Barrets esophagus,risk factors,screening,AGA guidelines

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Barrett Esophagus
Dr. Vijay K.C.
DM resident
Date: 2023 Dec 25

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Introduction
 Barrett esophagus is the condition in which an abnormal columnar epithelium
that has both gastric and intestinal features and that is predisposed to malignancy
replaces the stratified squamous epithelium that normally lines the distal
esophagus.
 Columnar epithelium + goblet cell ( American guidelines)
 Columnar epithelium ± goblet cell( British guidelines)
 BE is a consequence of chronic GERD
 columnar cells replace reflux-damaged squamous cells.
 clinical importance : risk factor for esophageal adenocarcinoma.

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 Some may be worried because I have changed my opinion
• The lesion should be called "the lower esophagus lined by columnar epithelium"
• probably the result of a failure of the embryonic lining of the gullet to achieve maturity.
 Lord RV. Norman Barrett, "Doyen of esophageal surgery". Ann Surg 1999;229:428.
 Aka Columner epithelium lined lower esophagus (CELLO)

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Introduction
 BE and dysplasia appear to be precursors or markers of EAC
development
• 10% of patients with GERD will have BE
• 10% of patients with BE will have dysplasia
• 10% of patients with BE will have EAC at the time of initial
diagnosis
• Longterm follow-up of patients with low grade dysplasia in Barrett
esophagus (Sharma 2004)
• 10% progress to high grade dysplasia
• 3% progress to carcinoma

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Introduction
• Followup of patients with high grade dysplasia in Barrett esophagus (Konda
2008)
• 40% develop carcinoma
• 87% of these are intramucosal
• Only 13% are invasive into submucosa or beyond

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Epidemiology
 BE discovered during endoscopy performed for the evaluation of GERD
symptoms in middle-aged and older adults.
 average age at diagnosis: 55 year
 uncommon in black and Asian populations
 long-segment Barrett esophagus is found in 3% to 5%
 10% to 20% have short-segment Barrett esophagus.
 In the general adult population of Western countries, the prevalence of Barrett
esophagus (predominantly short segment) is between 1.6% and 6.8%

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Epidemiology
 annual incidence of cancer in patients with LSBE have been as high as 2.9%.
 BE develop LGD @ 4.3% per year
 BE develop HGD @ 0.9% per year.
 HGD develops cancers at the rate of approx. 6% per year.
 Cancer risk for patients with NDBE was approx. 0.5% per year , even lower
(0.12-0.33 %) in newer studies.

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Pathogenesis
 BE begins with esophageal injury by GERD,
 patients with LSBE often have severe GERD
 SSBE have no GERD symptoms and no endoscopic signs of esophagitis
 acid exposure can damage the esophagus directly and indirectly when nitrite (generated
from dietary nitrate) reacts with acid to produce nitric oxide.
 High concentrations of nitric oxide in the distal esophagus have been observed in
patients with GERD who have ingested nitrate.
 GERD-induced molecular reprogramming of key developmental transcription factors in
the progenitor cells- giving rise to the metaplasia
 GERD causes abnormal differentiation of immature progenitor cells

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Pathogenesis
 Genes up-regulated by reflux esophagitis involved in columnar cell
differentiation :
1. CDX genes
2. Hedgehog target genes
3. BMP4 (bone morphogenetic protein-4)
4. FOXA2
 Barrett epithelial cells appear to be more capable of resisting reflux-
induced esophageal injury than the native squamous epithelial cell
 Barrett cells secrete mucins and express tight-junction protein claudin
18, features that render the epithelium more resistant to acid- peptic attack.

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Molecular biology of neoplasia
 Hanahan and Weinberg proposed hypothesis: Barrett epithelial cells accumulate genetic and
epigenetic alterations that endow the cells with the core physiologic attributes of malignancy
 self-sufficiency in growth signals
 insensitivity to antigrowth signals
 evasion of apoptosis, limitless replicative potential
 sustained angiogenesis
 abilities to invade adjacent structures and to metastasize
 ability to reprogram energy metabolism to support continuous proliferation, and the
ability to evade destruction by immune cells

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Molecular biology of neoplasia in Barrett esophagus

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 expression of
 oncogenes (e.g., cyclin D1, K-ras)
 growth factors such as TGF- -
𝛂
 growth factor receptors such as EGF receptor
 inactivation of tumor suppressor genes (e.g., TP53, p16).
 angiogenic factors such as VEGF.
 genomic instability and a tumor-promoting microenvironment.
 Barrett metaplasia and associated EAC exhibit mutations in the p53 tumor suppressor gene

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 “Genome-doubled pathway” in which p53 mutation is followed by whole genome
doubling, leading to genomic instability, onco- gene amplification, and malignant
transformation
 overlap of SNPs at specific locations in the genome, suggesting a shared genetic
susceptibility for Barrett esophagus and its cancer.
 SNP in the FOXP1 gene risk of developing Barrett esophagus and esophageal
adenocarcinoma.

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Hypothetical representation of risk factors and
pathways of development of BE & EAC

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Dysplasia
 Genetic and epigenetic alterations
 Dysplasia is categorized as low grade or high grade
 Interobserver agreement for the diagnosis of low-grade dysplasia may be less than 50%.
 Interobserver agreement is better (approximately 85%) for high-grade dysplasia
 Visible mucosal irregularities
 Dysplasia can be patchy in its extent and severity.
 Dysplasia is most likely to be present in the proximal ½ of Barrett metaplasia segment .

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Diagnosis
 BE is diagnosed by endoscopic examination, and 2 criteria must be fulfilled.
 Endoscopist must ascertain that columnar epithelium lines ≥1 cm of the
distal esophagus.
 Biopsy specimens of that columnar epithelium must show evidence of
metaplasia.
 demonstration of intestinal metaplasia with goblet cells ( American societies)

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Diagnostic modalities
 High-definition white-light endoscopy.
 Endoscopic mucosal resection (EMR )
 Chromoendoscopy
 Autofluorescence endoscopy
 Magnification endoscopy
 Narrow band imaging
 Optical coherence tomography,
 Raman detection methods
 Confocal laser endomicroscopy
 Volumetric laser endomicroscopy
 Routine clinical practice: high- definition white-light endoscopy and random 4-

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Endoscopy diagnosis
 Diagnosis - Endoscopic demonstration of at least 1 cm of columnar-lined
epithelium present in the lower oesophagus
• Long segment - Barrett's mucosa extends more than 3cm.
• Short Segment CLO - Barrett's mucosa extends less than 3cm.
• UltraShort Segment CLO - Barrett's mucosa extends less than 1 cm with
microscopic demonstration of intestinal metaplasia.

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Endoscopy/Gross pathology
• BE: well-defined area of salmon-pink, velvety mucosa similar to the adjacent
gastric mucosa.
• It has irregular margins and may contain islands of residual squamous, pearly
white esophageal mucosa, or it may be ulcerated.
• It is usually limited to the lower third of the esophagus
• In severe cases, it may extend to the middle and upper esophagus

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Prague classification & endoscopic images

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Vienna classification based on HPE
 Category 1: No dysplasia
 Category 2: Indefinite for dysplasia
 Category 3: Low-grade intraepithelial neoplasia (low-grade adenoma/dysplasia)
 Category 4: High-grade intraepithelial neoplasia (high-grade adenoma/dysplasia,
noninvasive carcinoma or suspicion of invasive carcinoma)
 Category 5: Invasive epithelial neoplasia (intramucosal carcinoma, submucosal
carcinoma, or beyond)

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Natural history of histopathology-BE

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Why diagnosis of BE ??
 Part of the reason esophageal cancer has such a high mortality, is because 70% patients
don't present until the disease is stage III or higher (TMN classification system)
• BE is one of the most important risk factors for oesophageal cancer
• Therefore if BE is diagnosed and treated before it becomes dysplastic, could the
esophageal carcinoma associated mortality.

z Seattle biopsy protocol
 Random biopsy sampling system in which 4-quadrant biopsies are taken at 1- to
2-cm intervals throughout the length of Barrett metaplasia.
 Often misses areas of dysplasia and even cancer.
 Cancers were present and missed at the time of the index procedure.
 Disadvantages: Time consuming , risk of bleeding, poor adherence, cost

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WATS3D
Wide-Area Transepithelial Tissue Sampling with computer-assisted 3D analysis
 used as an adjunct to standard biopsy sampling, has been shown to reliably detect
dysplasia before they develop into cancer.
 screening and surveillance of patients with suspected or known BE , as an adjunct to
routine biopsies
 Standard of care when used adjunctively to the Seattle protocol.
 The Seattle random forceps biopsy protocol does not reliably detect BE or dysplasia,
which are precursors to EAC

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Barret’s esophagus: Epithelium Lining??
• Initial descriptions :
• "ectopic gastric mucosa".
• Accurate reading: "columnar cells, mucus secreting units, tubular glands, no
oxyntic cells" (Barrett 1957)
• Morson & Belcher 1952: Intestinal metaplasia
• Paull et al 1976: Classical description of 3 types of metaplastic epithelium
• Modern" period: Intestinal metaplasia (goblet cells) is mandatory for the
diagnosis.

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Endoscopic methods
 High definition while light
endoscopy
 Transnasal Endoscope
 Video capsule endoscopy
 Video capsule endomicroscopy
Non-endoscopic methods
 Cytosponge and Trefoil factor-3 (TFF3)
 EsophaCap
 EsoCheck balloon
 Electronic nose (exhaled volatile organic compunds)
 Methylated DNA markers
 MicroRNAs
Current and emerging screening techniques for Barrett’s esophagus

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Rationale for screening and surveillance
• EAC is an important health problem
• Screening with endoscopy or other techniques AND surveillance with
endoscopy once BE is diagnosed ,will detect of cancer at an early stage
• Minimally invasive endoscopic treatment options exists for early stage disease
• Early detection will ultimately lead to more favorable patient outcomes

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Screening for barrett's esophagus - limitations
• Enormous burden to medical resources - high prevalence of GERD
• BE in asymptomatic individuals (6-25%)
• 20-50% of EAC patients have no symptoms
• <10% of EAC - prior diagnosis of BE (suggesting that current clinical referral
practices fail to identify majority of high-risk patients)
 Farrow DC et al, Cancer Causes Control 2000; Lagergren Jet al, NEJM 1999
 Rex DK et al, Gastro 2003; Gerson LB et al, Gastro 2002
 Inadomi J et al, Ann Intern Med 2003

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Does surveillance impact mortality?
• Meta-analysis of 4 cohort studies reported lower EAC related and all-cause
mortality associated with regular surveillance (RR 0.6; 95% Cl 0.5-0.71 and HR
0.75,95% CI 0.59-0.94)
• Meta-analysis of 12 cohort studies reported lower EAC-related and all-cause
mortality among surveillance-detected EAC vs. symptom detected EAC (RR
0.73; 95% CI 0.57-0.94 and HR 0.59; 95% CI 0.45-0.76)
 Codipilly D et al, Gastroenterology 2018

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Management
 Treatment of GERD
 Aspirin and Other NSAIDs
 Endoscopic Surveillance for Dysplasia
 Treatment of Mucosal Neoplasia
 Endoscopic Therapies :
1. endoscopic ablative therapy
2. endoscopic mucosal resection
3. Complete eradication of intestinal metaplasia (CE-IM)
4. Endcoscopic eradication therapy(EET)

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Treatment of GERD
 Similar to GERD without BE
 PPI maintenance therapy for patients with BE , irrespective of symptoms and
endoscopic signs of GERD.
 PPI therapy significantly decreased risk of high-grade dysplasia and/or EAC(adjusted
OR 0.29; 95% CI)
 Fundoplication might be more effective than medical therapy with PPIs for preventing
cancer in BE

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Aspirin and Other NSAIDs
 Indirect evidence suggests that aspirin and other NSAIDs protect against EAC
 In vitro, NSAIDs ,decrease cellular proliferation, increase apoptosis, and decrease
angiogenesis .
 Reduce the accumulation of somatic exomic mutations in Barrett metaplasia.
 Do not recommend the routinely for chemoprevention in BE pts.
 Patients with BE with cardiovascular disease and/or risk factors for which aspirin
therapy is indicated

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Treatment of Mucosal Neoplasia
 HGD and IMC in BE traditionally were treated with esophagectomy.
 Presently, most pts with mucosal neoplasia are treated with EET.
 Esophagectomy remains a valid option in highly selected cases.
 Management of LGD : controversial due to unclear diagnosis and the natural history
 Most recent guidelines consider EET the treatment of choice for LGD.

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Endoscopic Therapies
Types of endoscopic therapies available
(1) Endoscopic ablative therapy: which uses following to to destroy the Barrett epithelium
 heat (delivered by laser, electrocoagulation, argon plasma coagulation or radiofrequency energy)
 cold (cryotherapy, delivered by spraying cold carbon dioxide or nitrous oxide gas)
 photochemical energy (photodynamic therapy [PDT])
(2) Endoscopic resection EMR and endoscopic submucosal dissection, in which a diathermic
snare or endoscopic knife is used to remove a large segment of Barrett mucosa with submucosa.

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Post Endoscopic Therapies
 After these endoscopic treatments, patients are treated with PPIs so that the ablated or resected
mucosa can heal with the regrowth of normal esophageal squamous epithelium rather than with
the regeneration of more Barrett mucosa.
 ablative therapies destroy metaplastic tissue but do not provide a pathology specimen by which
to judge the depth of neoplastic invasion and the completeness of the ablation.
 In contrast, EMR and endoscopic submucosal dissection provide large tissue specimens that
can be examined by the pathologist

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Adverse events of endoscopic therapy
• Meta-analysis - 37 studies
• Pooled rate (RFA +/- EMR): 8.8% (95% CI 6.5-11.9)
• Strictures: 5.6% (95% CI 4.2-7.4)
• Bleeding: 1% (95% CI 0.8-1.3%)
• Perforation: 0.6% (95% CI 0.4-0.9)
• Adverse events higher with EMR (RR 4.4)
• BE length and baseline histology predictors of adverse events.
Qumseya et al CGH 201

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Endoscopic eradication therapy (EET)
 Use of any one or combination of endoscopic modalities with the goal of completely
eradicating Barrett metaplasia.
 EET can eliminate neoplasms that are confined to the esophageal mucosa
 For patients with EAC that involve the submucosa, the frequency of lymph node
metastases exceeds 10% and, therefore, EET generally is not advised

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Status of EET for Dysplasia in Barrett Esophagus
 procedure of choice for BE: LGD, HGD,IMC.
 EMR for any visible mucosal irregularities ,which provides crucial staging information.
 “endoscopists who plan to practice endoscopic ablative procedures should additionally
offer EMR.
 EET for submucosal neoplasms in BE is highly controversial and should be considered
an option only in expert centers.
 After achieving CE-IM for patients with HGD or IMC in BE : endoscopic surveillance
every 3 months for the 1st
year, every 6 months in 2nd
year, and annually thereafter.

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EET for Nondysplastic Barrett Metaplasia
 Barrett metaplasia can be neoplastic even if it does not manifest features of dysplasia.
 EET has a considerable rate of complications, its efficacy in reducing the already low
rate of cancer development in nondysplastic Barrett esophagus has not established.
 Presently, EET is not recommended for the general population of patients with Barrett
esophagus in the absence of dysplasia

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Endoscopic Ablative Therapies
 An ideal ablative technique would inflict an injury deep enough to destroy all abnormal
epithelium but not so deep as to cause serious complications such as esophageal
hemorrhage, perforation, and stricture formation
 Photodynamic Therapy
 Radiofrequency ablation

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Photodynamic Therapy
 patients are given a systemic dose of a light-activated chemical that is taken up by the
esophageal cells.
 The esophagus is then irradiated using a low-power laser that activates the chemical, which
transfers that acquired energy to molecular oxygen.
 This transfer results in the formation of singlet oxygen, a toxic molecule that destroys the
abnormal cells and their vasculature.
 high rate of complications and the difficulty of the procedure, PDT has largely been abandoned
as a treatment for dysplasia in Barrett esophagus in favor of RFA.

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Radiofrequency ablation
 Uses a balloon-based array of closely spaced electrodes to deliver radiofrequency (microwave)
energy to ablate the esophageal mucosa.
 This system was designed with the intent of inflicting a uniform, circumferential thermal injury
whose depth is controlled by a generator, which can vary the power, density, and duration of the
energy applied.
 There are also smaller, radiofrequency catheter ablation devices that are used to ablate short
segments of Barrett metaplasia or residual foci of metaplasia that persist after treatment with the
balloon-based system.
 RFA is now widely regarded as the procedure of choice for ablating Barrett esophagus with
dysplasia, both high grade and low grade

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RFA vs PDT:
Ertan A, Zaheer I, Correa AM, Thosani N, Blackmon SH. Photodynamic therapy vs radiofrequency ablation for Barrett's
dysplasia: efficacy, safety and cost-comparison. World J Gastroenterol. 2013 Nov 7;19(41):7106-13. doi:
10.3748/wjg.v19.i41.7106. PMID: 24222954; PMCID: PMC3819546.

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Endoscopic cryotherapy
 cryogen such as compressed carbon dioxide or liquid nitrous oxide is applied
endoscopically to the Barrett esophagus,
 Causing rapid tissue freezing and thawing that disrupts cell membranes, induces
apoptosis, and causes thrombosis of local blood vessels.
 Unlike RFA, cryotherapy causes no permanent change in protein structure and, thus,
preserves extracellular collagen matrix architecture.
 Cryotherapy also might have advantages over RFA for the treatment of bulky lesions.
 Cryotherapy has efficacies similar to RFA for the eradication of Barrett metaplasia and
dysplasia

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Endoscopic Mucosal Resection
1. “suck and cut” method
 EMR can be performed using a “suck and cut” method in which the endoscopist elevates the
dysplastic area by injecting fluid into the submucosa, after which the elevated mucosa is
suctioned into a cap that fits over the tip of the endoscope.
 A polypectomy snare is then deployed around the suctioned area to remove it.

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2. “band and snare” method
 This method uses a ligating device, similar to that used for EVL , which deploys elastic bands
around the suctioned mucosal segment without the requirement for prior submucosal fluid
injection.
 The banded segment is removed using a polypectomy snare.
 Noncircumferential EMR: few serious complications and no procedure-related mortality.
 EMR as T-staging early neoplasms in Barrett esophagus
 If EMR specimen shows submucosal invasion, then further endoscopic therapy is not advised.

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When to perfom EMR
• Any focal abnormality (typically raised or flat. Can even be depressed)
If depressed, consider submucosal injection to see if lesion lifts
• Lesions < 20 mm that require en bloc resection
• Larger lesions, however, can be resected piecemeal
Early results from RCT show comparable results of piecemeal EMR with ESD with
fewer adverse events
Note: It is extremely difficult to resect the muscularis propria (MP)

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 This technique has been used with high success rates
 Specialist centre in Wiesbaden, Germany involving 144 patients undergoing endoscopic
resection for HGD shower a 99% remission rate in patients, with a 98% 5 year survival
rate. (Pech et al. 2007).
 Studies involving 'higher-risk' patients showed poorer results.
 Reoccurrence is quite frequent, estimated at around 11% (Peters et al, 2006).
 Is this only treating 'the tip of the iceberg? Leaving behind residual, potentially
cancerous tissue?
 Could this compromise the long-term prognosis, and chances of actually 'curing' the
cancer?

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Summary of outcome measures per treatment category

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Comparing the efficacy and complication rate of various endoscopic techniques

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Surgical treatment
 Total oesophagectomy and lymphadenectomy
 20% post-operative mortality
• 85% ,5 year mortality
• Expensive
• post-operative complications

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Staging and lymph node (LN) involvement in dysplastic
and neoplastic BE

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Management of nodular and nonnodular BE

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Summary of Management of BE
NDBE surveillance every 3 to 5 years
Indefinite for dysplasiaOptimized acid suppression therapy and repeat EGD in 3-6
months.
LGD Confirm diagnosis by expert gastrointestinal pathologist.
Repeat examination under optimal acid suppression within 3-6
months with HDWLE and preferably optical chromoendoscopy.
EMR or ESD of any visible lesions. Endoscopic ablation therapy
of residual flat BE segment with the goal of CE-D and CEIM on
subsequent

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HGD Confirm diagnosis by expert gastrointestinal pathologist.
Repeat examination within 6-8 weeks with HDWLE and preferably optical
chromoendoscopy. EMR or ESD of any visible lesions.
Endoscopic ablation therapy of residual flat BE segment with the goal of CE-D and
CEIM on subsequent sessions.
T1a esophageal
cancer (IMC)
EMR or ESD of the visible lesion to confirm staging. If T1a confirmed on pathology
with negative margins, ablation of residual flat BE segment with the goal of CE-D and
CEIM on subsequent sessions
T1b esophageal
cancer
EMR or ESD of the visible lesion can be considered. If T1b confirmed and favorable
pathologic features (negative margins, submucosal invasion <500 um [sm1], well or
moderately differentiated, absent lymphovascular invasion), can consider EET on case-
by-case basis after multidisciplinary tumor board discussion.
If T1bsm2-3 (deeper submucosal invasion) or poor pathologic features, referral to
surgical oncology for esophagectomy.

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Refractory Barrett’s Esophagus
 complete eradication of Barrett’s esophagus cannot be achieved.
 In a multi-center prospective trial in 2013 identified several risk factors associated with
incomplete eradication including scar regeneration with Barrett’s epithelium resection,
active reflux esophagitis, narrow esophageal diameters, and longer years of dysplasia
presence
 further titration of their PPI regimen is imperative
 Antireflux surgery such as Nissen fundoplication.
 Transoral incisionless fundoplication (TIF)
 Endoscopic Resection System which is an automated mechanical non-thermal
endoscopic resection system that can be applied in refractory cases to dissect tissue
from peripheral margins

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AGA/ACG/ASGE Recommendations -summary
 Patients with BE should be treated with PPIs
 patients without GERD treated with OD PPI therapy for chemoprevention
 Antireflux surgery can be considered as an alternative to chronic PPI therapy
 patients with nondysplastic Barrett esophagus : surveillance every 3 to 5 years.
 Endoscopic biopsy :4-quadrant biopsy specimens every 2 cm throughout the
length of the Barrett metaplasia./ every 1 cm throughout the length of the Barrett
metaplasia in known dysplasia.
 If biopsies report showed “indefinite for dysplasia,” PPI therapy should be
optimized and endoscopy repeated in approximately 8 weeks, with biopsy
specimens taken at 1-cm intervals.

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AGA/ACG/ASGE Recommendations -summary
 When dysplasia of any grade is first noted histology slides should be interpreted by an expert
pathologist (preferably more than 1 expert).
 EET is recommended for patients with verified mucosal neoplasia (LGD,HGD,IMC) after
extensive biopsy sampling and EMR of mucosal irregularities.
 After achieving CE-IM for patients with HGD or IMC in BE, endoscopic surveillance is
performed every 3 months for 1st year, every 6 months in the 2nd
year, and annually thereafter.
 After achieving CE-IM for patients with LGD, endoscopic surveillance is performed every 6
months for the first year, and annually thereafter.

References
 Sleisenger and fordtran’s gastrointestinal and liver disease, 11th Edition
 Up to date
 AGA/ACG/ASGE guidelines .

Barrets esophagus,risk factors,screening,AGA guidelines

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