Editorial
989
The field effect in Barrett’s esophagus: can we use it for screening and surveillance?
Authors
Garry G. S. Farnham1, Janusz A. Jankowski1, 2, 3
Institutions
1
Plymouth University Schools of Medicine and Dentistry, Plymouth, United Kingdom Centre for Digestive Diseases, Queen Mary University of London, London, United Kingdom 3 Digestive Diseases Centre, Leicester Royal Infirmary, Leicester, United Kingdom
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1358935 Endoscopy 2013; 45: 989–991 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X
Esophageal adenocarcinoma (EAC) is a relatively uncommon but serious cancer afflicting 5 – 15 / 100000 population in the UK, and in which diagnosis at the late rather than the early stage decreases the 5-year survival rates from 90 % to between 10 % and 20 % [1]. Barrett’s esophagus is
present as a premalignant lesion in the majority of cases of EAC and although Barrett’s esophagus is a major risk factor, only 2.5 % – 5 % of cases progress to EAC. The increased risk generally initiates a program of endoscopic surveillance that enables early intervention if the disease progresses [2].
Corresponding author Garry Farnham, PhD Gastroenterology and Genomics University of Plymouth Peninsula School of Medicine and Dentistry Research Way Derriford Plymouth PL6 8BU United Kingdom Fax: +44-1752-517842 [email protected]
Methodological issues in surveillance of Barrett’s esophagus
Clonality and the origins of Barrett’s esophagus
!
!
Endoscopic surveillance of Barrett’s esophagus involves four-quadrant random biopsy, which, depending on the perceived risk, is performed every 1 – 2 cm along the Barrett’s lesion as recommended by the Seattle protocol [3]. The process is time-consuming and laborious, with protocol errors deriving from subjective sampling and poor adherence to surveillance protocols among endoscopists. Further sampling errors are derived from the patchy distribution and small size of dysplasia. Histopathological errors may also be introduced, as the subtle changes defining the transition from nondysplastic to high grade dysplasia result in wide observer variability [2]. Finally, the classification scheme used to stage disease progression is purely qualitative and does not address the underlying biology or the risk of disease progression. Thus, developments that address these faults are welcomed. A particular feature of many cancers is an area of histologically normal cells that carry genetic alterations predisposing to malignancy, termed the field of cancerization [4]. Unique molecular signatures in the fields of both Barrett’s esophagus and EAC have been identified, suggesting plausible routes for risk stratification and diagnosis of Barrett’s esophagus [5]. To achieve a risk stratification system, further understanding is required of the cancerized field prior to neoplastic progression of Barrett’s esophagus.
Barrett’s esophagus is an acquired condition promoted by chronic gastric reflux and replacement of the normal striated squamous esophageal epithelium with a specialized columnar mucosal intestinal epithelia [6, 7].The progression from Barrett’s esophagus to EAC, termed the metaplasia – dysplasia – adenocarcinoma sequence, is frequently associated with genetic alterations in TP53 (p53) and CDKN2A (p16), nonrandom loss of heterozygosity, and changes in ploidy, which can predispose cells to increased proliferation [7]. Additional genetic diversity may be derived from genetically distinct populations of clonal cell lines that originate from discrete esophageal crypts [8], and subsequent increases in genetic diversity through a process of clonal bifurcation, thus increasing both the spatial distribution of clonal populations and genetic diversity [9]. Accordingly, genetic and phenotypic heterogeneity are observed in some Barrett’s segments and clonal diversity is predictive of progression to EAC [10]. The early cellular changes that underlie Barrett’s esophagus are poorly described. However, similarities between the modified Barrett’s epithelium and colonic intestinal epithelium suggest shared developmental features. Field effects are common to esophageal and colon adenocarcinomas, with the field of cancerization in the colon proposed to occur through monoclonal expansion of stem cells present in the colonic crypts [11], whereas in the esophagus it may be oligoclonal [8]. Field effects are common in early-stage Barrett’s meta-
Farnham Garry GS et al. The field effect in Barrett’s esophagus … Endoscopy 2013; 45: 989–991
Downloaded by: WEST VIRGINIA UNIVERSITY. Copyrighted material.
2
Editorial
E
S1
S2
S3
S4
S5
S6
S7
T4
D
T3
C
T2
T1
T3
B
T2 T1
A
NDBE
Normal
Cancerized field
{
NDBE → DBE
NDBE
Barrett’s Esophagus Dysplasia
NDBE
NDBE → DBE
NDBE
Histopathology
Molecular signature
Identified by PWSM
Normal
Yes
Yes
Barrett’s Esophagus Metaplasia Normal
Yes
Unknown
Barrett’s Esophageal epithelia
Yes
Yes
Normal
plasia; consequently, understanding of the field effects in the esophagus requires consideration of the Barrett’s stem cells. Clues to the origin of Barrett’s stem cells come from observations that islands of neosquamous epithelium that repopulate Barrett’s dysplastic lesions after acid suppression therapies or surgical ablation are often genetically distinct from the adjacent Barrett’s epithelium, implying that the tissues are derived from different stem cells [12]. Furthermore, histological and genetic evidence suggest that stem cell populations located in the esophageal ducts are the source of both neosquamous epithelium and Barrett’s metaplasia [8, 13]. The study of stem cell origin in the stomach has used mitochondrial cytochrome C oxidase deficiency as a marker to track cell lineage [14]. Applying this approach to Barrett’s esophagus, Nicholson et al. concluded that normal esophageal glands and Barrett’s metaplasia glands contained multiple stem cells and that neosquamous epithelium and underlying glandular epithelium were derived from a common cell [15]. Crucially, studies of the esophageal glands suggest mechanisms that explain the temporal, spatial, and genetic heterogeneity observed in Barrett’s metaplasia [6], and suggest the same process may drive heterogeneity in the cancerized field. Candidate stem cells located in esophageal and Barrett’s glands were recently reported [16]. Characterization of these cells is now required to understand their role in the field cancerization and neoplastic development of Barrett’s esophagus.
Fig. 1 Detecting field effects during the progression of Barrett’s esophagus from metaplasia to dysplasia. Cancerized fields in Barrett’s esophagus are likely to be derived from progenitor (stem) cells in esophageal or Barrett’s crypts. A In an oligoclonal model of field cancerization, spatially discrete individual crypts produce clonal populations of mutant cells with a selective advantage forming cancerization fields associated with either nondysplastic Barrett’s esophagus (NDBE) or dysplastic Barrett’s esophagus (DBE) or both (NDBE → DBE). B Cancerized fields from individual crypts develop to cover larger areas of the epithelium (represented by cones). Assay for field effects is influenced by the time of sampling (T1, T2, or T3) due to the metachronous appearance of individual fields. C Schematic representation of expanding cancerized fields as they appear on the surface epithelium over time (T1, T2, and T3). D At later stages (T4), clonal expansion produces large areas derived from one or more cancerized fields. Successful assay for field effects is a product of sampling location (E) and sampling time (B and C). Cancerized fields associated with Barrett’s metaplasia (NDBE) and Barrett’s dysplasia (DBE) are histologically normal and associated with specific molecular features that are different to those in normal epithelium. Partial wave spectroscopy (PWS) can distinguish between DBE and normal esophageal tissue; however, the ability to distinguish between metaplasia and normal tissue is not known. This could be related to either lack of a discriminating feature between normal epithelium and Barrett’s metaplasia or sampling errors as a function of location (E) and time (B, C).
Nanostructural changes in the nondysplastic cells of the esophagus !
In this issue of Endoscopy, a study by Konda et al. quantitatively assessed nanostructural changes in nondysplastic cells comprising the field of Barrett’s esophagus and EAC using particle wave spectroscopy (PWS) [17]. This technique measures the disorder strength (Ld), a statistic that characterizes the spatial heterogeneity of mass distributions of macromolecules. PWS has demonstrated sensitivity to nanostructural alterations in the dysplastic field of several cancers. In contrast to invasive biopsy, Konda et al. derived cells from the proximal esophagus of controls, patients diagnosed with Barrett’s esophagus (nondysplastic, low grade dysplasia [LGD] or high grade dysplasia [HGD]), and patients with EAC using a standard endoscopic cytology brush that can, in principle, be performed without endoscopy. The results showed clear differences in the average Ld scores of patients with EAC and dysplastic Barrett’s esophagus that were 1.81 and1.64 times higher than controls, respectively. In addition, the area under the receiver operating characteristic curve (0.82) indicated fairly good accuracy at distinguishing collectively between cases with dysplastic Barrett’s esophagus and cancer when compared with controls. PWS did not resolve differences between cases with LGD and HGD or superficial and invasive cancer, and notably did not detect significant differences between nondysplastic Barrett’s esophagus and controls. PWS applied to cancerized fields in the human colon has been shown to be predictive of adenocarcinoma, with higher Ld scores correlated with
Farnham Garry GS et al. The field effect in Barrett’s esophagus … Endoscopy 2013; 45: 989–991
Downloaded by: WEST VIRGINIA UNIVERSITY. Copyrighted material.
990
more severe cancers [18]. In contrast, most nondysplastic Barrett’s lesions are not cancerous and it is unclear whether cells comprising nondysplastic Barrett’s esophagus fields are sufficiently aberrant for PWS to resolve. Clearly there is a need to characterize at what stage field effects are detectable by PWS and to determine whether there is a signal that can distinguish between controls and nondysplastic Barrett’s esophagus. In the Konda et al. study, the small size and lack of patient follow-up did not allow neoplastic progression of Barrett’s esophagus to be studied, although this area warrants further study. A major hurdle to detecting cancerized fields in nondysplastic Barrett’s esophagus samples may derive from the clonal heterogeneity of cells that comprise Barrett’s lesions, which could produce a patchy distribution of variably sized fields, thus promoting sampling " Fig. 1). This mechanism could explain the nonsignifierrors (● cant Ld scores reported for nondysplastic Barrett’s esophagus cases and controls by Konda et al., and assessing this idea will be central to development of PWS as a clinical technique. Overall, targeting cancerized fields in Barrett’s esophagus and EAC is an appealing idea as it exploits an acknowledged biological phenomena and could reduce the number of endoscopies. However, poor understanding of field cancerization in the esophagus currently limits the application of PWS in diagnosis and surveillance of Barrett’s esophagus. In practice, the clonal origins of Barrett’s esophagus make sampling of rare progenitor cells or cancerized fields at an early stage of disease problematic. Therefore, the development of markers that identify aberrant cells, including stem cells, at a very early stage of Barrett’s esophagus will be required to improve current practice. Competing interests: None
References 1 Hirst NG, Gordon LG, Whiteman DC et al. Is endoscopic surveillance for non-dysplastic Barrett’s esophagus cost-effective? Review of economic evaluations J Gastroenterol Hepatol 2011; 26: 247 – 254 2 Sharma P, Sidorenko EI. Are screening and surveillance for Barrett’s oesophagus really worthwhile? Gut 2005; 54: i27 – i32 3 Wang KK, Sampliner RE. Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 2008; 103: 788 – 797
4 Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: 963 – 968 5 Brabender J, Marjoram P, Lord RV et al. The molecular signature of normal squamous esophageal epithelium identifies the presence of a field effect and can discriminate between patients with Barrett’s esophagus and patients with Barrett’s-associated adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2005; 14: 2113 – 2117 6 Jankowski JA, Harrison RF, Perry I et al. Barrett’s metaplasia. Lancet 2000; 356: 2079 – 2085 7 Jankowski JA, Wright NA, Meltzer SJ et al. Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Pathol 1999; 154: 965 – 973 8 Leedham SJ, Preston SL, McDonald SA et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus. Gut 2008; 57: 1041 – 1048 9 Barrett MT, Sanchez CA, Prevo LJ et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nature genetics 1999; 22: 106 – 109 10 Maley CC, Galipeau PC, Finley JC et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet 2006; 38: 468 – 473 11 Greaves LC, Preston SL, Tadrous PJ et al. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci U S A 2006; 103: 714 – 719 12 Paulson TG, Xu L, Sanchez C et al. Neosquamous epithelium does not typically arise from Barrett’s epithelium. Clin Cancer Res 2006; 12: 1701 – 1706 13 Coad RA, Woodman AC, Warner PJ et al. On the histogenesis of Barrett’s oesophagus and its associated squamous islands: a three-dimensional study of their morphological relationship with native oesophageal gland ducts. J Pathol 2005; 206: 388 – 394 14 Gutierrez-Gonzalez L, Graham TA, Rodriguez-Justo M et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 2011; 140: 1251 – 1260 15 Nicholson AM, Graham TA, Simpson A et al. Barrett’s metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. Gut 2012; 61: 1380 – 1389 16 Pan Q, Nicholson AM, Barr H et al. Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus. Gastroenterology 2013; 144: 761 – 770 17 Konda VJA, Cherkezyan L, Subramanian H et al. Nanoscale markers of esophageal field carcinogenesis: potential implications for esophageal cancer screening. Endoscopy 2013; 45: 983 – 988 18 Subramanian H, Roy HK, Pradhan P et al. Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy. Cancer Res 2009; 69: 5357 – 5363
Farnham Garry GS et al. The field effect in Barrett’s esophagus … Endoscopy 2013; 45: 989–991
991
Downloaded by: WEST VIRGINIA UNIVERSITY. Copyrighted material.
Editorial
989
The field effect in Barrett’s esophagus: can we use it for screening and surveillance?
Authors
Garry G. S. Farnham1, Janusz A. Jankowski1, 2, 3
Institutions
1
Plymouth University Schools of Medicine and Dentistry, Plymouth, United Kingdom Centre for Digestive Diseases, Queen Mary University of London, London, United Kingdom 3 Digestive Diseases Centre, Leicester Royal Infirmary, Leicester, United Kingdom
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1358935 Endoscopy 2013; 45: 989–991 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X
Esophageal adenocarcinoma (EAC) is a relatively uncommon but serious cancer afflicting 5 – 15 / 100000 population in the UK, and in which diagnosis at the late rather than the early stage decreases the 5-year survival rates from 90 % to between 10 % and 20 % [1]. Barrett’s esophagus is
present as a premalignant lesion in the majority of cases of EAC and although Barrett’s esophagus is a major risk factor, only 2.5 % – 5 % of cases progress to EAC. The increased risk generally initiates a program of endoscopic surveillance that enables early intervention if the disease progresses [2].
Corresponding author Garry Farnham, PhD Gastroenterology and Genomics University of Plymouth Peninsula School of Medicine and Dentistry Research Way Derriford Plymouth PL6 8BU United Kingdom Fax: +44-1752-517842 [email protected]
Methodological issues in surveillance of Barrett’s esophagus
Clonality and the origins of Barrett’s esophagus
!
!
Endoscopic surveillance of Barrett’s esophagus involves four-quadrant random biopsy, which, depending on the perceived risk, is performed every 1 – 2 cm along the Barrett’s lesion as recommended by the Seattle protocol [3]. The process is time-consuming and laborious, with protocol errors deriving from subjective sampling and poor adherence to surveillance protocols among endoscopists. Further sampling errors are derived from the patchy distribution and small size of dysplasia. Histopathological errors may also be introduced, as the subtle changes defining the transition from nondysplastic to high grade dysplasia result in wide observer variability [2]. Finally, the classification scheme used to stage disease progression is purely qualitative and does not address the underlying biology or the risk of disease progression. Thus, developments that address these faults are welcomed. A particular feature of many cancers is an area of histologically normal cells that carry genetic alterations predisposing to malignancy, termed the field of cancerization [4]. Unique molecular signatures in the fields of both Barrett’s esophagus and EAC have been identified, suggesting plausible routes for risk stratification and diagnosis of Barrett’s esophagus [5]. To achieve a risk stratification system, further understanding is required of the cancerized field prior to neoplastic progression of Barrett’s esophagus.
Barrett’s esophagus is an acquired condition promoted by chronic gastric reflux and replacement of the normal striated squamous esophageal epithelium with a specialized columnar mucosal intestinal epithelia [6, 7].The progression from Barrett’s esophagus to EAC, termed the metaplasia – dysplasia – adenocarcinoma sequence, is frequently associated with genetic alterations in TP53 (p53) and CDKN2A (p16), nonrandom loss of heterozygosity, and changes in ploidy, which can predispose cells to increased proliferation [7]. Additional genetic diversity may be derived from genetically distinct populations of clonal cell lines that originate from discrete esophageal crypts [8], and subsequent increases in genetic diversity through a process of clonal bifurcation, thus increasing both the spatial distribution of clonal populations and genetic diversity [9]. Accordingly, genetic and phenotypic heterogeneity are observed in some Barrett’s segments and clonal diversity is predictive of progression to EAC [10]. The early cellular changes that underlie Barrett’s esophagus are poorly described. However, similarities between the modified Barrett’s epithelium and colonic intestinal epithelium suggest shared developmental features. Field effects are common to esophageal and colon adenocarcinomas, with the field of cancerization in the colon proposed to occur through monoclonal expansion of stem cells present in the colonic crypts [11], whereas in the esophagus it may be oligoclonal [8]. Field effects are common in early-stage Barrett’s meta-
Farnham Garry GS et al. The field effect in Barrett’s esophagus … Endoscopy 2013; 45: 989–991
Downloaded by: WEST VIRGINIA UNIVERSITY. Copyrighted material.
2
Editorial
E
S1
S2
S3
S4
S5
S6
S7
T4
D
T3
C
T2
T1
T3
B
T2 T1
A
NDBE
Normal
Cancerized field
{
NDBE → DBE
NDBE
Barrett’s Esophagus Dysplasia
NDBE
NDBE → DBE
NDBE
Histopathology
Molecular signature
Identified by PWSM
Normal
Yes
Yes
Barrett’s Esophagus Metaplasia Normal
Yes
Unknown
Barrett’s Esophageal epithelia
Yes
Yes
Normal
plasia; consequently, understanding of the field effects in the esophagus requires consideration of the Barrett’s stem cells. Clues to the origin of Barrett’s stem cells come from observations that islands of neosquamous epithelium that repopulate Barrett’s dysplastic lesions after acid suppression therapies or surgical ablation are often genetically distinct from the adjacent Barrett’s epithelium, implying that the tissues are derived from different stem cells [12]. Furthermore, histological and genetic evidence suggest that stem cell populations located in the esophageal ducts are the source of both neosquamous epithelium and Barrett’s metaplasia [8, 13]. The study of stem cell origin in the stomach has used mitochondrial cytochrome C oxidase deficiency as a marker to track cell lineage [14]. Applying this approach to Barrett’s esophagus, Nicholson et al. concluded that normal esophageal glands and Barrett’s metaplasia glands contained multiple stem cells and that neosquamous epithelium and underlying glandular epithelium were derived from a common cell [15]. Crucially, studies of the esophageal glands suggest mechanisms that explain the temporal, spatial, and genetic heterogeneity observed in Barrett’s metaplasia [6], and suggest the same process may drive heterogeneity in the cancerized field. Candidate stem cells located in esophageal and Barrett’s glands were recently reported [16]. Characterization of these cells is now required to understand their role in the field cancerization and neoplastic development of Barrett’s esophagus.
Fig. 1 Detecting field effects during the progression of Barrett’s esophagus from metaplasia to dysplasia. Cancerized fields in Barrett’s esophagus are likely to be derived from progenitor (stem) cells in esophageal or Barrett’s crypts. A In an oligoclonal model of field cancerization, spatially discrete individual crypts produce clonal populations of mutant cells with a selective advantage forming cancerization fields associated with either nondysplastic Barrett’s esophagus (NDBE) or dysplastic Barrett’s esophagus (DBE) or both (NDBE → DBE). B Cancerized fields from individual crypts develop to cover larger areas of the epithelium (represented by cones). Assay for field effects is influenced by the time of sampling (T1, T2, or T3) due to the metachronous appearance of individual fields. C Schematic representation of expanding cancerized fields as they appear on the surface epithelium over time (T1, T2, and T3). D At later stages (T4), clonal expansion produces large areas derived from one or more cancerized fields. Successful assay for field effects is a product of sampling location (E) and sampling time (B and C). Cancerized fields associated with Barrett’s metaplasia (NDBE) and Barrett’s dysplasia (DBE) are histologically normal and associated with specific molecular features that are different to those in normal epithelium. Partial wave spectroscopy (PWS) can distinguish between DBE and normal esophageal tissue; however, the ability to distinguish between metaplasia and normal tissue is not known. This could be related to either lack of a discriminating feature between normal epithelium and Barrett’s metaplasia or sampling errors as a function of location (E) and time (B, C).
Nanostructural changes in the nondysplastic cells of the esophagus !
In this issue of Endoscopy, a study by Konda et al. quantitatively assessed nanostructural changes in nondysplastic cells comprising the field of Barrett’s esophagus and EAC using particle wave spectroscopy (PWS) [17]. This technique measures the disorder strength (Ld), a statistic that characterizes the spatial heterogeneity of mass distributions of macromolecules. PWS has demonstrated sensitivity to nanostructural alterations in the dysplastic field of several cancers. In contrast to invasive biopsy, Konda et al. derived cells from the proximal esophagus of controls, patients diagnosed with Barrett’s esophagus (nondysplastic, low grade dysplasia [LGD] or high grade dysplasia [HGD]), and patients with EAC using a standard endoscopic cytology brush that can, in principle, be performed without endoscopy. The results showed clear differences in the average Ld scores of patients with EAC and dysplastic Barrett’s esophagus that were 1.81 and1.64 times higher than controls, respectively. In addition, the area under the receiver operating characteristic curve (0.82) indicated fairly good accuracy at distinguishing collectively between cases with dysplastic Barrett’s esophagus and cancer when compared with controls. PWS did not resolve differences between cases with LGD and HGD or superficial and invasive cancer, and notably did not detect significant differences between nondysplastic Barrett’s esophagus and controls. PWS applied to cancerized fields in the human colon has been shown to be predictive of adenocarcinoma, with higher Ld scores correlated with
Farnham Garry GS et al. The field effect in Barrett’s esophagus … Endoscopy 2013; 45: 989–991
Downloaded by: WEST VIRGINIA UNIVERSITY. Copyrighted material.
990
more severe cancers [18]. In contrast, most nondysplastic Barrett’s lesions are not cancerous and it is unclear whether cells comprising nondysplastic Barrett’s esophagus fields are sufficiently aberrant for PWS to resolve. Clearly there is a need to characterize at what stage field effects are detectable by PWS and to determine whether there is a signal that can distinguish between controls and nondysplastic Barrett’s esophagus. In the Konda et al. study, the small size and lack of patient follow-up did not allow neoplastic progression of Barrett’s esophagus to be studied, although this area warrants further study. A major hurdle to detecting cancerized fields in nondysplastic Barrett’s esophagus samples may derive from the clonal heterogeneity of cells that comprise Barrett’s lesions, which could produce a patchy distribution of variably sized fields, thus promoting sampling " Fig. 1). This mechanism could explain the nonsignifierrors (● cant Ld scores reported for nondysplastic Barrett’s esophagus cases and controls by Konda et al., and assessing this idea will be central to development of PWS as a clinical technique. Overall, targeting cancerized fields in Barrett’s esophagus and EAC is an appealing idea as it exploits an acknowledged biological phenomena and could reduce the number of endoscopies. However, poor understanding of field cancerization in the esophagus currently limits the application of PWS in diagnosis and surveillance of Barrett’s esophagus. In practice, the clonal origins of Barrett’s esophagus make sampling of rare progenitor cells or cancerized fields at an early stage of disease problematic. Therefore, the development of markers that identify aberrant cells, including stem cells, at a very early stage of Barrett’s esophagus will be required to improve current practice. Competing interests: None
References 1 Hirst NG, Gordon LG, Whiteman DC et al. Is endoscopic surveillance for non-dysplastic Barrett’s esophagus cost-effective? Review of economic evaluations J Gastroenterol Hepatol 2011; 26: 247 – 254 2 Sharma P, Sidorenko EI. Are screening and surveillance for Barrett’s oesophagus really worthwhile? Gut 2005; 54: i27 – i32 3 Wang KK, Sampliner RE. Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 2008; 103: 788 – 797
4 Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: 963 – 968 5 Brabender J, Marjoram P, Lord RV et al. The molecular signature of normal squamous esophageal epithelium identifies the presence of a field effect and can discriminate between patients with Barrett’s esophagus and patients with Barrett’s-associated adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2005; 14: 2113 – 2117 6 Jankowski JA, Harrison RF, Perry I et al. Barrett’s metaplasia. Lancet 2000; 356: 2079 – 2085 7 Jankowski JA, Wright NA, Meltzer SJ et al. Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Pathol 1999; 154: 965 – 973 8 Leedham SJ, Preston SL, McDonald SA et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus. Gut 2008; 57: 1041 – 1048 9 Barrett MT, Sanchez CA, Prevo LJ et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nature genetics 1999; 22: 106 – 109 10 Maley CC, Galipeau PC, Finley JC et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet 2006; 38: 468 – 473 11 Greaves LC, Preston SL, Tadrous PJ et al. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci U S A 2006; 103: 714 – 719 12 Paulson TG, Xu L, Sanchez C et al. Neosquamous epithelium does not typically arise from Barrett’s epithelium. Clin Cancer Res 2006; 12: 1701 – 1706 13 Coad RA, Woodman AC, Warner PJ et al. On the histogenesis of Barrett’s oesophagus and its associated squamous islands: a three-dimensional study of their morphological relationship with native oesophageal gland ducts. J Pathol 2005; 206: 388 – 394 14 Gutierrez-Gonzalez L, Graham TA, Rodriguez-Justo M et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 2011; 140: 1251 – 1260 15 Nicholson AM, Graham TA, Simpson A et al. Barrett’s metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. Gut 2012; 61: 1380 – 1389 16 Pan Q, Nicholson AM, Barr H et al. Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus. Gastroenterology 2013; 144: 761 – 770 17 Konda VJA, Cherkezyan L, Subramanian H et al. Nanoscale markers of esophageal field carcinogenesis: potential implications for esophageal cancer screening. Endoscopy 2013; 45: 983 – 988 18 Subramanian H, Roy HK, Pradhan P et al. Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy. Cancer Res 2009; 69: 5357 – 5363
Farnham Garry GS et al. The field effect in Barrett’s esophagus … Endoscopy 2013; 45: 989–991
991
Downloaded by: WEST VIRGINIA UNIVERSITY. Copyrighted material.
Editorial
