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>30 have a small increased risk of developing BE based on a
meta-analysis in 2009 [36]. When looking specically at abdominal obesity, which is measured by waist-to-hip ratio, males with
ratios ≥0.9 and females with ratios ≥0.85 have increased risk of
BE [37–40]. Smoking also increases the risk of BE.In matched
patients with GERD, smokers are 1.6 times more likely to develop
BE than nonsmokers [41]. Lastly, family history appears to play a
part in the development of BE. Twenty-eight percent of rstdegree relatives of patients with esophageal adenocarcinoma have
been found to have BE [42–44]. Currently, it is unclear if this
association is due to common environmental exposures or an
inherited mutation. There are several germline mutations (MSR1,
ASCC1, CTHRC1 genes) that confer a risk of BE and esophageal
adenocarcinoma [45]. Also, when looking at the genomes, genetic
variants have been identied at chromosomes 6p21 and 16q24
with association to BE [46]. H. pylori infection appears to be protective in the esophagus and protects against the development of
BE.This is especially true in H. pylori strains that express the
cytotoxin-associated gene A (cagA) [47, 48]. It should also be
noted that certain medications have been shown to reduce the risk
of progression of BE which include proton-pump inhibitors, aspirin, nonsteroidal-anti-inammatory agents, and statins [49–51].
J. Eagleston et al.
Pathogenesis
Barrett’s esophagus is secondary to chronic insult to the distal
esophagus secondary to gastroesophageal reux of acid and other
noxious agents including nitrous compounds as well as bile [52].
Multiple physiologic abnormalities have been proposed which
contribute to chronic gastroesophageal reux in patients with
Barrett’s esophagus. This includes gastric acid hypersecretion,
markedly low lower esophageal sphincter pressures, ineffective
esophageal motility, duodenogastric reux, decreased salivary
secretion of epidermal growth factor, and decreased esophageal
pain sensitivity [22]. Individual patients may have any, all, or
none of these factors. Patients with normal gastric acid secretions
have been found to have long segment Barrett’s esophagus. Many
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Fig. 29.2 Intestinal metaplasia as seen in Barrett’s esophagus (squamous
epithelium is replaced with columnar cells which can be seen at the periphery
of the pathologic specimen)
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patients without GERD symptoms have been shown to have
Barrett’s esophagus. Barrett’s develops through the process of
intestinal metaplasia; this occurs when gastric secretions damage
the distal esophageal squamous epithelium resulting in replacement with metaplastic columnar cells which appear to be more
resistant to reux-induced injury (Fig. 29.2). Unfortunately,
esophageal columnar metaplasia predisposes to the development
of adenocarcinoma [53].
Dysplasia
Dysplasia is the morphologic change in Barrett’s cells before they
become malignant. It is a constellation of histologic abnormalities
indicating genetic and epigenetic damage that renders Barrett’s
cells neoplastic and predisposed to malignancy [54]. Multiple
cytological and architectural abnormalities are characteristic of
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dysplasia. These include nuclear changes, loss of cytoplastic maturation, and crowding of tubules and villiform surfaces [55].
Based on the severity of these changes, dysplasia is categorized as
low grade or high grade. The diagnosis of dysplasia in Barrett’s
can be challenging. Interobserver agreement is better in highgrade dysplasia as compared to low grade, but any diagnosis of
dysplasia should be conrmed by a second pathologist who has
expertise in esophageal pathology [56]. Overall incidence of
development of cancer in patients with low-grade dysplasia is
approximately 0.5% per year [57]. In high-grade dysplasia, the
rate is anywhere from 4–8% per year.
J. Eagleston et al.
Diagnosis
The diagnosis of BE is conrmed with the presence of columnar
lined intestinal metaplasia within the distal esophagus. This diagnosis is achieved by obtaining biopsies of the salmon-colored
mucosa that extends at least 1cm proximal to the gastroesophageal junction during endoscopy. In patients with suspected BE,
the endoscopist should obtain biopsies from four circumferential
quadrants starting at the 1cm mark proximal to the GEJ. This
technique should be continued through the extent of the visual
changes on the esophagus with an additional biopsy on what
appears to be normal esophageal squamous mucosa [58].
Additionally, the endoscopist should report the location of the
diaphragmatic hiatus, GEJ, and squamocolumnar junction
(Z-line). Barrett’s esophagus that is ≥3cm is termed long segment Barrett’s, whereas a segment that is ≤3cm is termed short
segment Barrett’s esophagus [59]. Lastly, the endoscopist should
report the extent of the metaplastic changes within the esophagus
using the Prague classication [60]. The Prague classication was
rst presented in 2006 and is the standard for measuring the length
of BE [60]. First the true position of the GEJ is identied. Next,
the circumferential Barrett’s segment (C) is measured proximally
from the GEJ.Lastly, the longest tongue of metaplastic change
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(M) plus the circumferential segment is measured from the GEJ.If
the circumferential segment is 2cm and the tongue is an additional 2cm, it would be reported as C2M4 via the Prague classication. Assessment of the extent of Barrett’s esophagus on
endoscopy is clinically important as multiple studies have shown
that more extensive disease is associated with a higher risk of dysplasia and progression to esophageal adenocarcinoma.
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Surveillance
Despite the risk of progression to esophageal adenocarcinoma,
the American College of Gastroenterology does not recommend
screening the general population for BE [61]. Screening should be
done in patients with risk factors for esophageal adenocarcinoma
including hiatal hernia, age≥50, male sex, chronic GERD, caucasian race, central obesity, tobacco use, and conrmed history of
Barrett’s esophagus or esophageal adenocarcinoma in a rst
degree relative [62, 63]. After initial diagnosis is made, management and surveillance is performed based on presence or absence
of degree of dysplasia. If no dysplasia is recognized, surveillance
is recommended every 3–5 years. The American College of
Gastroenterology recommends that if biopsies are initially indenite for dysplasia, patients should be placed on medical anti-reex
therapy and endoscopy repeated after waiting at least 3months
[64]. Repeat endoscopy should not be delayed beyond 6months.
Patients with low-grade dysplasia may undergo surveillance every
12 months unless endoscopic therapy has been performed in
which case endoscopy should be performed every 6months for
1 year. Patients with high-grade dysplasia require surveillance
every 3months in the rst year following endoscopic therapy, followed by every 6months in the second year and annually thereafter. Endoscopic surveillance is done using the Seattle biopsy
sampling protocol with four quadrant biopsies every 2 cm in
patients without dysplasia and 1 cm intervals in patients with
known or suspected dysplasia.
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J. Eagleston et al.
Medical Treatment
General management involves control of acid reux with proton
pump inhibitors, even in asymptomatic patients. Multiple studies
suggest aggressive anti-reux therapy may prevent cancer and
hence, PPI therapy is usually indenite [50, 65–67]. In a metaanalysis of nine studies including over 5700 patients with BE, the
use of PPI’s was associated with a trend toward lower risk of
esophageal adenocarcinoma [68]. The recommended dose of PPI
is pantoprazole 40mg twice daily or lansoprazole 30mg twice
daily. Gashi, in 2018, published a prospective study, monitoring
50 patients with BE over 2years. He found that the length of BE
was inuenced by PPI therapy and noted that the extent/lengths of
short segment and long segment Barrett’s esophagus were signicantly improved following treatment with twice daily PPI [69].
There is some evidence that nonsteroidal anti-inammatory medications, including aspirin, can decrease the risk of esophageal
adenocarcinoma in patients with Barrett’s esophagus [70].
However, there is potential of side effects and a low absolute risk
of cancer precludes their regular use.
Endoscopic Management
Radiofrequency Ablation
Most cases of BE do not progress to dysplastic changes; however,
when high-grade dysplasia is present, there is a signicant risk of
progression to esophageal adenocarcinoma. There is controversy
in the use of RFA versus surveillance alone in the setting of lowgrade dysplasia. However, some studies have shown a benet to
RFA in low-grade dysplasia and have noted successful eradication
and lower progression rates when compared to surveillance [71,
72]. Radiofrequency ablation has become the standard of care for
high-grade dysplasia [73–79]. Ablation has a high rate of eradication of dysplasia. Endoscopic mucosal resection plays a role in
the ability for RFA to be successful. If there are any visible raised
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lesions, they must be addressed with EMR prior to ablation as
ablation is only successful if the ablation can reach the muscularis
mucosae. Postoperatively, it is important to place the patient on
acid suppressive medications (PPI) and sucralfate suspension can
also be added. Typically, patients are on a full liquid diet for 24h
followed by a regular diet as tolerated. RFA is well tolerated and
a common side effect is postoperative chest pain. A feared complication is a post RFA stricture, which have been reported from
0–8% postoperatively [73, 77–80]. Strictures post-RFA are managed with dilation. Additional complications include bleeding and
perforation, but these complications are rare.
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Endoscopic Mucosal Resection
RFA is extremely effective and safe for treating at lesions in the
esophagus. However, one of the limitations of RFA is the inability
to retain histology and provide staging information for neoplastic
tissue. RFA is also not effective for deeper mucosa or submucosal
lesions and can lead to inadequate treatment. Lesions that involve
the submucosa have a 20–25% risk of harboring lymph node
metastasis in patients with high-grade dysplasia [81, 82]. It is
important to remember that if patients undergo RFA for deeper
lesions and the lesion is treated inadequately, there is risk for
squamous overgrowth of the submucosal cancer [83]. Deeper
lesions are better treated with endoscopic mucosal resection
(EMR). EMR is also able to provide adequate T staging and has
been highly effective in eradicating early mucosal adenocarcinoma in the esophagus [84]. The combination of RFA and EMR
is extremely effective in the management of dysplastic Barrett’s
esophagus and has eradication rates of >90% [85]. The technique
of EMR involves identifying the lesion in question which can be
added with optical enhancement in the form of chemical chromoendoscopy (methylene blue) or optical chromoendoscopy (NBI).
The NBI was recently validated and can assess dysplastic areas
with 85% accuracy [86]. The technique of EMR involves the process of capturing mucosal tissue into a pseudopolyp conguration
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J. Eagleston et al.
and then snaring the pseudopolyp. The goal of the procedure is to
remove the mucosa and a portion of the submucosa while leaving
the muscularis propria intact. One technique is the cap-assisted
EMR, which ts over the endoscope and accommodates a snare.
First the mucosal lesion is identied, and a submucosal injection
is performed to lift the lesion. The cap is then centered over the
lesion and an assistant closes the snare around the lesion
(Figs.29.3 and 29.4). Electrocautery is used to resect the pseudopolyp. An alternative option is the band-assisted EMR.The technique is similar to the cap EMR; however, a submucosal injection
is not required. The lesion is centered within the cap, then completely suctioned into the cap. Next, a band is positioned around
the lesion. Lastly, the snare, with electrocautery, is used to resect
the pseudopolyp that was created with the band. The snare can be
used above or below the band. Postoperatively, patients may complain of chest pain which is usually a result of a self-limiting iat-
Fig. 29.3 Pseudopolyp (mucosa and submucosa only) is ensnared during
endoscopic mucosal resection
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Fig. 29.4 The result of endoscopic mucosal resection
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rogenic ulcer. Patients typically are on a liquid diet for 24 h
followed by a soft diet for up to 1week. After EMR, patients
require follow-up endoscopy in 2months to evaluate if additional
EMR or RFA needs to be performed. The most common complication with EMR is bleeding or perforation. These risks are 1.1%
and 0.2%, respectively [85]. Immediate bleeding is treated by
using the cap and hemostatic forceps to coagulate the vessel.
Perforation is a much more severe complication and can lead to
mediastinitis and rapid decompensation. Perforations can be managed with hemostatic clips, over the scope clips, or endoscopic
suturing devices. If the perforation is large, an esophageal stent is
also an option. The most common late complication is stricture
which is reported in up to 10% of patients. Strictures typically
occur in patients with EMR sites that take up >50% of the esophageal circumference. Most strictures are amenable to dilation
techniques.
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J. Eagleston et al.
Phototherapy
Less commonly utilized than the previously described modalities, photodynamic therapy (PDT) uses laser light and a photosensitizing agent (sodium pormer) to selectively destroy tissue.
The photosensitizing agent is given 48–72h prior to endoscopy
and hypermetabolic cells will preferentially take up the agent.
During endoscopy, a laser light is used to activate the photosensitizing agent. The agent then reacts with oxygen to create free
radicals that induce cell membrane death and apoptosis [87]. A
cohort study of 100 patients with Barrett’s esophagus and dysplasia was treated with phototherapy and followed for 51months
[88]. The mean reduction in length of Barrett’s mucosa was 7cm.
Fifty-four percent of patients had complete resolution of
BE.Ninety-three percent of patients with low-grade dysplasia,
78% of patients with high-grade dysplasia, and 48% of patients
with early cancer all had complete remission. Any small areas
that remained were treated with Nd:YAG laser thermal ablation
and the study concluded that PDT followed by Nd:YAG was
effective in patients with Barrett’s esophagus with dysplasia [88].
An additional study compared PDT with omeprazole vs omeprazole therapy alone and found a signicantly higher incidence of
complete ablation of dysplasia in the PDT plus omeprazole group
(77% vs. 39%) [89]. These patients were followed for 5years and
the response was similar, with an increased rate of complete ablation in the PDT group [87, 90–92]. Complications associated
with PDT include photosensitivity in 69% of patients, esophageal strictures in 36% of patients, and vomiting in 32% of patients
[89]. Other common complications reported were odynophagia
and fever. Additionally, there is a concern for “buried” Barrett’s
esophagus which is described as residual BE hidden under the
neosquamous esophagus that forms following PDT.This occurs
if the PDT does not destroy all of the metaplastic epithelium. A
retrospective review of 953 patients found the rate of “buried
metaplasia” to be 14% [93].
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Cryotherapy
Freeze-thaw cycles are used to create mucosal cellular destruction
in cryotherapy. Either nitrogen or carbon dioxide is sprayed to the
dysplastic area and the treatment is applied for a total of 40s (two
20s applications or four 10s applications). This produces a 2mm
depth of injury [94]. The freeze-thaw cycles disrupt the cell membranes and cause tissue ischemia through vascular stasis, endothelial damage, and vascular thrombosis [95]. A multicenter
retrospective study by Shaheen etal. included 98 patients undergoing cryotherapy [96]. Fifty-eight patients completed therapy
and were followed for 10.5 months. Eighty-seven percent of
patients had complete eradication of all dysplasia with persistent
BE.Fifty-seven percent had complete eradication of all BE.Three
patients developed strictures (5%). Two patients developed chest
pain requiring narcotics (3%). Buried esophagus was found in
two patients (3%). Another retrospective study by Gosain followed patients undergoing cryotherapy every 8weeks until eradication of high-grade dysplasia and Barrett’s esophagus was
conrmed on EGD [97]. The median follow-up was 37months.
At 2years, all 32 patients had complete resolution of their highgrade dysplasia and 84% of patients had complete resolution of
their Barrett’s esophagus. However, during the nal follow-up, it
was found that 18% of patients had developed recurrent highgrade dysplasia. One patient progressed to esophageal adenocarcinoma. Strictures were seen in 9% of patients and all were
successfully dilated. As a result of the above, cryotherapy has not
been adopted as a mainstay of treatment of Barrett’s esophagus.
Surgical Management
The goal of medical or surgical treatment of Barrett’s esophagus
is to provide relief from GERD symptoms, control esophagitis,
and prevent neoplastic progression of Barrett’s mucosa. As men-
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