April 2013, Vol. 20, No. 2Cancer Control 117
From the Section of Endoscopic Oncology of the Gastrointestinal Tu-
mor Program at the H. Lee Moffi tt Cancer Center & Research Institute,
Submitted April 16, 2012; accepted November 22, 2012.
Address correspondence to Shivakumar Vignesh, MD, Section of
Endoscopic Oncology, Gastrointestinal Tumor Program, Moffi tt
Cancer Center, 12902 Magnolia Drive, FOB-2 GI PROG, Tampa,
FL 33612. E-mail: Shivakumar.Vignesh@Moffi tt.org
No signifi cant relationship exists between the authors and the
companies/organizations whose products or services may be ref-
erenced in this article.
Expanded endoscopic techniques improve
esophageal lesion characterization and
treatment options for early-stage neoplasia.
Samuel Bak. BK1489 Supervision. Oil on canvas, 18ʺ × 24ʺ.
Endoscopic Therapy of Neoplasia Related to Barrett’s
Esophagus and Endoscopic Palliation of Esophageal Cancer
Shivakumar Vignesh, MD, Sarah E. Hoffe, MD, Kenneth L. Meredith, MD, FACS,
Ravi Shridhar, MD, PhD, Khaldoun Almhanna, MD, MPH, and Akshay K. Gupta, MBBS
Background: Barrett’s esophagus (BE) is the most important identifi able risk factor for the progression to
Methods: This article reviews the current endoscopic therapies for BE with high-grade dysplasia and intramucosal
cancer and briefl y discusses the endoscopic palliation of advanced esophageal cancer.
Results: The diagnosis of low-grade or high-grade dysplasia (HGD) is based on several cytologic criteria that
suggest neoplastic transformation of the columnar epithelium. HGD and carcinoma in situ are regarded as
equivalent. The presence of dysplasia, particularly HGD, is also a risk factor for synchronous and metachronous
adenocarcinoma. Dysplasia is a marker of adenocarcinoma and also has been shown to be the preinvasive
lesion. Esophagectomy has been the conventional treatment for T1 esophageal cancer and, although debated, is an
appropriate option in some patients with HGD due to the presence of occult cancer in over one-third of patients.
Conclusions: Endoscopic ablative modalities (eg, photodynamic therapy and cryoablation) and endoscopic
resection techniques (eg, endoscopic mucosal resection) have demonstrated promising results. The signifi cant
morbidity and mortality of esophagectomy makes endoscopic treatment an attractive potential option.
Barrett’s esophagus (BE) is the replacement of the
stratifi ed squamous esophageal epithelium with vari-
ous types of columnar epithelia and is thought to re-
sult from chronic gastroesophageal refl ux.1 BE is the
most important identifi able risk factor for progression
to esophageal adenocarcinoma, one of the cancers
with the fastest rising incidence and a 5-year survival
rate of approximately 10% to 15%.2-6 In BE, the squa-
mocolumnar junction is proximal to the esophago-
gastric junction (proximal end of gastric folds). The
American College of Gastroenterology has defi ned
BE as a “change in the esophageal epithelium of any
length that can be recognized at endoscopy and is
confi rmed to have intestinal metaplasia by biopsy.”7
Prospective studies have documented the progression
from BE to low- and high-grade dysplasia and even-
tually to invasive adenocarcinoma.8,9 There is poor
interobserver agreement among experienced patholo-
gists for the diagnosis of low-grade dysplasia (< 50%
118 Cancer Control April 2013, Vol. 20, No. 2
interobserver agreement) and high-grade dysplasia
(85% interobserver agreement). Interobserver repro-
ducibility was substantial at the ends of the spectrum
(BE and high-grade dysplasia/esophageal adenocarci-
noma). Both intraobserver and interobserver variation
improved overall after the application of a modifi ed
grading system that was developed at a consensus
This review focuses on the endoscopic therapies
for BE with high-grade dysplasia and intramucosal
cancer and briefl y discusses the endoscopic palliation
of advanced esophageal cancer.
Endoscopic Characteristics of BE
BE is arbitrarily divided into short- and long-segment
BE on the basis of the length of the esophageal intes-
tinal metaplasia: < 3 cm and ≥ 3 cm, respectively.12,13
Long-segment BE has been shown to be a risk fac-
tor for cancer and for recurrence of neoplasia with
endoscopic therapy.14 The Prague circumferential
and maximal length (C & M) criteria were developed
to standardize the endoscopic grading of BE as op-
posed to the use of subjective terms such as long,
short, or ultrashort.12 The Prague C & M criteria uses
the C value as the circumferential extent and the
M value as maximal extent of BE above the gastro-
esophageal junction in centimeters. Validated by 29
expert endoscopists from 14 countries,15 the Prague
criteria have helped to quantify BE in a uniform man-
ner and provide an objective measure to evaluate
endoscopic therapies for BE. Endoscopically visible
lesions (Fig 1) associated with high-grade dysplasia
have a higher risk for harboring cancer than fl at
areas of dysplasia have.16-18 Protruded, raised, or
depressed lesions are at higher risk for submucosal
invasion than fl at areas. Endoscopic resection (ER)
provides an opportunity to accurately stage the depth
of visible lesions in BE.14,19
Esophageal neoplasia is classifi ed according to the
internationally accepted Vienna classifi cation19: cat-
egory 1: no dysplasia; category 2: indefi nite for dys-
plasia; category 3: low-grade intraepithelial neoplasia/
dysplasia; category 4: high-grade intraepithelial neo-
plasia/dysplasia; category 5: invasive epithelial neo-
plasia; category 5.1: invasion into the lamina propria
(also referred to as intramucosal cancer); and category
5.2: submucosal cancer. Dysplasia is defi ned as neo-
plastic epithelium that remains confi ned within the
basement membrane of the epithelial surface within
which it arose. The diagnosis of low- or high-grade
dysplasia is based on several cytologic criteria that
suggest neoplastic transformation of the columnar
epithelium.11,20 High-grade dysplasia and carcinoma
in situ are regarded as equivalent. The presence of
dysplasia, particularly high-grade (Fig 2), is also a risk
factor for synchronous and metachronous adenocar-
cinoma. Dysplasia not only is a marker of adeno-
carcinoma, but also has been shown in prospective
studies to be the preinvasive lesion.8,21,22
Duplication of the muscularis mucosa is a char-
acteristic fi nding in BE, but it can pose diffi culty in
proper staging of superfi cial esophageal adenocar-
cinomas. Pathologists need to be aware of this dis-
tinctive anatomy of BE to accurately stage adenocar-
cinomas, particularly to avoid mistaking a thickened
muscularis mucosa for muscularis propria.
The terminology and classifi cation of early esoph-
ageal cancers have evolved and are outlined in the
2010 TNM staging system of the American Joint Com-
mittee on Cancer (AJCC).23 In the intramucosal cancer
category, neoplastic cells have penetrated through the
basement membrane and are further subdivided based
on their depth of invasion. A tumor limited to the
epithelial layer is defi ned as m1, which corresponds
to the Tis stage in the AJCC system. Lesions identi-
Fig 1. — Endoscopically visible nodular lesion within BE segment suspi-
cious for high-grade dysplasia or adenocarcinoma.
Fig 2. — High-grade dysplasia in BE (hematoxylin-eosin, original magni-
April 2013, Vol. 20, No. 2Cancer Control 119
fi ed as m2 and m3 are more invasive and comprise
the T1a category (Fig 3). An m2 lesion invades the
lamina propria, while an m3 lesion invades into but
not through the muscularis mucosa. The submucosal
carcinoma tumor, staged T1b by the AJCC, invades
beyond the muscularis mucosa into the submucosa
but not into the muscularis propria.
Subdivisions have also been categorized within
the submucosal carcinoma category. Lesions that have
penetrated the shallowest third of the submucosa are
identifi ed as sm1, those that have penetrated the in-
termediate third are sm2, and those in the deepest
third are sm3. These subdivisions are important since
deeper lesions are associated with higher rates of
lymph node involvement. Ancona et al24 reported
that the rates of lymph node metastasis were 0% for
T1m1 (mucosal) lesions and 28% in T1sm1 lesions.
Compared with T1sm2/3 lesions, T1sm1 carcinomas
have a lower rate of lymph node metastasis.24,25 In
addition to the depth of invasion, factors that predict
lymph node involvement in early esophageal cancer
are angiolymphatic and neural invasion as well as
Role of Endoscopic Ultrasound in
Staging Early Esophageal Neoplasia
Endoscopic ultrasound is an accurate technique for
locoregional staging of esophageal cancer (Fig 4). It
is less accurate for detecting submucosal invasion
(T1a vs T1b) in patients with high-grade dysplasia and
intramucosal cancer and does not have a signifi cant
affect on the management of intramucosal cancer. In
addition, accuracy is infl uenced by the experience
of the endosonographer.26,27 However, endoscopic
ultrasound with fi ne needle aspiration can diagnose
malignant adenopathy in the setting of high-grade
dysplasia or intramucosal cancer and help identify
patients who are not eligible for endoscopic therapy.15
When lymph node involvement is present, the patient
should be referred for esophagectomy. The utility of
endoscopic ultrasound in fl at high-grade dysplasia is
questionable28 but is usually helpful in patients with
endoscopically visible lesions. To improve accuracy,
some studies have evaluated high-frequency endo-
scopic ultrasound with miniprobes. However, results
have shown that while this may improve the accuracy
of T staging, the accuracy of N staging may be inferior
because the visualization is more superfi cial. Finally,
differentiating mucosal lesions (T1a) from lesions in-
vading into the submucosa (T1b) is more diffi cult in
BE than in the squamous esophagus due to factors
such as associated infl ammation in BE, duplication of
the muscularis mucosa, and hiatal hernia.7,29
Treatment Options for High-Grade Dysplasia
and T1 Esophageal Cancer
Esophagectomy is the conventional treatment for T1
esophageal cancer and, although debated, is an ap-
propriate option in some patients with high-grade
dysplasia due to the presence of occult cancer in
over a third of patients.30 Alternative modalities have
been increasingly studied, and promising results for
patients with T1 cancers have been reported with
endoscopic ablative modalities in particular, including
photodynamic therapy (PDT) and endoscopic mucosal
resection (EMR).14,19 Endoscopic treatment is a par-
ticularly appealing modality, given the signifi cant mor-
bidity and mortality associated with esophagectomy.
Esophagectomy is generally preferred for lesions
that invade the submucosa (T1b), given the higher
rates of lymph node metastasis associated with these
lesions. The rationale for esophagectomy in high-
grade dysplasia is both prevention and cure of occult
cancer. Patients with high-grade dysplasia are at a
higher risk for progressing to esophageal adenocar-
cinoma than are patients with nondysplastic BE or
low-grade dysplasia. Based on retrospective studies,
the rate of cancer in patients who were undergoing
esophagectomy for prophylactic treatment of high-
grade dysplasia varies from 0% to 73%; among 23
studies, the pooled average was 39.9% in the 441 pa-
tients who underwent esophagectomy for high-grade
Fig 3. — Focal lesion within BE segment pathologically staged as T1m3
adenocarcinoma (hematoxylin-eosin, original magnification ×10).
Fig 4. — Endoscopic ultrasound of T1 cancer.
120 Cancer ControlApril 2013, Vol. 20, No. 2
dysplasia.16,31-33 Prospective studies with rigorous en-
doscopic criteria for ER have reported lower rates of
occult submucosal invasive disease. Among patients
with high-grade dysplasia and intramucosal cancer
undergoing complete endoscopic mucosal resection
in the setting of BE, the rate of occult submucosal
invasive cancer was 4%.34 Therefore, the incidence
of invasive cancer in this population is likely much
lower that the 40% rate previously reported.30,34 As
the morbidity of esophagectomy is high,35,36 even in
high-volume centers, it is now reserved for T1b le-
sions (submucosal invasion), node-positive cancers,
and T1a cancers where endoscopic therapy has failed.
Endoscopic Therapies for BE
Endoscopic therapies include tissue-acquiring modali-
ties such as focal ER (Fig 5), complete Barrett’s eradica-
tion endoscopic mucosal resection (CBE-EMR; Fig 6),
and endoscopic submucosal dissection. Tissue-acquir-
ing modalities are important to pathologically stage
a visible lesion in the setting of high-grade dysplasia
and for the treatment of known intramucosal cancer.
While ablative therapies such as photodynamic therapy
(PDT), radiofrequency ablation (RFA), and cryotherapy
accomplish tissue destruction and permit treatment
of larger areas, they do not provide a specimen for
histopathological evaluation. To date, the longest ex-
perience of ablative therapies has been with PDT.37
Endoscopic ultrasound does not accurately dif-
ferentiate between a T1a tumor (intramucosal cancer)
and a T1b tumor (submucosal invasion). Obtaining
a pathology specimen with diagnostic ER (Fig 7) ac-
curately differentiates between these lesions.38-41 ER
is an endoscopic approach in which the neoplastic
epithelium is excised, providing an accurate histologic
diagnosis and T stage with the potential of being cu-
rative for mucosal lesions.42,43 ER has been applied
not only to BE with high-grade dysplasia but also
to intramucosal cancer (Fig 8) in which the risk of
lymph node involvement or hematogenous dissemina-
tion is low enough to justify a relatively conservative
approach compared with esophagectomy.17,43,44 It is
important to differentiate between the presence of
intramucosal cancer (confi ned to the mucosa), which
has a low nodal metastasis risk, from cancer with in-
vasion into the submucosa, which is associated with
Fig 6. — Complete Barrett’s eradication endoscopic mucosal resection
Fig 5. — Focal endoscopic resection on nodule within BE.
Fig 8. — Endoscopic resection for intramucosal cancer.
Fig 7. — Endoscopic resection pathology specimen with high-grade dys-
plasia in BE (hematoxylin-eosin, original magnification ×10).
April 2013, Vol. 20, No. 2Cancer Control 121
a higher nodal metastasis risk and generally requires
multimodality therapy.45,46 Interobserver agreement
for a diagnosis of dysplasia was signifi cantly improved
with analysis of ER specimens than with conventional
biopsies. In addition, submucosa was present in up
to 88% of ER specimens but in only 1% of biopsy
samples, and the presence of muscularis mucosae
was observed in only 58% of biopsy specimens.47
The histologic examination of ER specimens can also
assess the degree of angiolymphatic invasion, an im-
portant risk factor for the presence of lymph node
metastasis.48-50 Other studies have shown that fi nal
staging by ER modifi es the previous diagnosis (Figs
9 and 10) in up to 48% of cases38,50 and dramatically
changes the clinical management of these patients.
The demonstration of tumor-negative margins in ER
samples directly correlates with the absence of re-
sidual tumor at esophagectomy.39
In a review of 742 ER specimens, carcinomas in-
fi ltrating the submucosal layer were rare (sm1: 7.5%;
sm2: 3.7%; sm3: 4.8%), as were those invading lymph
vessels (3.5%), and there were none with venous inva-
sion.40 In that study, 75% of patients had an R0 resec-
tion. Several studies have demonstrated the effi cacy
and safety of ER.14,40,41 Complete ER was achieved in
91% of the focal lesions, in 86% of cases treated under
the (stepwise) radical ER protocol, and in 100% for
escape treatment after RFA.51 In BE neoplasia, ER
is considered appropriate for lesions limited to the
superfi cial mucosa (M1 and M2 tumors having low
rates of lymph node metastasis, < 3%). While there
Pathology specimen from endoscopic mucosal resection showing intramucosal cancer invading into the muscular mucosa (hematoxylin-eosin, original
Fig 9. — Pathology specimen from endoscopic mucosal resection of a
nodule showing high-grade dysplasia in a patient with a history of low-
grade dysplasia (hematoxylin-eosin, original magnification ×1.25).
122 Cancer ControlApril 2013, Vol. 20, No. 2
is less consensus with regard to lesions that extend
to the muscularis mucosa (T1m3 tumors, Fig 3), most
centers consider this an accepted indication for endo-
scopic treatment. Some groups have suggested that
ER may be appropriate for lesions that penetrate into
the superfi cial submucosal layer (sm1 tumors with
submucosal penetration < 500 microns). ER may be
an adequate treatment option in selected T1sm1 le-
sions with good histologic grade and the absence of
angiolymphatic invasion and also in patients who are
high-risk surgical candidates.24,25,52 Larger prospective
studies are required before recommending ER for all
Two ER techniques have been well studied and
are in common use. They involve using either a plas-
tic cap mounted on the endoscope tip or a modifi ed
band ligation device to facilitate targeted piecemeal
With this technique, the target area is marked with the
tip of a snare and coagulation current. Submucosal
injection of a fl uid, which may be saline or diluted
epinephrine (1:100,000), creates a submucosal cush-
ion to minimize the risk of perforation. A transparent
cap with a distal ridge that allows positioning of a
crescent-shaped ER snare is attached to the tip of the
endoscope. The lesion is sucked into the cap, thus
creating a pseudopolyp and captured by forcefully
closing the snare. The lesion is then removed using
electrocoagulation. Using a large-caliber fl exible cap
(with an outer diameter of 18 mm), lesions with a
diameter of more than 2 cm can be removed en bloc.
Multiband mucosectomy (MBM) is a technically easy
and relatively safe ER technique (Fig 11). This “suck-
band-ligate” technique uses a modifi ed variceal band
ligator and involves placing bands over the mucosa
to create pseudopolyps (Fig 12); these can be re-
sected with a snare that can be passed alongside the
banding device. Up to six consecutive resections
can be performed without prior submucosal lifting.
The muscle layer does not get sucked into the band
(pseudopolyp), and therefore resection can be safely
performed without creating a submucosal cushion. A
large area can be resected piecemeal, taking care to
overlap the margins of each resection by 1 to 2 mm
to avoid residual areas of mucosa between resections.
The advantages of this technique are that it does not
require submucosal injection, it permits multiple re-
sections without removing the endoscope using the
same snare, and it is technically easier to perform. A
multiband mucosectomy device is now commercially
available (Duette, Cook Medical, Limerick, Ireland).
In a prospective randomized study, 100 consecu-
tive ERs were performed in 72 patients with early-
stage esophageal cancer.42 Fifty of these resections
utilized a “suck-band-ligate” device without prior sub-
mucosa injection, and 50 used the cap technique after
a submucosal lift. No signifi cant differences were
observed between the two groups with regard to the
maximum diameters, calculated area of the resected
specimens, or complication rate. A multicenter ran-
domized controlled trial compared the cap and MBM
techniques and found that procedure times and costs
were signifi cantly reduced with the MBM technique.37
No signifi cant differences were seen in the amount
of specimen resected.
Evolving ER Techniques:
Combination ER and Ablative Therapy
A drawback of ER monotherapy is the high recurrence
rate within a 5-year follow-up. Endoscopic ablative
therapy with PDT or RFA permits treatment of the
whole Barrett’s segment, which may permit treatment
Fig 11. — Multiband mucosectomy.
Fig 12. — “Suck-band-ligate” technique placing bands over the mucosa to
April 2013, Vol. 20, No. 2Cancer Control 123
of larger lesions and may be associated with a lower
recurrence rate. Because of the risk for recurrence,
patients treated with ER require regular endoscopic
follow-up to detect recurrent lesions. In most reports,
patients were followed every 3 months during the fi rst
year and annually thereafter.
In practice, focal ER of visible lesions is effec-
tively and safely combined with ablative modalities
to eradicate the BE mucosa. A prospective study that
included 279 patients receiving ER, 55 receiving PDT,
and 13 receiving both provided a 5-year follow-up
after ER and PDT of BE with high-grade dysplasia.14
A complete response was achieved in 96.6%. Sur-
gery was necessary in 3.7% after endoscopic therapy
failed. Metachronous lesions developed in 21.5% but
were endoscopically managed. No patients died of
esophageal adenocarcinoma or procedure-related
complications, and 56 died of concomitant disease.
The calculated 5-year survival rate was 84%. Larger
lesion diameter (> 2 cm), long-segment BE, piece-
meal resection, lack of adjunctive ablative therapy,
multifocal neoplasia, and the presence of residual
dysplasia are among the risk factors associated with
recurrence following ER. This study showed that
endoscopic therapy was effective and safe, with an
excellent long-term survival rate. The identifi ed risk
factors help stratify patients who are at risk for re-
currence and require intensive follow-up. Lower-risk
lesions (protruded and fl at lesions), a lesion diameter
up to 20 mm that is limited to the mucosa, and well-
to moderately well-differentiated tumors predict a suc-
cessful outcome with endoscopic therapy.14,38,39,41,53,54
In multivariate analyses, tumor differentiation has
not been identifi ed as an independent risk factor for
lymph node metastasis or tumor recurrence.41,55
To enable en bloc resection of larger areas of
neoplastic mucosa, the endoscopic submucosal dis-
section technique was developed in Japan. This mo-
dality has been extensively studied for early gastric
cancer and laterally spreading colorectal adenomas.
Endoscopic submucosal dissection requires special
training and a high level of technical expertise, and
it is time-consuming and potentially risky compared
to piecemeal ER. In addition, large-area resection in
the esophagus using this technique may result in a
higher rate of stricture. However, refi nements of the
technique and hybrid techniques (combining ER and
endoscopic submucosal dissection) may have a role
in the endoscopic management of Barrett’s-related
neoplasia in the future.56,57
Complications of ER
ER does have risks and should be performed by gas-
troenterologists with appropriate training. Acute
bleeding occurs in about 3% of patients and delayed
bleeding in 2%, but they were endoscopically man-
aged in most studies (Fig 13). Esophageal stricture
occurred in 37% to 48% of patients (stepwise radical
resection), and patients treated for focal lesions or in
escape treatment showed no stenosis.34,51 Stricture
formation are common if large areas (> 3 cm length
or > 50% of the circumference) of Barrett’s mucosa are
resected.58-60 The reported incidence of perforation
is 0% to 5%.59 Adequate acid suppression following
ER is important to ensure complete wound healing
with neosquamous epithelium and also to minimize
scarring and potentially reduce the rate of stricture
formation. Most centers use high-dose proton pump
inhibitors for 4 to 6 weeks after ER.
Complete Barrett’s Eradication Endoscopic
The goal of this therapy (CBE-EMR, Fig 6) is the resec-
tion of all Barrett’s epithelium, with the curative intent
of eliminating high-grade dysplasia and intramucosal
cancer and reducing the risk of metachronous lesions.
Chennat et al34 conducted a retrospective study of 49
patients with histologically confi rmed BE and high-
grade dysplasia or intramucosal cancer. The mean
number of sessions per patient was 2.1 and the mean
BE segment length was 3.2 cm. Surveillance biop-
sies showed normal squamous epithelium in 97% of
patients. No perforations or uncontrollable bleeding
occurred. About 37% patients developed symptomatic
esophageal stricture and all were managed endoscopi-
cally. The high rate of stricture with CBE-EMR should
be considered carefully; patients should be counseled
and considered for endoscopic ablation after focal
endoscopic mucosal resection of visible lesions.
Although expertise might vary from site to site
and patient characteristics need to be taken into ac-
count, ER and endoscopic ablation are established
therapies for BE-related high-grade dysplasia and
intramucosal cancer. Esophagectomy is reserved for
Fig 13. — Acute bleeding managed endoscopically.
124 Cancer Control April 2013, Vol. 20, No. 2
cases with submucosal invasion (T1b) or with evi-
dence of lymph node metastasis, or for those in whom
endoscopic therapy is unsuccessful.
Endoscopic Ablative Therapies of BE
As noted earlier, ablative therapies permit tissue de-
struction without providing a histologic specimen for
accurate diagnosis and staging. Ablative therapies
are well suited for “fl at” areas of BE dysplasia. Any
nodularity or mucosal irregularity within the BE seg-
ment is best evaluated with ER that provides a histo-
logic specimen for accurate diagnosis and T staging.
Ablative modalities are not the primary treatment of
esophageal adenocarcinoma, including T1a lesions.
In patients with intramucosal esophageal adenocar-
cinoma treated with ER, ablative modalities serve an
adjunct to eradicate the background BE.
The fi rst use of a balloon-based bipolar electrode for
complete ablation of esophageal epithelium in the
human esophagus was described in 2004.61,62 Since
then, more than 40 studies have been published re-
garding the use of RFA for the treatment of BE with
or without dysplasia and early esophageal carcinoma.
RFA is the preferred ablative modality in many cen-
ters due to the larger amount of observational data
compared with newer modalities, as well as its ease
of use, greater standardization, and greater familiarity
Its commonly used mode employs energy emitted
from a controlled radiofrequency source (HALO360+ or
HALO90, BÂRRX Medical Inc, Sunnydale, CA). The
HALO360+ is used for circumferential ablation (Fig 14),
and the HALO90 is intended for a more focal targeted
ablation (Fig 15). The use of HALO360+ involves a
sizing balloon catheter that is introduced into the
esophagus and measures esophageal width, followed
by an appropriately sized RFA balloon catheter. For
the treatment of Barrett’s related dysplasia, the con-
troller of the RFA source is preset to deliver energy of
12 J/cm2, which causes complete destruction of the
mucosa, but without injury to the submucosa. The
RFA balloon is 3 cm long and consists of 60 narrowly
spaced electrode rings in a bipolar fashion. After the
esophageal diameter is measured by the sizing bal-
loon, the RFA balloon catheter is introduced in the
esophagus and placed in its position. The balloon
is then infl ated and the RFA source releases energy
circumferentially on the esophageal surface for 300
milliseconds. In another form, a more targeted and
focal ablation may be carried out using the HALO90
catheter, which does not require a sizing catheter. The
HALO90 is a square-shaped catheter with the same
electrodes on its external surface, which is attached
to the tip of the endoscope. It allows the focal abla-
tion of small areas of residual Barrett’s epithelium.
After thermal dose-escalation animal testing and
pre-esophagectomy human experiments,62,63 the fi rst
larger clinical evaluation of RFA included BE patients
without dysplasia in a study by Sharma et al64 on
the ablation of intestinal metaplasia. This multicenter
trial demonstrated a 70% complete remission of BE in
the circumferential balloon-treated group at 1 year of
follow-up, without evidence of subsequent stricture
formation or buried BE among 4,306 evaluated biopsy
fragments. A subsequent study reported 98% complete
remission of intestinal metaplasia following stepwise
circumferential therapy with additional focal ablative
therapy of remaining BE.65 In the only multicenter,
randomized, and sham-controlled trial conducted to
date, 127 patients with prior diagnosis of dysplastic BE
(63 high-grade dysplasia and 64 low-grade dysplasia)
were randomized in a 2:1 ratio to receive either RFA or
a sham endoscopic procedure (control group). After
a 1-year follow-up, all measured primary and second-
ary outcomes showed signifi cant differences favoring
the treatment group: progression rate, progression
Fig 14. — The HALO360+ used for circumferential ablation.
Fig 15. —The HALO90 intended for a more focal targeted ablation.
April 2013, Vol. 20, No. 2Cancer Control 125
rate to cancer, complete regression of intestinal meta-
plasia, complete regression of low-grade dysplasia,
and complete regression of high-grade dysplasia.61 A
systematic review of nine observational studies involv-
ing 429 patients and at least 12 months of follow-up
was recently published.66 After analysis, complete
eradication of intestinal metaplasia was achieved in
46% to 100% of patients and complete regression of
neoplasia in 46% to 100%.
RFA is associated with the fewest complications
since it involves a limited depth of injury, although
stricture formation occurs in approximately 6% in pro-
spective series.61,67 A patient with a straight esopha-
geal segment without strictures is ideal for this mo-
dality. Patients with a tortuous esophagus may fare
better with a treatment such as PDT, which can be
applied more readily in this situation. RFA has also
been studied in patients who failed PDT. Fourteen
patients with residual high-grade dysplasia follow-
ing aminolevulinic acid or Photofrin PDT underwent
RFA and/or rescue ER. An overall complete rever-
sal of dysplasia was achieved in 86%, and the rate
of strictures was 7%.68 Although preliminary, this
study suggests RFA with rescue ER may be effective
for eradication of high-grade dysplasia in patients in
whom PDT has failed.
PDT is a minimally invasive treatment of solid tumors
that uses a photosensitizing drug (photosensitizer)
and laser light. It has been approved for use to treat
BE with dysplasia. The photosensitizer accumulates
in the tumoral tissue. Once a specifi c wavelength of
light is endoscopically applied with a laser, the treat-
ment works by a mechanism of free oxygen radical
production. This generation of free radicals results
in ischemic necrosis of tumor cells.
A prospective randomized study showed a signifi -
cant difference for the study group treated with PDT
and omeprazole compared with the group treated
with omeprazole only regarding the ablation of high-
grade dysplasia (77% vs 39%; P = .004) and the re-
currence of neoplasia (15% vs 29%; P = .027).69 The
patients followed a maximum of three PDT sessions at
intervals of at least 3 months. The treatment was well
tolerated and was associated with a median survival of
60.5 months. The technique might be used in elderly
patients and/or in those with signifi cant comorbidi-
ties. Overholt et al70 retrospectively studied a cohort
of 103 patients who had varying degrees of BE with
dysplasia and intramucosal cancer who were treated
with PDT. With a median follow-up of 50 months, the
intent-to-treat success rates for eradication of dysplas-
tic epithelium were 92.9% for the low-grade dysplasia
group, 77.5% for the high-grade dysplasia group, and
44.4% for the intramucosal cancer group.
Due to several limitations associated with this
therapy, clinicians have shown increased interest in
newer ablative treatment modalities. One limitation is
the additional time required from both the patient and
the provider for the administration of the photosen-
sitizing agents prior to endoscopic therapy. Another
is the systemic distribution of the photosensitizing
agents that requires patients to avoid direct sunlight
and wear full protective clothing (eg, sunglasses, wide-
brim hats, long-sleeved shirts) for several weeks to
prevent sunburn, which could be signifi cant.71,72 Also,
patients can develop esophageal strictures following
prior ablative treatments. Overholt et al70 reported
cases of adenocarcinoma that arose from buried Bar-
rett’s glands following PDT.
Endoscopic spray cryotherapy is a relatively new ab-
lative modality for the treatment of gastrointestinal
diseases. Endoscopic spray cryotherapy using liquid
nitrogen is a novel method of destruction of BE tissue
and has been studied extensively.73,74 It uses a visu-
ally directed, noncontact method that directly exposes
the Barrett’s mucosa to liquid nitrogen at −196° C at
low pressure (2 to 3 psi) via a disposable 7F spray
catheter that is introduced in the working channel of
a regular endoscope. A modifi ed orogastric decom-
pression tube is placed to vent excess nitrogen gas
from the esophagus and stomach. The esophageal
mucosa is exposed to the liquid nitrogen for 10 to 20
seconds and then allowed to thaw for approximately
1 minute. The freeze/thaw cycles are repeated 3 to
4 times per session. The session is repeated in 6 to 8
weeks if needed. The intracellular and extracellular
ice crystals that are formed during the freeze cycle
have an abrasive action and disrupt the integrity of
dysplastic cell membranes. Two mechanisms of cell
death then occur: (1) an immediate cellular lysis at
the coldest site of direct ablation and (2) induction of
infl ammatory apoptosis by cryoinjury in areas more
peripheral to the therapy that are initially damaged
but not initially destroyed.75
Several trials have shown cryotherapy as a safe
and effective tool. Short-term results are promising,
with eradication of intestinal metaplasia in 46% to 78%
of cases and of dysplasia between 79% and 87% of
cases.74,76 Johnston et al76 published a pilot study in
2005 suggesting that cryospray ablation is effective in
downgrading dysplasia and promoting the regenera-
tion of normal squamous epithelium in areas of BE.
In this single-center study, serial cryospray ablation
sessions were performed at monthly intervals on 11
patients with metaplasia and/or dysplasia. Complete
histologic eradication of BE was noted in 78% of the
patients. Dumot et al77 performed a nonrandomized
prospective cohort trial that included 30 patients with
126 Cancer Control April 2013, Vol. 20, No. 2
either high-grade dysplasia or intramucosal cancer un-
dergoing cryospray ablation. Results were promising:
68% of those with high-grade dysplasia and 80% of
those with intramucosal cancer had elimination of can-
cer or downgrading of high-grade dysplasia. Shaheen
et al74 retrospectively assessed 98 patients with BE and
high-grade dysplasia, the largest cohort to date. Of the
60 enrolled subjects completing all cryospray ablation
treatments with a mean of four treatments, 58 (97%)
had complete eradication of high-grade dysplasia at
a mean follow-up of 10.5 months.
The technique has been in use at our institute
for the last several years and has been employed to
ablate residual Barrett’s epithelium after defi nitive
chemoradiation of esophageal adenocarcinoma.78
After complete clinical response of esophageal ad-
enocarcinoma to chemoradiation therapy, cryoabla-
tion reduced the median length of persistent BE and
resulted in histologic downgrading in 14 patients.
Among 10 patients with high-grade dysplasia, 2 were
reduced to low-grade dysplasia, 6 to BE with no
dysplasia, and 2 to no BE. Among 4 patients with
low-grade dysplasia, 3 were reduced to BE with no
dysplasia and 1 to no BE. No major complications
have been reported except for a gastric perforation in
1 patient with Marfan syndrome. This therapy is now
contraindicated in patients with limited distensibility
of the stomach.79
Palliation of Dysphagia in Advanced
Palliation of dysphagia related to esophageal can-
cer may be accomplished with esophageal dilation,
stent placement, or other ablative modalities. Dilation
provides temporary relief and needs to be repeated
frequently. Ablative modalities such as PDT, neodym-
ium-doped yttrium aluminum garnet laser (Nd:YAG),
and cryoablation have been tried but not shown to
be consistently effective or safe in this situation. In
this article we focus primarily on the role of self-
expanding metal stents (SEMS) in the palliation of
Ablative Therapies for Malignant Dysphagia
In a prospective randomized trial involving 236 pa-
tients, PDT and laser therapy had similar effi cacy in
terms of dysphagia relief, although there was a trend
toward a better response with PDT for tumors located
in the upper two-thirds of the esophagus.80 PDT was
associated with esophageal strictures and photosen-
sitivity (19%) that may persist for 6 weeks but with
fewer perforations than with the Nd:YAG laser (1% vs
7%). Chest pain and worsening dysphagia are com-
mon after PDT and usually resolve over several weeks.
With the widespread availability of newer SEMS, PDT
is rarely used for the palliation of malignant dyspha-
gia. Cryospray ablation is another noncontact therapy
that uses supercooling to cause cryonecrosis and has
been used to palliate esophageal cancer.81
Endoscopic stent placement is used to palliate dyspha-
gia in patients with locally unresectable or advanced
metastatic esophageal cancer, in those with poor
functional status and weight loss, or in those with
locally recurrent disease. Stents may also be used as a
bridge to surgery during neoadjuvant chemoradiation.
The location of disease within the esophagus is an
important factor, given that expandable metal stents
are more effective for upper rather than distal lesions.
This discussion focuses only on SEMS as plastic
stents are rarely used in this situation.
SEMS are composed of a variety of metal alloys
such as nitinol, and they are available in several
lengths and diameters. Metal stents are available in
three varieties: uncovered, partially covered, and fully
covered. Covered stents resist tumor ingrowth, but
they have a higher migration rate, especially when
fully covered.82 Partially covered stents are uncovered
at their ends, allowing the stent to embed in the tis-
sue and thus prevent migration. Fully covered stents
offer the advantage of potentially being removable,
but they are associated with an increased risk of mi-
gration. Uncovered stents are less likely to migrate
but are subject to tumor ingrowth and resultant ob-
struction. In addition, some stents have an antirefl ux
valve to prevent esophageal refl ux in patients with
stents placed across the gastroesophageal junction.
Stents can be used as a bridge to surgery for
esophageal cancer. Brown et al83 reported on 32
patients with dysphagia related to esophageal ad-
enocarcinoma who underwent SEMS placement prior
to neoadjuvant therapy. Initial stent placement was
successful in all patients, and mean dysphagia scores
improved signifi cantly; however, stent migration oc-
curred in 8 patients. Twenty of the 32 patients subse-
quently underwent esophagogastrectomy. Stents were
removed in 5 of these 20 patients prior to surgery,
while the stents in the remaining 15 patients were
removed with the resected specimen. No surgical
complications were attributed to stent placement.
Gastrointestinal SEMS can be placed under endoscop-
ic guidance without the aid of fl uoroscopy. Initial
stricture dilation is generally recommended, and the
diameter of the stent to be deployed should not be
greater than 2 mm of the estimated stricture diameter.
The length of the stenosis must be accurately mea-
sured and a stent chosen that is at least 4 cm longer
than the stricture. Placement can be accomplished
endoscopically by visualization and documentation of
distances measured from the incisors to the proximal
margin of the tumor, followed by stent placement
April 2013, Vol. 20, No. 2Cancer Control 127
under endoscopic visualization. At our institute, we
investigated dysphagia response, stent migration, and
adverse events, with small-caliber (≤ 16 mm body di-
ameter) covered SEMS for malignant dysphagia in a
cohort of 31 patients. Small-caliber SEMS were placed
under direct endoscopic visualization without fl uo-
roscopic assistance. The overall migration rate was
35%, and the dysphagia score improved signifi cantly
in 97% of patients.
Patients with large, bulky, mid and proximal
esophageal tumors should be evaluated for possible
tracheal compression. Imaging such as CT scans
should be reviewed to determine if tracheal com-
pression is present. Such patients may benefi t from
airway stent placement prior to esophageal stent
placement. During the placement of stents, the en-
doscopist should be prepared for the possibility of
tracheal compression and the need for endotracheal
intubation and emergent stent removal if stridor de-
velops. Balloon dilatation prior to stent deployment
at the level of the stricture could indicate airway com-
promise. After deployment, the SEMS expands against
the stenosis, and this anchors the stent and helps
prevent stent migration. For stent placement in the
very distal esophagus, it is important to avoid leaving
an excessive length of stent within the stomach to
prevent contact with the opposite gastric wall, which
could result in obstruction and/or ulceration.
Following stent placement, patients should be
advised to consume a soft mechanical diet to avoid
food impaction. In addition, if an open stent (non–
anti-refl ux) is placed across the esophagogastric junc-
tion, then strict anti-refl ux precautions and high-dose
proton pump inhibitors are needed. Greater than
95% of patients undergoing stent placement for ma-
lignant esophageal obstruction are able to tolerate
a liquid diet.84-86
In patients with malignant dysphagia in the pres-
ence of a tracheoesophageal fi stula, SEMS restored
luminal patency in about 98% and sealed the fi stula
in 70% to 100% of patients.87,88 However, subsequent
tumor ingrowth is common, and many patients require
additional interventions for recurrent dysphagia or
complications related to the stent, such as migration.86
A meta-analysis that included 40 trials and 2,542 pa-
tients found that SEMS insertion is safer and more ef-
fective than rigid plastic tube insertion.89 This review
also found that SEMS insertion provided more rapid
palliation of dysphagia compared with brachytherapy,
but the difference gradually diminished over time.
Complications of SEMS Placement
In a survey that included 212 endoscopists who had
placed a total of 434 SEMS,90 the overall rate of intra-
or post-procedural technical complications was 5.4%.
The complications included misplacement (0.3%),
failed expansion (3.9%), failed deployment (0.8%), and
migration (0.3%). The overall rate of intra- or post-
procedural clinical complications was 14.7%, including
chest pain (12.2%), perforation (0.6%), bleeding (0.6%),
and death (1.4%). Delayed technical complications
occurring in 18.1% included overgrowth/ingrowth
(11.3%) and migration (6.8%). Delayed clinical com-
plications occurred in 26.9%, including gastroesopha-
geal refl ux disease (3.7%), recurrent dysphagia (8.2%),
tracheoesophageal fi stula (2.8 %), bleeding (3.9%),
perforation (0.8%), and death within 30 days that was
not related to immediate stent placement (7.4%).
In the last decade, signifi cant advances have devel-
oped in the endoscopic management of Barrett’s
esophagus (BE)-related neoplasia. Endoscopic re-
section and ablative modalities have become the
standard of care in the management of high-grade
dysplasia and intramucosal cancer in patients with
BE. Further refi nements and modifi cations in these
techniques and devices can be expected over the
next decade. Endoscopic submucosal dissection is
a promising new en bloc resection technique that is
widely used in Asia and Europe and is being studied
in North America. The accurate pathological stag-
ing provided by endoscopic resection has resulted
in a better selection of patients for esophagectomy.
The safety and effi cacy of endoscopic radiofrequency
ablation have been demonstrated in several studies,
and this therapy is now used in many countries in
the management of BE dysplasia. A multimodality
endoscopic approach involving endoscopic resection
for visible lesions and ablative therapy for eradica-
tion of the BE is the widely accepted approach in the
management of BE-related neoplasia. The signifi cant
improvements in the design of self-expanding metal
stents may improve the quality of life of patients with
severe malignant dysphagia.
Appreciation is expressed to Masoumeh Ghayouri, MD,
for providing the histopathology images included in this
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