Esophagus: Barretts esophagus, dysplasia and adenocarcinoma

2009-08-01   DunFa Peng , Wael El-Rifai 

1.Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

Summary

Note

Barretts adenocarcinoma is one of malignancies with the most rapid increase in incidence during past decades in the Western countries. It is defined as adenocarcinoma of the lower esophagus and gastroesophageal junction associated with Barretts esophagus. Barretts esophagus is the only known precursor for Barretts adenocarcinoma through Barretts dysplasia (also called metaplasia-dysplasia-adenocarcinoma sequence).

Clinics and Pathology

Note

Barretts esophagus is defined as the normal esophageal squamous epithelium that is replaced by intestinalized metaplastic columnar epithelia.

Phenotype stem cell origin

The progenitor cell from which Barretts oesophagus develops is still unclear. Progenitor cells resident in the submucosal glands or the interbasal layer of the epithelium, bone-marrow-derived stem cells, or transdifferentiated squamous cells are included in the candidate cells.

Etiology

Gastroesophageal reflux disease (GERD) is considered the major risk factor for Barretts esophagus. About 1 in 10 patients with GERD are found to have Barretts esophagus. GERD generates reactive oxygen species that produce oxidative stress and subsequent oxidative DNA damage. Some DNA damage may cause DNA mutations that accumulate and cause tumor formation.

Epidemiology

Barretts esophagus is more common in men than in women, with a male:female ratio of about 2:1. The risk factors of Barretts esophagus include Age (increasing with age), Race (more common in Caucasians), smoking (not clear), alcohol consumption (not clear), gastroesophageal reflux disease (GERD, major factor), and obesity. On the other hand, some controversial reports indicate that H. pylori infection and the virulent cagA strains in particular, may protect against the development of Barretts oesophagus and progression to adenocarcinoma.

Clinics

Heartburn is the most common symptom of GERD and Barretts esophagus.
Atlas Image
Normal esophagus is covered by squamous epithelia (A). However, in Barretts esophagus (B), the squamous epithelia are replaced by intestinalized metaplastic columnar epithelia.

Note

Barretts dysplasia is defined morphologically as unequivocal neoplastic epithelium that remains confined within the basement membrane of the epithelium from which it developed. In patients with Barretts esophagus, dysplasia is graded as either low or high, depending on its cytological and architectural features.

Epidemiology

Most Barretts esophagus never progress to dysplasia and carcinoma. It has been reported that the male gender, longstanding gastroesophageal reflux disease, hiatal hernia size, and segment length are strongly associated with Barretts dysplasia. On the other hand, successful antireflux surgery protects the Barretts mucosa from developing high-grade dysplasia and esophageal adenocarcinoma.

Note

Adenocarcinoma of lower esophagus and gastroesophageal junction associated with Barretts esophagus through metaplasia-dysplasia-adenocarcinoma sequence.

Note

Classification: Tumor classification is based on UICC TNM classification for esophageal cancers.

Etiology

Barretts esophagus with dysplasia

Epidemiology

Barretts esophagus is the only known precursor for Barretts adenocarcinoma. The patients with Barretts esophagus have 20 folds more risk for developing esophageal adenocarcinoma. However, only 1-5% of Barretts esophagus progress to Barretts adenocarcinoma. Although longstanding gastroesophageal reflux disease, hiatal hernia size, and segment length are strongly associated with adenocarcinoma, Barretts esophagus with dysplasia is likely the true precursor for developing to adenocarcinoma.

Clinics

Heartburn is the most common symptom of GERD and Barretts esophagus. As for Barretts adenocarcinoma, it shares the symptoms with other esophageal type cancers, such as difficulty swallowing, unexplained weight loss, pain in the throat or mid-chest, etc.

Pathology

There is no difference in the term of histology of Barretts adenocarcinoma from that in the stomach and colon. It can be graded into well-, moderately- and poorly-differentiated adenocarcinoma based on their cytologic and architectural atypia. The Lauren classification for gastric cancer has also been used by some pathologists and physicians to divide into either intestinal or diffuse histological type.
Atlas Image
A representative image of a Barretts adenocarcinoma with moderate to poor differentiation. Atypic tumor cells form quite irregular tubules and some form solid cord.

Treatment

Esophagectomy is still the most common primary treatment. Other treatment modalities include chemotherapy, radiation therapy, stents, photodynamic therapy, and endoscopic therapy with an Nd:YAG laser. Combined modality therapy (i.e., chemotherapy plus surgery or chemotherapy and radiation therapy plus surgery) is under clinical evaluation.

Prognosis

The prognosis of Barretts adenocarcinoma depends on the stage at diagnosis, treatment and the patients general condition. The overall 5-year survival rate in patients amenable to definitive treatment ranges from 5 to 30%.

Cytogenetics

Note

The chromosomal alterations most frequently identified in Barretts adenocarcinoma by CGH were: gains in 8q (80%), 20q (60%); 2p, 7p and 10q (47% each), 6p (37%), 15q (33%), and 17q (30%). Losses were observed predominantly in the 4q (50%); 5q and 9p (43% each), 18q (40%), 7q (33%), and 14q (30%).
Atlas Image
CGH analysis of a case of Barretts esophageal adenocarcinoma. Tumor DNA was labeled with FITC (Green) and reference DNA was labeled with TRITC (red). The hybridizations were analyzed using an Olympus fluorescence microscope and the ISIS digital image analysis system (Metasystems GmbH, Altlussheim, Germany) based on integrated high-sensitivity monochrome CCD camera and automated CGH analysis software. The green colon indicates areas of DNA gains whereas the red color indicates DNA losses in the tumor sample.

Genes Involved and Proteins

Note

There are many genes that have been reported to be genetically and/or epigenetically dysregulated, such as gene mutation, amplification, and LOH and DNA methylation that involved cell cycle control, apoptosis, cell adhesion and antioxidative stress, etc. Some representative genes are described below.

Gene name

ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))

Location

17q12

Note

ERBB2 protein over-expression and/or DNA amplification have been reported in 10-70% of esophageal adenocarcinomas. The present literature data suggest that ERBB2 overexpression may be a late event in the dysplasia-carcinoma sequence, as it occurred predominantly in high-grade dysplasia and adenocarcinomas. It has been reported that ERBB2 over-expression/amplification in carcinoma correlated significantly with tumor invasion, lymph node metastasis, and poor prognosis in patients with Barretts related adenocarcinoma.

Protein description

The ERBB2 (also called HER2 or NEU) gene encodes an integral type I protein of 185 kDa, 1255 amino acids, with a cysteine-rich extracellular ligand-binding domain, a transmembrane domain and an intracellular region endowed with a tyrosine kinase activity.

Gene name

MYC v-myc myelocytomatosis viral oncogene homolog (avian)

Location

8q24.21

Note

Frequent high-level chromosomal amplification of 8q21 has been reported in Barretts adenocarcinoma and c-myc is the potential target gene for this amplification. It has been reported that amplification of c-myc was detected in 25% of high-grade dysplasia and 44% of adenocarcinomas, but in none of Barretts metaplasia and low-grade dysplasia.

Protein description

DNA binding protein with 439 amino acids and 48 kDa (p64); 454 amino acids (p67, 15 additional amino acids in N-term), contains a transactivation domain, an acidic domain, a nuclear localization signal, a basic domain, a helix-loop-helix motif, and a leucin zipper.

Gene name

CDX1 (caudal type homeobox 1)

Location

5q32

Note

CDX1 is predominantly expressed in the small intestine and colon, but not in normal esophageal squamous epithelia or gastric epithelia.
CDX1 was over-expressed in Barretts esophagus and adenocarcinomas, most likely through promoter DNA hypomethylation.

Protein description

Member of the caudal-related homeobox transcription factor gene family. The encoded protein regulates intestine-specific gene expression and differentiation of intestine.

Gene name

CDX2 (caudal-related homeobox 2)

Location

13q12.2

Note

CDX2 is predominantly expressed in the small intestine and colon, but not in normal esophageal squamous epithelia or gastric epithelia.
CDX2 expression is observed in the intestinal metastasis area.

Protein description

Member of the caudal-related homeobox transcription factor gene family. The encoded protein regulates intestine-specific gene expression and differentiation of intestine. It is suggested that CDX2 is a master switch gene whose normal expression determines the proximal and distal specialization of the gut in embryogenesis.

Gene name

CDKN2A (cyclin dependent kinase 2a / p16)

Location

9p21.3

Note

Tumor suppressor gene controls the G1/S transition of the cell cycle. Inactivation of CDKN2A is among the most common genetic/epigenetic alterations through Barretts carcinogenesis and is an early event. LOH, promoter hypermethylation, or sequence mutations have been reported in over 85% of Barretts esophagus that were associated with p16 inactivation.

Dna rna description

7288 bp.
Exon Count: 3.

Protein description

Tumor suppressor protein having 156 aa, functions as an inhibitor of CDK4 kinase in cell cycle G1 control.

Gene name

TP53 (Tumour protein p53 (Li-Fraumeni syndrome))

Location

17p13.1

Note

Loss of p53 occurs through either LOH, sequence mutation, or both. Loss of p53 has been reported in Barretts esophagus and likely correlates with progression to adenocarcinoma, as patients with LOH in TP53 are 16 times more likely to progress to adenocarcinoma than patients without TP53 LOH.

Dna rna description

Exon Count: 11.

Protein description

A tumor suppressor protein essential in cell cycle regulation and in DNA damage repair. p53 transcriptionally regulates multiple genes functioning as an inhibitor of cell growth and proliferation and inducer of apoptosis. Loss of TP53 functions promotes tumor progression, most likely by preventing cell cycle arrest, suppressing apoptosis and permitting genetic instability for subsequent genetic alterations.

Gene name

CDKN1B (cyclin-dependent kinase inhibitor 1 B)

Location

12p13.1

Note

It has been reported that in 83% of Barretts adenocarcinomas, p27 protein was down-regulated by an immunohistochemical study. And for p27 to arrest cell cycle, it must localize in the nucleus. However, in approximately 50% of high-grade dysplasia, p27 was observed in cytoplasmic localization, which renders it inactive.

Protein description

A tumor suppressor protein essential in cell cycle regulation, a CDK inhibitor.

Gene name

GPX3 (Glutathione peroxidase 3)

Location

5q33.1

Note

GPX3 is one of the glutathione peroxidase family members, which functions in the detoxification of hydrogen peroxide. Frequent GPX3 gene promoter hypermethylation has recently been demonstrated in Barretts adenocarcinomas and its precancerous lesions, Barretts esophagus and dysplasia, and was significantly associated with gene down-regulation. It is noted that GPX3 has been recently reported as a potential tumor suppressor in prostatic carcinomas.

Protein description

GPX3 is a secretory protein.

Gene name

GPX7 (glutathione peroxidase 7)

Location

1p32.3

Note

GPX7 is one of the glutathione peroxidase family members which function in the detoxification of hydrogen peroxide. Unlike other glutathione peroxidase family members, GPX7 incorporates cysteine instead of selenocysteine in the conserved catalytic motif. Frequent GPX7 gene promoter hypermethylation has recently been demonstrated in Barretts adenocarcinomas and its precancerous lesion, Barretts dysplasia, and was significantly associated with gene down-regulation. Recent research indicates that GPX7 may have dual functions, antioxidative activity and tumor suppressor function in Barretts adenocarcinoma.

Dna rna description

Genomic Size: 6679.
Coding Exon Count: 3.

Gene name

MGMT (O-6-methylguanine-DNA methyltransferase)

Location

10q26.3

Note

It is recently reported that hypermethylation was detected in 78.9% of esophageal adenocarcinomas, in 100% of Barretts intraepithelial neoplasia, in 88.9% of Barretts metaplasia, in only 21.4% of normal esophageal mucosa samples (P

Dna rna description

Genomic Size: 299903.
Exon Count: 5.
Coding Exon Count: 4.

Protein description

O6-methylguanine-DNA methyltransferase is involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. It repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O6 position to a cysteine residue in the enzyme.

Gene name

APC (adenomatous polyposis coli)

Location

5q22.2

Note

LOH of 5q has been reported as a higher occurrence in high-grade dysplasia and adenocarcinomas of the esophagus. Hypermethylation of the APC gene has been found in 68-100% of Barretts adenocarcinomas and approximately 50% of Barretts esophagus. More importantly, hypermethylation of APC with other genes such as p16, strongly predicts progression to high-grade dysplasia or cancer in patients with BE. Absence of p16 and APC hypermethylation is associated with a benign course.

Dna rna description

Genomic Size: 138719.
Exon Count: 16.
Coding Exon Count: 15.

Protein description

Adenomatous polyposis coli protein which possesses tumor suppressor functions, works as an antagonist of the Wnt signaling pathway. APC binding to beta catenin leads to ubiquitin-mediated beta catenin destruction; loss of APC function increases transcription of beta catenin targets, such as C-MYC and Cyclin D. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product.

Bibliography

Pubmed IDLast YearTitleAuthors
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119103612002p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett's esophagus.Bian YS et al
115227432001Genetic differences between adenocarcinomas arising in Barrett's esophagus and gastric mucosa.El-Rifai W et al
171241602006Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma.Fitzgerald RC et al
162997872005The molecular biology of esophageal adenocarcinoma.Koppert LB et al
190272272009Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus.Kuester D et al
162298082005Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis.Lee OJ et al
167136722007Multistage carcinogenesis in Barrett's esophagus.Maley CC et al
159731012005Barrett esophagus: risk factors for progression to dysplasia and adenocarcinoma.Oberg S et al
186645052009DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett's adenocarcinoma.Peng DF et al
176365452007Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: serial analysis of gene expression.Razvi MH et al
156453982005Epidemiologic risk factors for Barrett's esophagus and associated adenocarcinoma.Wong A et al

Citation

DunFa Peng ; Wael El-Rifai

Esophagus: Barretts esophagus, dysplasia and adenocarcinoma

Atlas Genet Cytogenet Oncol Haematol. 2009-08-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5591/esophagus-barretts-esophagus-dysplasia-and-adenocarcinoma