocarcinoma.  

Is there a way for pathologists to decrease interobserver variability in the diagnosis of dysplasia?

Montgomery E.

Department of Pathology, Johns Hopkins Hospital, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Arch Pathol Lab Med. 2005 Feb;129(2):174-6. Abstract quote

Many obstacles interfere with our efforts to screen patients with Barrett esophagus. Probably the largest is choosing the appropriate patient group for screening.

Beyond this problem, sampling error on the part of endoscopists is probably more serious a problem than observer variation among pathologists reviewing patient samples. Pathologists agree well on lesions that merit close follow-up or other intervention (high-grade dysplasia and invasive carcinoma), although interobserver agreement between pathologists interpreting lesser lesions is not good.

This lack of agreement is not likely to improve substantially, and many adjunct markers are being sought in an attempt to identify patients with lesions of lower grades that are most likely to progress, allowing doctors to identify patients who would benefit from upgraded surveillance.
Negative for dysplasia

The metaplastic glands consistently show nuclear atypism when contrasted with normal columnar epithelium. This atypism comprises nuclear enlargement, crowding, hyperchromatism, prominence of nucleoli, and occasional mild stratification.

These mild abnormalities may be misinterpreted as dysplasia, but can usually be separated from it because they are confined to the lower portion of the glands, while the upper portion of the glands and surface epithelium shows less abnormality or is normal. This feature is best recognized in well-oriented biopsy specimens.

Indefinite for dysplasia

This category is reserved for biopsies in which there is doubt as to the significance of the epithelial abnormalities.

Often there is mild nuclear stratification of the surface epithelium, but the cytologic features fall short of those typical of dysplasia. The nuclei may be enlarged, but they are uniform in size and shape and have less hyperchromatism and irregularity of nuclear contour than seen in dysplasia.

When the nuclear features on the mucosal surface appear dysplastic, but there is prominent active inflammation, granulation tissue, or an adjacent ulcer, the diagnosis of dysplasia is difficult, and unless it is overt, the term "indefinite for dysplasia." is used.

Active inflammation can cause nuclear changes that mimic dysplasia; therefore the threshold for dysplasia is raised in its presence.   In poorly oriented biopsies, or in those with an eroded surface, the glands may appear dysplastic, but no surface epithelium is available for evaluation. These biopsies may be classified as indefinite for dysplasia, or as dysplastic but without assigning a grade, depending on the degree of abnormality.

Low-grade dysplasia

The atypical nuclei of dysplastic epithelium extend onto the mucosal surface so both the surface and the glands contain nuclei that are much larger and hyperchromatic than the nuclei in unaffected epithelium. Two major patterns of abnormal epithelium in Barrett's esophagus have been described.

The first pattern is characterized by glands lined by cells with crowded, stratified, hyperchromatic nuclei that extend onto the mucosal surface. Depending on the degree of cytologic atypism, this pattern may be interpreted as indefinite for dysplasia, or as low-grade dysplasia.    

The second pattern consists of cells on the mucosal surface with obviously dysplastic nuclei (large, hyperchromatic, irregular contours) that are basally located in the cell with minimal or no stratification. This phenotype of dysplasia may be overlooked at low power as it often lacks goblet cells and may be confused with gastric cardiac epithelium.

Frequently, both an absence of goblet cells and mucin depletion in the non-goblet columnar cells may be seen in dysplastic epithelium. At low power, these areas appear more hyperchromatic as compared to uninvolved areas. Entire biopsies composed of dysplastic epithelium may not contain goblet cells and may be confused with reactive gastric cardiac epithelium. However, the degree of nuclear atypia can help in differentiating dysplastic epithelium from reactive gastric mucosa. Less frequently, dysplastic epithelium may secrete excessive mucus and once again may be confused with gastric cardiac epithelium. Careful examination of the nuclei in this pattern of dysplasia reveals prominent atypism with indentations in the nucleus produced by the mucin. The presence of obviously dysplastic epithelium elsewhere within the biopsy will help characterize this pre-malignant phase of Barrett's esophagus.    

One feature that is commonly seen in non-dysplastic reactive Barrett's epithelium is the presence of apical mucin. One should hesitate to make a diagnosis of dysplasia when apical mucin persists and usually make the diagnosis of negative or indefinite for dysplasia, depending on the nuclear features. Reactive metaplastic columnar epithelium shows atypism; but the nuclei are uniformly enlarged with little hyperchromatism, and they maintain a basal orientation. It is the uniformity and lack of pleomorphism that indicate a reactive, rather than a neoplastic, process.    

High-grade dysplasia

At low power, distortion of glandular architecture usually is present and may be marked; it is composed of branching and lateral budding of crypts, a villiform configuration of the mucosal surface, or intraglandular bridging of epithelium to form a cribriform pattern of "back-to-back" glands.

Most importantly, there should be dysplastic epithelium on the mucosal surface with loss of nuclear polarity, characterized by "rounding up" of the nuclei, and absence of a consistent relationship of nuclei to each other.

Intramucosal adenocarcinoma

Glandular architecture can be highly complex in high-grade dysplasia. This complexity often makes it difficult to exclude the diagnosis of intramucosal adenocarcinoma. Before making the diagnosis of invasive carcinoma, we require the presence of individual cytologically malignant cells or abortive glands infiltrating the lamina propria.

Typically, the desmoplastic stroma often present in carcinomas invading the submucosa is absent when invasion is limited to the lamina propria.


Ulcer/Erosion with marked active inflammation

Active inflammation may cause nuclear changes that mimic high-grade dysplasia. One should be cautious when numerous neutrophils infiltrate the overlying epithelium; however, the degree of inflammation is important to note. Barrett's esophagus with high-grade dysplasia may be associated with a few neutrophils in the overlying epithelium, but the nuclear changes are so dramatic that the diagnosis of high-grade dysplasia can be made.

If numerous neutrophils or an adjacent ulcer are present, we avoid the diagnosis of dysplasia and use the category of "indefinite for dysplasia." Chronic inflammatory cells do not cause the nuclear abnormalities associated with active inflammation.

Metaplastic columnar epithelium underlying squamous epithelium

Use of proton-pump inhibitors may cause caudad migration of the squamo-columnar junction, or squamous islands may develop within the Barrett's segment.

In either case, Barrett's metaplastic epithelium may still present underneath the squamous epithelium on the surface (squamous overgrowth). Because dysplasia and adenocarcinoma may develop within the metaplastic columnar epithelium underneath the squamous surface, the endoscopist must biopsy these squamous islands. Unfortunately, since no overlying columnar epithelium is present for evaluation (being completely replaced by squamous epithelium) the criterion of mucosal surface involvement by atypical epithelium cannot be used to make the diagnosis of dysplasia. Look for marked nuclear atypia in combination with architectural distortion before raising the possibility of dysplasia.

It is difficult to make the diagnosis of low-grade dysplasia based on the deep glands alone; but a diagnosis of high-grade dysplasia can be rendered if the nuclear features (loss of nuclear polarity, hyperchromatism, pleomorphism) are consistent with high-grade dysplasia.    

Metaplastic columnar epithelium adjacent to a squamous island

Frequently the columnar epithelium immediately adjacent (1 to 2 glands) to a squamous island displays atypical nuclear features that are present on the mucosal surface. It is difficult to make the diagnosis of dysplasia in this context. Look for nuclear atypia involving the surface epithelium in areas several crypts away from the squamous island before making the diagnosis of dysplasia.

In Barrett's esophagus negative for dysplasia, the epithelium on the mucosal surface should appear normal 2 or 3 glands away from the squamous island. Abnormal nuclear changes beyond this point probably indicate dysplasia.  

Detached fragments of atypical epithelium

The surface epithelium in Barrett's esophagus may become detached from the lamina propria, and these detached fragments may display features suggesting dysplasia.

For reasons that are not clear, but possibly due to the trauma that removed them from the surface, the nuclei of the cells within these strips of detached atypical epithelium may appear highly atypical when there is no dysplasia.

Caution is warranted in making the diagnosis of dysplasia based on these fragments if no dysplastic epithelium is present within the intact biopsy. A diagnosis of high-grade dysplasia based on detached fragments alone should probably not be made. If the nuclear changes are highly atypical, consider the diagnosis of indefinite for dysplasia or, possibly, dysplasia, without assigning a grade.

Reactive gastric cardiac mucosa

Reactive gastric cardiac mucosa displays nuclear atypia that may be misinterpreted as dysplastic metaplastic epithelium. 

The absence of goblet cells may be an important clue; but it must be remembered that in dysplastic epithelium, goblet cells may not be seen on biopsy specimens. 

Dysplastic epithelium lacking goblet cells will display greater nuclear atypia than seen in reactive gastric cardiac epithelium.  


Biologic Properties of Columnar Epithelium Underneath Reepithelialized Squamous Mucosa in Barrett's Esophagus.

Hornick JL, Blount PL, Sanchez CA, Cowan DS, Ayub K, Maley CC, Reid BJ, Odze RD.

From the *Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and daggerFred Hutchinson Cancer Research Center, Seattle, WA.
Am J Surg Pathol. 2005 Mar;29(3):372-380. Abstract quote  

Chronic proton pump inhibitor (PPI) therapy may lead to partial regression of Barrett's esophagus (BE), resulting in the development of reepithelialized islands of squamous mucosa that may cover the underlying BE.

The purpose of this study was to evaluate the clinical, histologic, and biologic characteristics of BE that is situated underneath squamous islands (BUSI). A total of 97 mucosal biopsies from 44 BE patients with BUSI were evaluated for a variety of histologic features (eg, type of epithelium, anatomic relationship of the underlying glands to the luminal surface, presence of adjacent mucosal glands or ducts, and the presence and degree of dysplasia), and immunostained for Ki-67, cyclin D1, and p53. BUSI was compared with adjacent areas of BE for all parameters. A clinical control group consisting of 50 BE patients without microscopic evidence of BUSI was selected for comparison of clinical and endoscopic features.

The study group (34 males, 10 females; mean age, 67 years; mean length of BE, 5.5 cm) consisted of 27 (61%) and 12 (27%) patients on low- and high-dose PPI, respectively. On endoscopy, visible islands of squamous mucosa were noted in only 43% of study group patients (despite the presence of BUSI microscopically in all cases); one island was noted in 2%, multiple islands in 27%, and extensive islands in 14% of patients. The extent of squamous islands was unrelated to PPI dose. The study group was significantly more likely to have endoscopic evidence of extensive squamous islands compared with the control group (P = 0.009).

Histologically, 89% of biopsies with BUSI showed intestinal-type, and 11% showed cardia-type, epithelium. Low- and high-grade dysplasia was noted in 4 (4%) and 5 (5%) biopsies, respectively. All patients with dysplasia in BUSI also showed dysplasia in other areas of the esophagus as well. Interestingly, BUSI reached the mucosal surface either by penetrating directly through, or by wrapping around, islands of squamous epithelium, in 68% of biopsies. Twenty-one percent of biopsies showed BUSI adjacent to submucosal glands or ducts. BUSI showed a significantly lower Ki-67 proliferation rate (29% vs. 49%, P < 0.001), and a lower, albeit nonsignificant, degree of cyclin D1 (16% vs. 29%) and p53 (4% vs. 17%) positivity in comparison to adjacent areas of BE. Furthermore, significantly lower proliferation rates were observed in BUSI that did not reveal an opening to the mucosal surface in comparison to foci that did. BUSI is phenotypically similar to typical surface BE but shows less severe proliferative abnormalities, particularly in buried glands that have no detectable connection to the esophageal lumen. Reduced proliferation may be due either to decreased exposure to luminal contents or to disruption of sloughing of surface epithelial cells into the crypt lumen.

Prospective studies of large numbers of patients with BUSI will be required to determine the magnitude of its risk of progression to cancer.
Ciliated Surface in the Esophagogastric Junction Zone: A Precursor of Barrett's Mucosa or Ciliated Pseudostratified Metaplasia?

Takubo K, Vieth M, Honma N, Izumiyama N, Sawabe M, Arai T, Iwakiri K, Kammori M, Mafune KI.

From the *Human Tissue Research Group, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; daggerInstitute of Pathology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; and double daggerDepartment of Pathology, Tokyo Metropolitan Geriatric Medical Center, section signThird Department of Internal Medicine, Nippon Medical School, and parallelDepartment of Gastroesophageal Surgery, University of Tokyo, Tokyo, Japan.
Am J Surg Pathol. 2005 Feb;29(2):211-217. Abstract quote

We have previously reported squamous metaplasia-like change at the esophagogastric junction (EGJ). In the present study, we examined these lesions histologically and by immunohistochemistry and electron microscopy. Samples of EGJ mucosa, 3 cm long and comprising 1.5-cm long portions of both columnar and squamous mucosa, were obtained from 43 esophagectomy resection specimens. Squamous metaplasia-like change was observed in 21 (49%) of the 43 cases. The squamous metaplasia-like change was generally positive with immunohistochemical stains for tubulin and cytokeratins (CKs) 4, 7, 8, 13, and 18, and was generally negative with stains for CKs 10, 14, and 20.

This pattern of immunoreactivity is very similar to that of bronchial mucosa. Also, many cilia were detected at the apices of the cells by electron microscopy in 5 (31%) of the 16 cases that were able to be examined. Therefore, squamous metaplasia-like change at the EGJ has both a similar appearance and a similar immunohistochemical profile to respiratory bronchial epithelium.

These findings may suggest that squamous metaplasia-like change at the EGJ is not a precursor of Barrett's mucosa but rather is a form of pseudostratified metaplasia.
Crypt Dysplasia With Surface Maturation: A Clinical, Pathologic, and Molecular Study of a Barrett's Esophagus Cohort.

Lomo LC, Blount PL, Sanchez CA, Li X, Galipeau PC, Cowan DS, Ayub K, Rabinovitch PS, Reid BJ, Odze RD.

*Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA daggerDivisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA double daggerDepartment of Medicine, University of Washington, Seattle, WA section signDepartment of Gastroenterology, Virginia Mason Medical Center, Seattle, WA perpendicularDepartment of Pathology, University of Washington, Seattle, WA paragraph signDepartment of Genome Sciences, University of Washington, Seattle, WA.

Am J Surg Pathol. 2006 Apr;30(4):423-435. Abstract quote  

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.

Hyperplastic Polyps of the Esophagus and Esophagogastric Junction Histologic and Clinicopathologic Findings

Susan C. Abraham, M.D.; Vikesh K. Singh, M.D.; John H. Yardley, M.D.; Tsung-Teh Wu, M.D., Ph.D.

From the Division of Gastrointestinal/Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Am J Surg Pathol 2001;25:1180-1187 Abstract quote

Hyperplastic polyps of the esophagus and esophagogastric junction region (EGJ) are uncommon lesions characterized by hyperplastic epithelium (foveolar-type, squamous, or both) with variable amounts of inflamed stroma. They have been reported almost exclusively in the radiologic and clinical literature as occurring predominantly in association with gastroesophageal reflux disease (GERD). Comprehensive histologic and clinicopathologic evaluation of these polyps, their association with background mucosal pathology, and their association with Barrett's esophagus has not been previously performed.

We studied 30 hyperplastic polyps from 27 patients and characterized the histologic, endoscopic, and clinical features of both the polyps and the background esophagus. Hyperplastic polyps were most common in the region of the EGJ (67%), followed by the distal esophagus (30%) and mid-esophagus (3%). Most (80%) were composed of predominantly cardiac-type mucosa, predominantly squamous mucosa (17%), or an admixture (3%). Intestinal metaplasia of the polyp was present in only 7% and low-grade dysplasia in only 3%. In the majority of cases (67%) hyperplastic polyps were associated with concurrent or recent ulcers or erosive esophagitis. In most cases (48%) esophageal injury was associated with GERD, but other potential etiologies included medications, infection, anastomotic or polypectomy sites, vomiting, and photodynamic therapy. Four patients (15%) had Barrett's esophagus, three of whom had or developed dysplastic Barrett's mucosa.

These results underscore the pathogenesis of esophageal/EGJ region hyperplastic polyps as a mucosal regenerative response to surrounding mucosal injury. Careful clinical history and biopsy of the nonpolypoid mucosa are essential for determining the clinicopathologic context in which the polyps have developed.



Histology of gastroesophageal junction in fetal and pediatric autopsy.

Park YS, Park HJ, Kang GH, Kim CJ, Chi JG.

Department of Pathology, Seoul National University College of Medicine and Seoul National University Hospital Clinical Research Institute, Seoul, Korea.


Arch Pathol Lab Med 2003 Apr;127(4):451-5 Abstract quote

CONTEXT: There is much debate over whether the gastric cardia exists from birth as a normal structure or is a metaplastic structure that develops as the result of gastroesophageal reflux disease. This question has become a matter of concern since the incidence of adenocarcinoma at the gastroesophageal junction has been increasing rapidly in the Western world for more than 2 decades. Various groups of investigators have tried to clarify this matter by examining the histology of the gastroesophageal junction in autopsy cases, and there have been striking discrepancies in their findings. In one group, it was observed that cardiac mucosa was present in all pediatric autopsies. On the contrary, another group concluded that pure cardiac mucosa was absent in 56% of their autopsy cases.

OBJECTIVE: Without regard to the definition of the cardiac mucosa, we focused on the distance between the squamocolumnar junction and the most proximal parietal cells to elucidate the histologic features of the gastroesophageal junction on the gastric side.

DESIGN: The entire gastroesophageal junction and the proximal part of the stomach from 23 fetal and pediatric autopsies were mapped. We measured the distance from the squamocolumnar junction to the most proximal parietal cells identified. The extent of the transitional zone, defined as the mucosa between the squamocolumnar junction and the fundic mucosa, was also evaluated.

RESULTS: The transitional zone was identified in 78% of cases, and it always harbored some scattered parietal cells in mucous glands. The parietal cells were consistently identified adjacent to the squamocolumnar junction in all cases. Although the transitional zone in fetal stomach was usually composed of several pits of foveolar epithelium without glandular portions, it contained glandular structures in the pediatric cases.

CONCLUSIONS: The mucosa composed of pure mucous cells does not exist as a normal developmental structure.

Histopathology of the gastroesophageal junction: a study on 36 operation specimens.

Sarbia M, Donner A, Gabbert HE.

Am J Surg Pathol 2002 Sep;26(9):1207-12 Abstract quote

The entire gastroesophageal junction of 36 patients who had been operated for squamous cell carcinoma of the upper or middle esophagus was examined. Hematoxylin and eosin-stained slides were evaluated by two pathologists for the following histologic details: minimal and maximal length of cardiac mucosa (CM) and oxyntocardiac mucosa (OCM, mixture of cardiac and fundic glands), degree of inflammation in CM and OCM, and presence of intestinal metaplasia or pancreatic metaplasia.

Sections of gastric corpus mucosa were evaluated for the presence of gastritis and infection; sections of esophageal squamous epithelium were evaluated for the presence of reflux esophagitis. CM was present in the entire circumference of the gastroesophageal junction in 20 cases, in parts of the circumference in 15 cases, and entirely absent in one case. The maximal length per case ranged between 1 and 15 mm (median 5 mm). OCM was circumferentially present in 22 cases and partially present in 14 cases. The maximal length ranged between 2 and 24 mm (median 7 mm). Locations of CM/OCM over submucosal esophageal glands or squamous epithelium-lined ducts, both indicating a location in the esophagus, were found in eight cases (22%) and in four cases (11%), respectively. In 18 cases (50%) intestinal metaplasia was present in CM/OCM; pancreatic metaplasia was found in 22 cases (61%). A statistically not significant trend for increase of minimal length of CM, OCM, and the sum of both was found in the presence of gastroesophageal reflux disease. Neither the presence of intestinal metaplasia nor of pancreatic metaplasia in CM/OCM was correlated with gastroesophageal reflux disease. In conclusion, the high variability in length, the frequent occurrence of intestinal metaplasia and pancreatic metaplasia, and the frequent extension into the esophagus suggest that CM/OCM is a dynamic structure that probably mirrors the influence of underlying gastroesophageal diseases.

Because of the short length and incomplete circumferential extension of CM/OCM, future endoscopic-bioptic investigations will probably have to be based on more extensive sampling of the gastroesophageal junction.

The gastric cardia: fact or fiction?

Kilgore SP, Ormsby AH, Gramlich TL, Rice TW, Richter JE, Falk GW, Goldblum JR.

Center for Swallowing and Esophageal Disease and the Department of Anatomic Pathology, The Cleveland Clinic Foundation, Ohio 44195, USA

Am J Gastroenterol 2000 Apr;95(4):921-4 Abstract quote

OBJECTIVE: It is unclear whether the gastric cardia is present from birth or is metaplastic and develops as a result of gastroesophageal reflux disease. To this end, we evaluated the histology of the entire esophagogastric junction in consecutive pediatric autopsies to determine the presence and extent of cardiac mucosa.

METHODS: The entire esophagogastric junction of 33 consecutive pediatric (< or =18 yr) autopsies was examined. The precise location of the squamocolumnar junction and its relationship to the esophagogastric junction was noted in all cases. Slides were evaluated by two pathologists in a blinded fashion to look for cardiac mucosa, characterized by unequivocal periodic acid-Schiff (PAS)-positive mucous glands in a lobular configuration. Sections from the antrum and esophagogastric junction were examined for the presence of Helicobacter pylori.

RESULTS: Three cases were excluded due to autolysis. The mean age of the 30 remaining patients was 6.3 yr (range: 16 days-18 yr). A regular-appearing squamocolumnar junction was identified at the esophagogastric junction in all 30 cases. Cardiac mucosa was present in all specimens (mean length: 1.8 mm; range: 1.0-4.0 mm), always on the gastric side of the esophagogastric junction. There was no significant association between patient age or gender and length of cardiac mucosa. None of the patients had a known history of gastroesophageal reflux disease or Barrett's esophagus, and none were taking acid-suppressing medications before death. All were negative for Helicobacter pylori by Giemsa stain.

CONCLUSIONS: In an unselected pediatric patient population with little or no propensity for gastroesophageal reflux disease, a short segment of cardiac mucosa was consistently present on the gastric side of the esophagogastric junction, independent of gender or age. These results support the concept that the gastric cardia is present from birth as a normal structure.

The location and frequency of intestinal metaplasia at the esophagogastric junction in 223 consecutive autopsies: implications for patient treatment and preventive strategies in Barrett's esophagus.

Ormsby AH, Kilgore SP, Goldblum JR, Richter JE, Rice TW, Gramlich TL.

Center for Swallowing and Esophageal Disorders, Cleveland Clinic Foundation, Ohio 44195, USA.

Mod Pathol 2000 Jun;13(6):614-20 Abstract quote

The frequency of intestinal metaplasia at the esophagogastric junction is as high as 36% in endoscopy studies; the majority of cases (approximately 67%) occur in short segments of esophageal columnar mucosa. The validity of these studies has been questioned, however, because of heterogenous underlying diseases prompting endoscopy.

To determine the frequency and origin of intestinal metaplasia at the esophagogastric junction, we histologically evaluated the entire esophagogastric junction for the presence of intestinal metaplasia using Alcian blue/periodic acid-Schiff mucin stains in 223 consecutive autopsies. Precise localization of the Z line in relation to the esophagogastric junction and tongues of esophageal columnar-appearing mucosa were noted in each case.

Mean patient age was 47 years; 69% of patients were male, and 63% were white. Twenty five of 223 cases (11%) had intestinal metaplasia at the esophagogastric junction. Only 2 of 25 cases (8%) had intestinal metaplasia in the esophagus; the remaining 23 cases (92%) had intestinal metaplasia in the gastric cardia. Male gender, advanced age, white ethnic origin, and short tongues of esophageal columnar mucosa were not associated with gastric cardia intestinal metaplasia. An association of distal gastric intestinal metaplasia (P < .01) and chronic gastritis (P < .01) with gastric cardia intestinal metaplasia suggests a role for Helicobacter pylori infection in this process.

The frequency of intestinal metaplasia at the esophagogastric junction in an unselected autopsy population is low (11%) even after exhaustive histologic evaluation using Alcian blue mucin stains. Furthermore, intestinal metaplasia is confined to the gastric cardia in more than 90% of cases with no association to male gender, white ethnic origin, advanced age, or the presence of short segments of esophageal columnar-appearing mucosa at endoscopy.

These results demonstrate that caution is warranted when applying the findings of endoscopy studies to the development of preventive and screening strategies aimed at identifying Barrett's esophagus in an asymptomatic general population.


Pathologic Features of Reflux and Helicobacter pylori-Associated Carditis: A Comparative Study.

Wieczorek TJ, Wang HH, Antonioli DA, Glickman JN, Odze RD.

Am J Surg Pathol. 2003 Jul;27(7):960-8. Abstract quote

Inflammation of the gastric cardia, which is the most proximal portion of the stomach, in most instances is the result of either gastroesophageal reflux disease or H. pylori infection. Histologic distinction between these two entities is important because the treatment, natural history, and risk of malignancy are different. Moreover, multilayered epithelium, a possible precursor to Barrett's esophagus, has only recently been described in the gastric cardia, and its relationship to gastroesophageal reflux disease is unknown.

The aim of this study was to compare the histologic features of the gastric cardia and the prevalence of multilayered epithelium in patients with reflux versus H. pylori-associated carditis. Routinely processed hematoxylin and eosin-stained mucosal biopsies of the gastric cardia from 30 patients with reflux-associated carditis, 25 with H. pylori-associated carditis, and 30 control patients (no reflux, no H. pylori) were evaluated for a wide variety of histologic features such as goblet cell metaplasia, presence of multilayered epithelium, type of glandular epithelium (mucous, oxyntic, mixed mucous/oxyntic), pancreatic metaplasia, overall degree of inflammation, and the quantity of individual types of inflammatory cells. The clinical and histologic features were compared between the two study groups and controls. Clinically, the reflux carditis group (male/female ratio: 21/9, mean age 56 years) had a significantly higher male/female ratio (p <0.01) and a slightly higher mean age in comparison with the H. pylori group (male/female ratio: 9/16, mean age 50 years).

Histologically, the reflux group had significantly less overall inflammation (p <0.05), with fewer plasma cells (p <0.04) and neutrophils (p <0.006), but a higher prevalence of multilayered epithelium [9 of 30 (30%) vs 1 of 25 (4%) in the H. pylori group, p = 0.01]. In the reflux carditis group, multilayered epithelium was significantly associated with neutrophilic inflammation (p <0.05), but not any other features of chronic carditis or with any of the specific epithelial cell types.

The control group showed less inflammatory activity in comparison with the H. pylori group and a lower prevalence of multilayered epithelium and eosinophilic inflammation in comparison with the reflux group. The clinical and pathologic features of reflux carditis are distinct from H. pylori carditis and are characterized by less overall inflammation and fewer neutrophils and plasma cells.

Multilayered epithelium not uncommonly occurs in the cardia of patients with gastroesophageal reflux disease but without Barrett's esophagus, further supporting our hypothesis that multilayered epithelium may represent an early precursor in the development of columnar metaplasia in Barrett's esophagus.

Histologic classification of patients based on mapping biopsies of the gastroesophageal junction.

Chandrasoma PT, Der R, Ma Y, Peters J, Demeester T.


Am J Surg Pathol. 2003 Jul;27(7):929-36. Abstract quote

This study consists of 959 consecutive patients in whom endoscopic biopsies were taken according to a protocol that permitted mapping and measurement of epithelial types in the gastroesophageal region.

The epithelial types were classified as normal (oxyntic and squamous) and questionably abnormal (oxyntocardiac, cardiac, intestinal) by strict histologic criteria. Patients were classified into four groups based on the length of histologically defined abnormal glandular epithelium in the measured biopsies.

A total of 811 (84.6%) patients had 0 to 0.9 cm of questionably abnormal columnar epithelium between normal oxyntic mucosa and squamous epithelium. Of these, 161 (19.9%) patients had no abnormal epithelium, 158 (19.4%) patients had oxyntocardiac mucosa, 372 (45.9%) patients had cardiac mucosa, and 120 (14.8%) patients had intestinal metaplasia. A total of 148 (15.4%) patients had >/=1 cm of abnormal columnar epithelium. All but one patient in this group had cardiac or intestinal epithelia.

The prevalence of intestinal epithelium increased progressively with increasing length of abnormal columnar epithelium, being present in 70.4% in the 1- to 2-cm group, 89.5% in the 3- to 4-cm group, and 100% with in the >/=5 cm group.

We propose a histologic grading system of biopsies based on these findings.

Gastric cardia intestinal metaplasia: biopsy follow-up of 85 patients.

Goldstein NS. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

Mod Pathol 2000 Oct;13(10):1072-9 Abstract quote

BACKGROUND: Gastric cardia intestinal metaplasia (CIM), denoted by goblet cells is common. The frequency of persistent CIM is unknown.

METHODS: 85 patients with CIM and follow-up endoscopies were prospectively identified during the time period of 10/6/94-12/21/97. The presence of goblet cells was the defining feature of CIM, other metaplastic cell types were not evaluated. AU 85 patients initially had biopsies that straddled the squamocolumnar junction (SCJ) showed CIM, an otherwise normal proximal stomach, lower esophagus, and squamocolumnar junction. The SCJ lay within the 2 cm of mucosa immediately proximal to the uppermost gastric fold and overlaid the junction of the tubular esophagus and the saccular dilatation of the stomach in all patients. The patients underwent endoscopy for many reasons. They were randomly identified based on the absence of a hiatal hernia and the presence of CIM.

RESULTS: Ten of the 85 patients had CIM on repeat biopsy. Among patients with no CIM in the first repeat endoscopy, the degree of cardia inflammation decreased between the initial and first repeat endoscopy, whereas there was no change in the amount of inflammation among patients who had CIM in the first repeat endoscopy. The changes in mean inflammation score was significantly different between the two groups (P = .024). Twenty-two patients underwent a second repeat endoscopy and five had a third repeat endoscopy. Including all follow-up biopsies, six of the 85 patients (7%) had CIM. Four patients who did not have CIM on initial repeat endoscopy had CIM on their second repeat endoscopy, probably reflecting sampling issues. None of the biopsies had dysplasia.

CONCLUSIONS: Cardia inflammation is a stimulus for cardia intestinal metaplasia, and a reduction in inflammation may allow the metaplastic mucosa to revert to normal.

Gastric cardia inflammation and intestinal metaplasia: associations with reflux esophagitis and Helicobacter pylori.

Goldstein NS, Karim R.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073-6769, USA.

Mod Pathol 1999 Nov;12(11):1017-24 Abstract quote

Gastric cardia inflammation and intestinal metaplasia are the subjects of recent investigation. Some authors have found associations with gastroesophageal reflux disease, whereas others have identified relationships with Helicobacter pylori (HP).

We studied 150 consecutive patients who underwent upper endoscopy, had normal gastroesophageal anatomy, and had biopsies of the antrum, cardia, and lower esophagus, to evaluate relationships between reflux esophagitis, cardia inflammation, intestinal metaplasia, and HP gastritis.

Forty-two patients had HP infection. Cardia inflammation was significantly related to esophageal squamous inflammation in the non-HP-infected patient group and to antral inflammation and cardia HP infection in the HP-infected patient group. The differences between the patient groups was most apparent in the patients with moderate or marked inflammation. Twenty-seven percent of patients had cardia intestinal metaplasia that was related to cardia inflammation.

Cardia inflammation and intestinal metaplasia probably have multiple causes. Pathologists should refrain from applying the term Barrett's esophagus for biopsies procured from the cardia that show intestinal metaplasia in patients with a normal squamocolumnar junction.

Inflammation and intestinal metaplasia of the gastric cardia: Helicobacter pylori, gastroesophageal reflux disease, or both.

Goldblum JR.

Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

Dig Dis 2000;18(1):14-9 Abstract quote

The gastric cardia is a microscopic zone that is normally found in the most proximal portion of the stomach, although cardiac-type mucosa may arise in the distal esophagus as a metaplastic phenomenon secondary to gastroesophageal reflux disease (GERD).

Inflammation of the native gastric cardia is strongly associated with Helicobacter pylori infection, although there may be a second form of 'carditis' in which metaplastic cardiac-type mucosa becomes inflamed secondary to GERD. Intestinal metaplasia of the cardia may be difficult to recognize because of the difficulty in accurately identifying the esophagogastric junction by endoscopy and the histologic similarities of intestinal metaplasia in the proximal stomach and distal esophagus.

However, cytokeratin 7 and 20 immunoreactivity patterns appear to be useful in distinguishing between these forms of intestinal metaplasia.

The preponderance of data suggests that intestinal metaplasia of the cardia is associated with H. pylori infection as opposed to GERD, and preliminary data suggest a lower risk of progression to dysplasia and adenocarcinoma when compared to intestinal metaplasia of the distal esophagus.

Gastric Cardia: Controversial Topics

John R. Goldblum, MD

From the Cleveland Clinic Foundation, Cleveland, OH

Pathol Case Rev 2002;7:12-18 Abstract quote

Because of the increasing incidence of adenocarcinoma of the gastric cardia, inflammatory processes involving the gastric cardia have become of interest. This article addresses the following major issues: (1) Does the gastric cardia exist as a native structure, or is it a metaplastic mucosa that arises secondary to gastroesophageal reflux? (2) What is the cause or causes of carditis? (3) What is the significance of intestinal metaplasia of the gastric cardia, and can it be distinguished from Barrett’s esophagus?

Several recent autopsy studies have found that the gastric cardia exists as a normal structure, although it is extremely small (1–4 mm). However, cardiac-type mucosa, closely resembling the native gastric cardia, can arise in the distal esophagus as a metaplastic phenomenon secondary to gastroesophageal reflux. Biopsy specimens taken near the esophagogastric junction with cardiac-type mucosa are frequently inflamed (so-called carditis). Although some have found this inflammatory process to be closely associated with gastroesophageal reflux disease, others have found it to be a manifestation of a Helicobacter pylori pangastritis. Much of the confusion likely exists because of difficulties in precisely localizing the esophagogastric junction at endoscopy and the presence of histologically similar-appearing cardiac-type mucosae in the distal esophagus and proximal stomach, both of which may be inflamed for different reasons. All available data suggest that there are at least two causes of “carditis.” One form involves inflammation of metaplastic cardiac-type mucosa in the distal esophagus secondary to gastroesophageal reflux, and the second form involves inflammation of the native gastric cardiac mucosa secondary to H. pylori infection.

The etiology and significance of cardia intestinal metaplasia is controversial. Most available data suggest that intestinal metaplasia of the cardia is secondary to an H. pylori-induced multifocal atrophic gastritis. Recent data suggest the risk of progression of cardia intestinal metaplasia to dysplasia-adenocarcinoma is much lower than that of short- or long-segment Barrett’s esophagus.

Immunohistochemical stains for cytokeratins 7 and 20 may be useful in this regard, as there is a reproducible cytokeratin pattern found in Barrett’s esophagus that is typically absent in intestinal metaplasia of the cardia.

Morphology of the Cardia and Significance of Carditis in Pediatric Patients

Jonathan N. Glickman, M.D., Ph.D.; Victor Fox, M.D.; Donald A. Antonioli, M.D.; Helen H. Wang, M.D., Dr.P.H.; Robert D. Odze, M.D., F.R.C.P.(C.)

Am J Surg Pathol 2002; 26(8):1032-1039 Abstract quote

The morphology of the gastric cardia in children and the significance of inflammation in this region are unknown. Some investigators propose that the cardia is comprised of mucous glands at birth, whereas others suggest that mucous glands, when present, represent a metaplastic response to gastroesophageal reflux disease.

The aim of this study was to evaluate the morphologic features of the cardia in a pediatric population and to determine the significance of inflammation in this region by correlating the pathologic features with clinical and endoscopic data.

Routinely processed hematoxylin and eosin-stained mucosal biopsies of the cardia from 74 pediatric patients (age range 0.1-18 years; male/female ratio 0.76:1) without endoscopic evidence of Barrett's esophagus were examined for a variety of histologic features, such as the type of glandular epithelium (mucous, mixed mucous/oxyntic, oxyntic), and the amount and type of inflammation both within 1.0 mm and >1.0 mm from the squamocolumnar junction. The results were correlated with the patients' clinical symptoms and with other histologic features, such as esophagitis, gastritis, Helicobacter pylori, and the presence of goblet cells. Our results show that either pure mucous glands (81%) or mixed mucous/oxyntic-type glands (19%) were present within 1 mm of the squamocolumnar junction in all of the patients (100%) in this study. Patients with mixed mucous/oxyntic glands located <1 mm from the squamocolumnar junction were more likely to have goblet cells than were patients with mucous glands alone, but they did not differ with respect to any other feature, including patient age. However, both active esophagitis and increased inflammation in the cardia correlated positively with a longer length of pure mucous glands in the gastroesophageal junction region.

Of the cases with inflammation (carditis), eosinophils correlated with the presence of active esophagitis (a histologic manifestation of gastroesophageal reflux disease), whereas increased lymphocytes correlated with chronic H. pylori gastritis. In summary, a small amount of pure mucous-type glands is present in the cardia in most pediatric patients, a finding that supports a congenital origin for this type of epithelium. However, our finding of an association between length of mucosa occupied by pure mucous glands and active esophagitis suggests that injury and repair related to gastroesophageal reflux disease may contribute to expansion of the zone occupied by cardia-type mucous glands.


Inlet patch: prevalence, histologic type, and association with esophagitis, Barrett esophagus, and antritis.

Tang P, McKinley MJ, Sporrer M, Kahn E.

Department of Pathology, North Shore University Hospital, Manhasset, NY 11030, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):444-7. Abstract quote

CONTEXT: Inlet patch is a congenital anomaly of the cervical esophagus consisting of gastric mucosa. Case reports have documented the histologic type and its associated complications.

OBJECTIVE: To report the prevalence and histologic types of inlet patch as well as its association with Barrett esophagus and Helicobacter pylori-associated gastritis.

DESIGN: We reviewed 1821 consecutive pathology reports from endoscopies of the upper gastrointestinal tract between 1995 and 2002 and identified 20 patients with inlet patch. The patients' ages ranged from 16 to 75 years (mean, 55 years). We examined biopsies from these patients of the cervical esophagus, distal esophagus, and antrum that had been stained with hematoxylin-eosin and the Steiner stain. Biopsies from the cervical esophagus composed of nonoxyntic gastric mucosa were also stained for gastrin-producing cells.

RESULTS: In our patient population, inlet patch occurred in 1.1% of all patients in whom an inlet patch had been searched for endoscopically and a biopsy performed. In the inlet patch, oxyntic mucosa was the most common histologic type (11/20), followed by cardiac mucosa (5/20). Four specimens of the inlet patch contained only foveolar epithelium and were therefore considered too superficial to be classified. Twelve of 20 biopsies of the inlet patch were inflamed, and 1 of them was associated with H pylori. Pancreatic acinar tissue was noted in 2 patients; no intestinal metaplasia was found. In the distal esophagus, 4 patients with inlet patch had distal esophagitis, 4 had Barrett esophagus, 5 had oxyntic mucosa, 3 had pancreatic acinar tissue (1 coexisting with oxyntic mucosa), and 5 presented with only unremarkable esophageal squamous mucosa. Antral gastritis was seen in 2 patients, 1 of them with H pylori. The same patient also had H pylori in the inlet patch.

CONCLUSION: Inlet patch occurred in about 1% of our study population. Oxyntic mucosa constituted the most common histologic type; inflammation was common. The H pylori infection of the inlet patch correlated with that of the antrum. None of the inlet patch biopsies showed intestinal metaplasia. Pancreatic acinar tissue occurred with similar frequency in the inlet patch and distal esophagus. Esophagitis was noted in 25% of the patients with inlet patch, and Barrett esophagus was noted in 20%.
Islands of squamous epithelium and their surrounding mucosa in columnar-lined esophagus: A pathognomonic feature of Barrett's esophagus?

Takubo K, Vieth M, Aryal G, Honma N, Sawabe M, Arai T, Kammori M, Mafune K, Iwakiri K.

Hum Pathol. 2005 Mar;36(3):269-74. Abstract quote  

Summary We examined 23 patients with columnar-lined esophagus (2 with long segment and 21 with short segment) endoscopically. After staining with Lugol's iodine solution, squamous islands were identified in the columnar mucosa in 18 (78%) of the 23 patients. When biopsy specimens were obtained from these islands, esophageal glands proper or their ducts were seen in 12 (67%) of the 18 cases.

Because the identification of esophageal glands proper is a definite indicator that a piece of biopsy tissue is of esophageal origin, a diagnosis of columnar-lined esophagus could be made purely on the basis of the histological findings in these biopsy specimens of squamous islands. This was the case in 12 (52%) of the 23 patients examined in this study. Staining with Lugol's iodine solution, with subsequent biopsy of stained squamous islands, may assist in the diagnosis of short-segment columnar-lined esophagus.

We also conclude, on the basis of our study, that columnar metaplasia of the esophagus cannot develop by direct outgrowth of epithelium from the ducts of esophageal glands proper. In addition, intestinal metaplasia was not always observed in the columnar mucosa around the duct orifices.

From a practical point of view, biopsy specimens from columnar-lined mucosa of the esophagus do not always show intestinal metaplasia (specialized intestinal metaplasia).


GENERAL Hollande's fixative, which is a modification of Bouin's solution, has been advocated as a superior fixative.
Alcian blue/PAS May highlight the intestinal metaplastic goblet cells
High iron diamine Stains sulfated mucin brown and nonsulfated mucin blue

Intestinal Metaplasia of the Esophagus or Esophagogastric Junction Evidence of Distinct Clinical, Pathologic, and Histochemical Staining Features

Johanna W. van Sandick, MD
J. Jan B. van Lanschot, MD
Lonneke van Felius, MD
Jelle Haringsma, MD
Guido N.J. Tytgat, MD
Wim Dekker, MD
Paul Drillenburg, MD
G. Johan A. Offerhaus, MD
and Fiebo J.W. ten Kate, MD

Am J Clin Pathol 2002;117:117-125 Abstract quote

Our purpose was to evaluate the clinical, histologic, and histochemical staining characteristics of intestinal metaplasia (IM) at an endoscopically normal-appearing esophagogastric junction (IM-EGJ) compared with IM in a columnar-lined esophagus (IM-CLE).

A prospective study included 253 patients referred for elective upper gastrointestinal endoscopy. Biopsy specimens were obtained from 2 cm above and immediately distal to the squamocolumnar junction, the gastric corpus, and the antrum. Any red mucosa above the EGJ was sampled. IM-CLE (prevalence, 5.5%) typically occurred in white male smokers with a long history of reflux symptoms. IM-EGJ (prevalence, 9.1%) was associated with corpus and antrum gastritis and with IM at these sites. IM-CLE usually (13/14 [93%]) was the incomplete type IM, whereas only 12 (52%) of 23 patients in the IM-EGJ group had incomplete IM. IM-EGJ and IM-CLE should be considered as separate entities.

Further research is needed to evaluate whether neoplastic progression of IM-EGJ is related to its mucin profile.


Mucin Core Peptide Expression Can Help Differentiate Barrett's Esophagus From Intestinal Metaplasia of the Stomach.

Glickman JN, Shahsafaei A, Odze RD.
Am J Surg Pathol. 2003 Oct;27(10):1357-65. Abstract quote  

SUMMARY: It is important to distinguish Barrett's esophagus (BE) from intestinal metaplasia related to carditis because these conditions have a different natural history, risk of malignancy, and treatment. However, the distinction between these entities is difficult both clinically and pathologically. The aim of this study was to evaluate and compare the immunostaining pattern of five mucin core polypeptides in BE to cases of carditis or antritis with intestinal metaplasia. Routinely processed mucosal biopsies from 22 patients with intestinal-type BE, 24 patients with cardia intestinal metaplasia (10 Helicobacter pylori positive), 17 patients with antral intestinal metaplasia (all H. pylori positive), 20 control patients with a normal antrum, and 22 control patients with a normal cardia were immunostained with monoclonal antibodies against MUC1, MUC2, MUC3, MUC5AC, and MUC6 mucin core polypeptides.

Staining was evaluated separately for goblet cells and non-goblet columnar cells and compared between all groups. A significantly higher number of BE cases (P < 0.05) showed goblet cell staining for MUC1 (55%) or MUC6 (32%) compared with patients with carditis with intestinal metaplasia (MUC1 14%, MUC6 7%) or antritis with intestinal metaplasia (MUC1 6%, MUC6 0%). BE also showed a higher frequency of MUC1 and MUC6 positivity in non-goblet columnar cells compared with carditis and antritis cases with intestinal metaplasia. Only cases of BE showed combined MUC1 and MUC6 staining (sensitivity 23%, specificity 100%). The sensitivity and specificity of MUC1 staining for BE are 55% and 96%, respectively, and for MUC6 staining 30% and 96%, respectively. Interestingly, normal gastric cardia mucosa also showed a significantly higher prevalence of MUC2 and MUC3 expression in glandular epithelium (29% and 38%, respectively) compared with the antrum (0% for both markers) (P < 0.05).

In conclusion, MUC1 and MUC6 expression in BE is distinct from that of the cardia and antrum with intestinal metaplasia; thus, immunophenotyping for these markers may have some value in a subset of patients in helping to separate BE from patients with intestinal metaplasia of the cardia. Columnar epithelium in the "normal" gastric cardia has a partially intestinalized phenotype and, as a result, may represent an early form of metaplastic epithelium.

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

Sarbia M, Donner A, Franke C, Gabbert HE.
Hum Pathol 2004;35:371-376 Abstract quote

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.
AMACR Immunostaining is Useful in Detecting Dysplastic Epithelium in Barrett's Esophagus, Ulcerative Colitis, and Crohn's Disease.

Dorer R, Odze RD.

Department of Pathology, Brigham and Women's Hospital, Boston, MA.

Am J Surg Pathol. 2006 Jul;30(7):871-877. Abstract quote  

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.

Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia.

Groisman GM, Amar M, Meir A.

1Department of Pathology, Hillel Yaffe Medical Center, Hadera, Israel.

Mod Pathol. 2004 Oct;17(10):1282-8. Abstract quote  

Barrett's esophagus is diagnosed when goblet cells are found in the lower esophageal mucosa. However, the distribution of these cells is patchy and they may not represent the earliest marker of intestinal metaplasia. Cdx2 is a transcription factor whose expression in normal tissues is restricted to intestinal-type epithelium. Its distribution in the columnar-lined esophagus with and without intestinal metaplasia has been seldom studied.

We evaluated Cdx2 expression in lower esophageal biopsies from 90 patients with endoscopic diagnosis of short segment Barrett's esophagus, including 45 consecutive cases showing intestinal metaplasia (goblet cells present in hematoxylin eosin and/or Alcian blue stains) and 45 consecutive cases without goblet cells. 25 samples of cardiac-type mucosa without intestinal metaplasia biopsied from the stomach served as controls. All cases with intestinal metaplasia revealed Cdx2 reactivity in goblet cells and adjacent nongoblet columnar cells. Dysplastic foci, seen in five cases from this group, were Cdx2 positive. In the group without goblet cells, Cdx2 was focally expressed by columnar cells in 17 (38%) cases. All control cases were Cdx2 negative. Strips of Alcian blue-positive nongoblet columnar cells ('columnar blues') were observed in 11 (24%) of the cases without intestinal metaplasia. All these foci were Cdx2 negative.

In conclusion, Cdx2 is a highly sensitive marker for Barrett's esophagus. It is also expressed in a significant minority of cases of columnar-lined esophagus without goblet cells, suggesting that it may detect intestinal phenotypic modifications in the absence of goblet cells. Accordingly, Cdx2 immunostaining could help identify patients with Barrett's metaplasia in cases where no goblet cells are visible in biopsies from the columnar-lined esophagus. Finally, lack of Cdx2 expression in the 'columnar blues' suggests that these cells are not diagnostic of intestinal metaplasia.

Cdx2 as a marker of epithelial intestinal differentiation in the esophagus.

Phillips RW, Frierson HF Jr, Moskaluk CA.

Department of Pathology, University of Virginia Medical Center, Charlottesville, VA 22908-0214, USA.
Am J Surg Pathol. 2003 Nov;27(11):1442-7. Abstract quote  

The histologic diagnosis of Barrett's esophagus requires the presence of goblet cells, but this finding may not be the earliest indicator of intestinal metaplasia.

We used immunohistochemistry to detect Cdx2, a transcriptional regulator important in the early differentiation and maintenance of intestinal epithelium, in 134 esophageal biopsy or resection specimens, including 62 with junctional-type epithelium (13 of which had equivocal histologic features of Barrett's epithelium), 34 with Barrett's epithelium without dysplasia, and 38 with Barrett's epithelium and dysplasia or carcinoma (13 low-grade dysplasias, 19 high-grade dysplasias, and 6 adenocarcinomas). We also performed PAS-alcian blue staining (pH 2.5) on adjacent sections. Cdx2 was observed in all cases of Barrett's epithelium. In some dysplasias (chiefly high-grade) and adenocarcinomas, there was diminution or focal loss of detectable protein. Cdx2 was detected in 20 of 62 cases (30%) of junctional-type epithelium, including 10 of 13 (77%) with equivocal histologic features of Barrett's epithelium. Acid mucin was present in goblet cells and non-goblet columnar cells in all cases of Barrett's esophagus and in non-goblet columnar cells in 48 of 62 cases (77%) with junctional-type epithelium only, including 17 of 20 (85%) that were Cdx2 positive and 31 of 42 (74%) that were Cdx2 negative. These results provide evidence that Cdx2 protein is a sensitive marker of intestinal metaplasia in the upper gastrointestinal tract and may be useful in detecting histologically equivocal cases of Barrett's esophagus.

Cdx2 is present in dysplasia and adenocarcinoma, with some loss of protein primarily in high-grade dysplasia and adenocarcinoma. Acid mucin in non-goblet columnar cells is a common feature of Barrett's and junctional-type epithelium and may not always be indicative of intestinal metaplasia.
Cytokeratins 7 and 20 and Mucin Core Protein Expression in Esophageal Cervical Inlet Patch.

Lauwers GY, Mino M, Ban S, Forcione D, Eatherton DE, Shimizu M, Sevestre H.

From the *Gastrointestinal Pathology Service, Department of Pathology, and daggerDepartment of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA; double daggerDepartment of Pathology, Saitama Medical School, Saitama, Japan; and section signDepartement d'Anatomopathologique, Centre Hospitalo-Universitaire d'Amiens, Amiens, France.

Am J Surg Pathol. 2005 Apr;29(4):437-442. Abstract quote  

Cervical inlet patch (CIP) is defined by the presence of gastric mucosa within the first few centimeters of the esophagus. Several endoscopic series have demonstrated a frequent association of CIP with Barrett's esophagus (BE) suggesting a pathogenetic link. A histochemical study reporting the presence of acid mucin in CIP, including sulfomucin, supports this hypothesis.

We evaluated mucin core protein expression and cytokeratins 7 and 20 (CK7/CK20) pattern in biopsies of CIP, normal antrum, and BE to comment on a possible relationship of CIP with BE. We observed that both lesions have similar cytokeratin patterns with mixed CK7/CK20 reactivity on the surface and pits and lone CK7 positivity in the glands. MUC5AC was strongly expressed on the surface and pits but not in the glands of CIP and antral mucosa. Within BE, MUC5AC positivity was noted not only on the surface and pits but also in the glands. MUC6 similarly decorated the glands of CIP and BE. MUC2 was expressed rarely in CIP with goblet cells but conspicuously on the surface and pits of BE. MUC5B was seen in both CIP and BE and rarely in the antral mucosa. The similarities between CIP and BE but not with normal antral mucosa fits with the hypothesis that both lesions may originate from submucosal esophageal mucous glands.

Two pathogenetic pathways can be entertained: focal upper esophageal mucosal misdevelopment in pediatric population and patchy metaplastic replacement of squamous mucosa in adults with gastroesophageal reflux disease.
Interinstitutional variability and effect of tissue fixative on the interpretation of a Barrett cytokeratin 7/20 immunoreactivity pattern in Barrett esophagus.

Glickman JN, Ormsby AH, Gramlich TL, Goldblum JR, Odze RD.
Hum Pathol. 2005 Jan;36(1):58-65. Abstract quote

Summary A unique pattern of cytokeratin (CK) 7/20 immunostaining (diffuse staining with CK7 and surface and superficial crypt staining with CK20) has been reported to be useful in differentiating Barrett esophagus (BE) from intestinal metaplasia of the stomach. However, there are conflicting results regarding the prevalence of a BE CK7/20 staining pattern in BE between different studies.

Therefore, this study was performed to determine the degree of variability in interpretation of a BE CK7/20 pattern and to determine the reasons for variability when present. Esophageal and gastric mucosal biopsies from 67 patients with BE and antral intestinal metaplasia at 2 institutions were immunostained for CK7/20. All cases were evaluated for the presence of a BE CK7/20 pattern by 2 gastrointestinal pathologists from each institution, and the degree of agreement between institutions was determined.

To determine the effect of tissue fixation and staining methods on the pattern of CK7/20 staining, unstained slides were exchanged between institutions, stained separately by each institution, and reexamined by all pathologists. There was excellent agreement on the presence of a BE CK7/20 staining pattern between pathologists at the same institution but only moderate agreement between pathologists at different institutions (71% overall, kappa = 0.58). Among BE cases, a BE CK7/20 staining pattern was identified in 50 (96%) of 52 cases by Cleveland Clinic Foundation pathologists but only 35 (67%) of 52 cases by Brigham and Women's Hospital pathologists. The major source of disagreement related to the interpretation of weak or variable CK7 staining of deep intestinalized mucosa in BE biopsies that were fixed in Hollande, but not those that were fixed in formalin. After the creation of a new set of criteria for a positive BE CK7/20 staining pattern, which took into account the effects of Hollande's fixative, the degree of agreement between pathologists at each of the 2 institutions was excellent (100%, kappa value = 1.0).

Therefore, the CK7/20 staining pattern is influenced by the type of fixative used. Only a moderate level of interobserver agreement among pathologists regarding a BE CK7/20 pattern can be achieved if one is not aware of these effects. Nevertheless, specific criteria for interpretation of CK7/20 staining can be successfully applied between institutions and need to be developed before use of this technique in clinical practice.
What is the role of cytokeratins in Barrett/cardia differentiation?

Younes M.

Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Arch Pathol Lab Med. 2005 Feb;129(2):181-2. Abstract quote

The importance of distinguishing between Barrett metaplasia and intestinal metaplasia of the gastric cardia is now accepted, and the management of each entity is quite different. Patients with Barrett metaplasia are enrolled in surveillance programs, consisting of periodic endoscopy and biopsy, because of the known risk of developing adenocarcinoma of the esophagus. Patients with intestinal metaplasia of the gastric cardia, however, are not currently enrolled in such programs, because this condition carries a low risk of developing adenocarcinoma of the gastric cardia.

The distinction between both conditions by morphologic examination of routine histologic sections of endoscopic biopsies is extremely difficult if at all possible. A group of investigators proposed the use of immunostains for cytokeratin (CK) 7 and CK20 to overcome such difficulty.

They concluded that the Barrett CK7/CK20 pattern was a highly sensitive and specific marker for Barrett metaplasia. Their observations, however, were not confirmed by other investigators. However, because it may be associated with premalignant lesions elsewhere in the gastric mucosa, we propose that intestinal metaplasia of the gastric cardia may have the same clinical implication as Barrett metaplasia.
Phenotype of Barrett's esophagus and intestinal metaplasia of the distal esophagus and gastroesophageal junction

Am J Surg Pathol 2001;25:87-94

Study examined biopsies from long, short segment disease, intestinal metaplasia of the GE junction and intestinal metaplasia of the gastric antrum, secondary to H. pylori

Monoclonal antibodies used:
Das1 (specific for colonic goblet cells)
45M1 (recognizes the M1 gastric mucin antigen)
CK7 and 20

Similar staining pattern observed in nonintestinalized cardia type epithelium from long and short segment and GEJ but distinct from normal gastric antrum

Features of short, long, and intestinal metaplasia of the GE junction are similar but distinct from intestinal metaplasia of the gastric antrum

Utilization of Cytokeratins 7 and 20 Does Not Differentiate between Barrett's Esophagus and Gastric Cardiac Intestinal Metaplasia.

Mohammed IA, Streutker CJ, Riddell RH.

Department of Pathology and Molecular Medicine (IAM, CJS, RHR), McMaster University, Hamilton, Ontario, Canada.


Mod Pathol 2002 Jun;15(6):611-6 Abstract quote

Long segment Barrett's esophagus (LSBE) is a recognized risk factor for the development of esophageal dysplasia and carcinoma. However, the risk of dysplasia arising within intestinal metaplasia below a normal-appearing Z-line (i.e., in native cardiac mucosa) is unknown. Regular endoscopic surveillance is required in patients with LSBE and is frequently performed in short segment BE (SSBE), but the need for surveillance in cardiac intestinal metaplasia (CIM) is unknown. Unfortunately IM arising in SSBE and immediately below a normal Z-line can be indistinguishable histologically on H&E stains.

Previous reports suggest that the appearance of superficial CK20 immunohistochemical staining accompanied by intermediate and deep CK7 positivity is characteristic of BE, whereas CIM specimens show superficial and deep CK20 positivity and weak to absent CK7 staining.

We hypothesized that CK7/20 immunostaining of metaplastic biopsies from the esophagus and stomach would allow complete differentiation of these two entities when correlated with the endoscopic appearance. We undertook an evaluation of gastric and esophageal specimens to determine whether these characteristics were valid. Cases of both BE (long and short segment) and CIM, as well as cases of gastric cardiac biopsies lacking IM, were evaluated for CK7 and CK20 and correlated with the endoscopic appearance. We observed that, although the "Barrett's" pattern of CK7/20 was maintained for many cases of BE, the sensitivity and specificity were only moderate (65% and 56%, respectively). The pattern of staining for the CIM was variable, i.e., some cases showed a CK7/20 Barrett's pattern despite a normal appearance at endoscopy. The differences between this and previous studies may be due to inaccurate visualization of SSBE on endoscopy, the development of very early SSBE cases, inter-observer variability, fixation differences, or antibody differences.

Whatever the cause of the differences, if results between laboratories are not comparable, CK7/20 immunostaining cannot be used to differentiate reliably between IM present in biopsy specimens taken from above versus below the Z-line. However, further studies should be performed to determine whether the presence or absence of a Barrett's pattern of CK7/20 immunostaining could predict progression to dysplasia or carcinoma.


Hepatocyte antigen as a marker of intestinal metaplasia.

Chu PG, Jiang Z, Weiss LM.


Am J Surg Pathol. 2003 Jul;27(7):952-9 Abstract quote

Intestinal metaplasia is a histologic hallmark of Barrett's esophagus and chronic gastritis. Intestinal metaplasia may progress to dysplasia or carcinomas without proper treatment. Most cases of intestinal metaplasia are easily recognized on hematoxylin and eosin-stained sections. However, some cases of intestinal metaplasia may be hard to recognize if they lack the characteristic mucin-producing cells and Paneth cells, or if they are small in size.

Recently, keratin 7, keratin 20, and MUC2 expression patterns were reported to be useful in confirming the diagnosis of intestinal metaplasia. We studied hepatocyte (Hep) antigen (a hepatocellular antigen mainly expressing in normal and neoplastic hepatic tissues) in 33 cases of Barrett's esophagus (9 cases associated with esophageal adenocarcinoma) and 13 cases of chronic gastritis associated with intestinal metaplasia and gastric adenocarcinoma. Hep monoclonal antibody recognizes intestinal metaplasia in all cases. We also compared expression of Hep with that of keratin 7, keratin 20, and MUC2 in intestinal metaplasia. The specificity and sensitivity of Hep for intestinal metaplasia were higher than that of keratin 7 and keratin 20, or MUC2.

We conclude that Hep may be used as a single diagnostic marker for intestinal metaplasia.


Phenotypic differences between esophageal and gastric intestinal metaplasia.

Piazuelo MB, Haque S, Delgado A, Du JX, Rodriguez F, Correa P.

1Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Mod Pathol. 2004 Jan;17(1):62-74 Abstract quote.  

Intestinal metaplasia is a cancer precursor in the esophagus and the stomach. Marked differences exist between the carcinogenic processes in the two locations in terms of natural history and clinical significance.

We investigated biopsies from 52 patients with Barrett's esophagus and from 50 patients with gastric intestinal metaplasia in an attempt to throw light on their pathogenic processes. Morphologic characteristics, presence of Helicobacter pylori (H. pylori), and markers of differentiation, inflammation, and proliferation were evaluated by histochemical and immunohistochemical techniques. The area covered by incomplete type of intestinal metaplasia and the proportion of sulfomucins were significantly higher in the esophagus than in the stomach. Immunoreactivity with MUC1, MUC2, MUC5AC, Das-1, cytokeratins 7 and 20, inducible nitric oxide synthase and cyclooxygenase-2 antibodies was also significantly greater in Barrett's esophagus than in gastric intestinal metaplasia. In gastric intestinal metaplasia, the presence of MUC1, MUC5AC, Das-1 and cytokeratin 7 was restricted to areas with the incomplete type of metaplasia. Cell proliferation (Ki-67) was significantly higher in Barrett's esophagus than in gastric intestinal metaplasia. H. pylori was absent in all of the patients with Barrett's esophagus, while it was present in 70% of the patients with gastric intestinal metaplasia.

Our observations made clear that Barrett's esophagus shares some phenotypic characteristics with gastric intestinal metaplasia, leading us to suggest that both could arise in response to injuries with eventual carcinogenic potential. However, the progression to more advanced lesions could be modulated by the nature of the carcinogenic insult.



In patients with greater than 2 cm of Barrett's mucosal changes, there is a 30 to 40 fold increased rate of adenocarcinoma developing compared to the normal population.

Prevalence rate of adenocarcinoma at time of Barrett's diagnosis is 7-15%


The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression.

Skacel M, Petras RE, Gramlich TL, Sigel JE, Richter JE, Goldblum JR.

Department of Anatomic Pathology, The Cleveland Clinic Foundation, Ohio 44195, USA.

Am J Gastroenterol 2000 Dec;95(12):3383-7 Abstract quote

OBJECTIVE: The reported risk of progression from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or carcinoma (CA) in Barrett's esophagus varies. However, the validity of a diagnosis of LGD may be questioned because of interobserver variability.

METHODS: A search of the Cleveland Clinic Foundation surgical pathology files between 1986 and 1997 yielded biopsy specimens from 43 patients with Barrett's esophagus diagnosed and coded as LGD. Patients with concurrent or prior diagnoses of HGD or carcinoma were excluded. The LGD cases were randomized and blindly reviewed by three gastrointestinal (GI) pathologists along with cases originally diagnosed as Barrett's esophagus without dysplasia (ND; n = 28), indefinite for dysplasia (IND; n = 14), or HGD (n = 15). Each pathologist classified every biopsy specimen as ND, IND, LGD, or HGD, and interobserver agreements were determined by kappa statistics (K). Follow-up data were available on 25 patients originally diagnosed with LGD. Progression was defined as a subsequent diagnosis of HGD or CA on esophageal biopsy or resection specimens.

RESULTS: Agreement between two GI pathologists for a diagnosis of LGD was fair (K = 0.28) and poor (K = 0.21 and -0.04). Individual GI pathologists agreed with the original diagnosis of LGD in 70%, 56%, and 16% of cases. The 25 patients with follow-up included 21 men and four women (mean age, 67 yr) with a mean follow-up of 26 months (range: 2-84 months). Seven patients (28%) with follow-up developed HGD (five patients) or CA (two patients), 2-43 months (median: 11 months) after a diagnosis of LGD. The individual GI pathologists' diagnosis did not correlate with progression. However, when at least two GI pathologists agreed on LGD, there was a significant association with progression (seven of 17 patients, 41%, p = 0.04). When all three GI pathologists agreed on a diagnosis of LGD, four of five patients progressed (p = 0.012). In contrast, of the eight patients with follow-up and no agreement among GI pathologists for a diagnosis of LGD, none progressed.

CONCLUSIONS: A high degree of interobserver variability is seen in the histological diagnosis of Barrett's esophagus-related LGD. Although the number of observations is low, a consensus diagnosis of LGD among GI pathologists suggests an increased risk of progression from LGD to HGD or carcinoma.


Are ulcers a marker for invasive carcinoma in Barrett's esophagus? Data from a diagnostic variability study with clinical follow-up.

Montgomery E, Bronner MP, Greenson JK, Haber MM, Hart J, Lamps LW, Lauwers GY, Lazenby AJ, Lewin DN, Robert ME, Washington K, Goldblum JR.

Department of Pathology, The Johns Hopkins University, Baltimore, Maryland 21205, USA.

Am J Gastroenterol 2002 Jan;97(1):27-31 Abstract quote

OBJECTIVES: We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers.

METHODS: A group of pathologist participants were asked to contribute patients' initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients.

RESULTS: There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients.

CONCLUSION: If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.


The diagnosis of low-grade dysplasia can be difficult; however, it may be reassuring to know that the difference in patients with biopsies diagnosed as indefinite for dysplasia versus those with low-grade dysplasia may not be clinically relevant.

The endoscopist may decrease the time interval between surveillance endoscopies and increase the number of biopsies, but therapeutic interventions are usually not initiated. There is significant interobserver and intraobserver variation in the diagnosis of dysplasia in Barrett's esophagus, particularly at the indefinite/low-grade interface.

For this reason the categories of indefinite and low-grade dysplasia may be combined for clinical management purposes. The accurate diagnosis of high-grade dysplasia is critically important because thereapeutic intervention of some form, often esophagectomy, may be initiated based on this diagnosis.

Histopathologic Aspects of Photodynamic Therapy for Dysplasia and Early Adenocarcinoma Arising in Barrett's Esophagus.

Ban S, Mino M, Nishioka NS, Puricelli W, Zukerberg LR, Shimizu M, Lauwers GY.

From the Departments of *Pathology, Gastrointestinal Pathology Service, and double daggerMedicine (Gastrointestinal Unit), Massachusetts General Hospital, Boston, MA; and daggerDepartment of Pathology, Saitama Medical School, Saitama, Japan
Am J Surg Pathol. 2004 Nov;28(11):1466-1473. Abstract quote  

The efficacy of photodynamic therapy (PDT) is currently evaluated for the treatment of superficial neoplasms arising in Barrett's esophagus (BE). An accurate assessment of this technique requires the evaluation of biopsies before and after treatment. However, despite the importance of pathology, only a limited number of studies have systematically assessed the mucosal changes after PDT.

To evaluate mucosal changes after PDT, and pathologic variables that may impact on the success of this therapy, we analyzed the pre- and post-PDT biopsies of a cohort of patients treated by this modality. Thirty-three patients (mean age, 71 years) with high-grade dysplasia (HGD) and/or intramucosal carcinoma (IMC) arising in BE and followed up after PDT using Porfimer sodium form the basis of this study. In all patients, a review of all pre- and post-PDT biopsies was performed. The variables recorded included the histologic grade and architecture of neoplasms, the distribution of neoplasms, and squamous re-epithelialization. IMC and HGD coexisted in the pre-PDT biopsies of 18 patients (54.5%). IMC and HGD showed a prominent tubular proliferation in 14 patients and displayed a papillary pattern (at least partially) in 19 patients. In post-PDT, patches of specialized columnar epithelium were buried under squamous epithelium in 17 patients (51.5%), and foci of dysplasia/carcinoma covered by squamous epithelium were found in 9 patients (27.3%). HGD and/or IMC were eradicated in 17 patients (eradicated group) and persisted in 16 patients (persistent group). In the persistent group, grade and architecture were unchanged after PDT in 62.5% and 87.5% of patients, respectively. The persistent group was characterized by: 1) a more frequent papillary architecture (P < 0.05), and 2) a diffuse distribution of the neoplasms on pre-PDT biopsies (P = 0.05). Singularly, the persistent neoplastic lesions were observed in the distal esophagus (P < 0.05).

A systematic histopathologic evaluation allowed us to draw attention to the fact that distally located and papillary-type neoplasia seem resistant to PDT. The higher than expected incidence of buried residual neoplastic epithelium should also be emphasized since it represents a risk for undetected growth of malignancy.
Management of Superficial Barrett's Epithelium-Related Neoplasms by Endoscopic Mucosal Resection: Clinicopathologic Analysis of 27 Cases.

Mino-Kenudson M, Brugge WR, Puricelli WP, Nakatsuka LN, Nishioka NS, Zukerberg LR, Misdraji J, Lauwers GY.

From the Departments of *Pathology, Gastrointestinal Pathology Service, and daggerMedicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Am J Surg Pathol. 2005 May;29(5):680-686. Abstract quote  

Endoscopic mucosal resection (EMR), a relatively new endoluminal therapeutic technique with low morbidity and no mortality reported to date, is advocated for the treatment of Barrett's esophagus (BE)-related superficial neoplasms. However, recent studies revise its success downward, particularly regarding the ability to achieve complete excision.

To evaluate what remains an evolving technique, we analyzed our experience with a series of 27 esophageal EMRs (20 lesions in 18 patients). Our goal was to evaluate the diagnostic, staging, and therapeutic advantages of EMR separately by correlating the initial biopsies and pre-EMR endoscopic ultrasound (EUS) staging with the final histologic diagnoses and stage. Persistence/recurrence of neoplastic tissue was also correlated with the margin status of the resections. The mean size of the neoplasms, which included low-grade dysplasias (n = 2), high-grade dysplasias (n = 8), intramucosal carcinomas (n =14), and submucosal invasive carcinomas (n = 3), was 11 mm. EUS correctly reported an intramucosal or submucosal lesion in 70% of the cases while it overstaged 18% and understaged 12% of the cases.

The biopsy diagnosis corresponded to the EMR diagnosis in 63% of the cases. The biopsy underestimated the grade of the lesion in 21% of the cases. EMR revealed a lower histologic grade compared with the biopsy in 16% of the cases. The resection was microscopically complete in only 4% of the cases. No residual/recurrent disease was observed in 10 lesions (9 patients) at 4 to 63 months (mean, 23 months) post-EMR. However, 9 lesions (8 patients) persisted/recurred 28 days to 25 months (mean, 6 months) after treatment; 56% of the cases with positive lateral margin(s) and negative deep margin persisted/recurred. However, 86% of the EMRs with positive deep margin showed residual tumor/recurrence on follow-up biopsies.

In conclusion, we observed that EMR offers improved diagnosis and staging as compared with biopsy and EUS. This is a significant advantage since it can modify patients' management. However, frequent incompleteness of resection and high persistence/recurrence are significant pitfalls that dictate continued endoscopic surveillance.

The rationale for esophagectomy as the optimal therapy for Barrett's esophagus with high-grade dysplasia.

Edwards MJ, Gable DR, Lentsch AB, Richardson JD.

Department of Surgery, School of Medicine, University of Louisville, Kentucky 40292, USA.

Ann Surg 1996 May;223(5):585-9; discussion 589-91 Abstract quote

OBJECTIVE: The authors determined the incidence of invasive adenocarcinoma after esophagectomy in patients endoscopically diagnosed as having Barrett's esophagus with high-grade dysplasia.

SUMMARY BACKGROUND DATA: Barrett's esophagus is a well-recognized premalignant condition. There is controversy with regard to the optimal treatment of high-grade dysplasia in Barrett's esophagus. Recognizing the morbidity and mortality associated with esophagectomy, some recommend a selective approach, reserving esophagectomy only for evidence of invasive cancer identified through endoscopic surveillance. Other advocate esophagectomy for all suitable operative candidates.

METHODS: The authors reviewed their experience between 1985 and 1995 with 11 patients with high-grade dysplasia arising in Barrett's esophagus diagnosed by endoscopic biopsy and treated by esophagectomy.

RESULTS: All patients were white men ranging in age from 47 to 70 years. Ten patients underwent esophagectomy by the Ivor Lewis technique; one had a transhiatal resection. Eight patients (73%) had invasive adenocarcinoma identified after esophagectomy; two (18%) had positive lymph nodes; one required a prolonged hospital stay for an anastomotic leak; two (18%) temporarily suffered delayed gastric emptying. The authors' review identified 85 additional patients previously reported during the same period. Including the current series, 39 patients (41%) had invasive adenocarcinoma identified in the resected specimen. A preponderance of early, potentially curable carcinomas are characteristically found in these patients.

CONCLUSION: A high incidence of endoscopically undetected invasive carcinoma strongly supports esophagectomy as the preferred approach for suitable operative candidates with high-grade dysplasia in Barrett's esophagus.

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Adenocarcinoma of the esophagus



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