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Figure 1 Histological feature of Barrett mucosa. In Barrett esophagus,
the esophageal squamous epithelium is replaced by metaplastic columnar
epithelium with Goblet cells in background of chronic inflammation in the
lamina propria. The non-dysplastic Barrett mucosa shows basally located
small nuclei without cytological atypia.
Dysplasia in Barrett Esophagus
Barrett esophagus is a preneoplastic condition, and it follows
the scheme of progression through the metaplasia, dysplasia
and adenocarcinoma. Therefore, it is important to evaluate for
the presence of dysplasia during endoscopic surveillance
biopsies and each Barrett mucosa biopsy will be classified as
negative for dysplasia, indefinite for dysplasia, low grade dysplasia, high grade dysplasia or adenocarcinoma based on the
characteristic histological features including cytology of the
cells, glandular architecture, surface maturation, and presence
of inflammation (Montgomery E, Human Pathol 2001).
• Negative for dysplasia: The Barrett epithelium shows no
cytological atypia with typical small basally located nuclei,
and the glands are even spaced without crowding or architectural complexity.
• Indefinite for dysplasia: This classification is used when the
Barrett epithelium demonstrates epithelial atypia but does
not reach the degree of low grade dysplasia or cannot be
determined whether the changes are truly dysplastic or reactive in the presence of acute inflammation or tissue artifacts.
• Low grade dysplasia: The dysplastic epithelium shows mild
nuclear hyperchromatism, mildly increased nuclear:cytoplasmic
ratios with nuclear stratification, typically involves both deeper
glands and surface epithelium. The nuclear polarity and
glandular architecture are generally preserved with only mild
crowding or distortion (Figure 3).
• High grade dysplasia: The dysplastic epithelium demon-
strates more pronounced cytological atypia with enlarged
nuclei and increased nuclear:cytoplasmic ratios, nuclear
stratification involving full thickness of the cells and loss of
nuclear polarity (Figure 4). Glandular architecture is more
distorted than low grade dysplasia with marked crowding
Figure 2 Duplicated muscularis mucosae in Barrett esophagus. The
inner muscularis mucosae (inner MM) is the duplicated layer, and the
outer muscularis mucosae (outer MM) is the layer continuous with the
single layer of muscularis mucosae underlying the normal esophageal
squamous mucosa. The space between inner and outer muscularis
mucosae is loose fibroconnective rich with lymphatic vessels (arrows).
diffuse and is identified in up to 92% of Barrett esophagus in
esophagectomy specimen (Abraham SC, AJSP 2007) and in 2/3
of EMR specimens (Prasad GA, AJG 2007) (Figure 2). The
space between the duplicated muscularis mucosae contains
loose connective tissue rich in lymphatics and medium sized
vessels. Awareness of the presence of duplicated muscularis
mucosae is important to avoid overstaging invasive Barrett adenocarcinoma in particularly in specimens from endoscopic
therapy (EMR or ESD).
Figure 3 Barrett mucosa with low grade dysplasia. The dysplastic
columnar epithelium (arrowheads) shows nuclear stratification and
nuclear hyperchromatism involving surface and crypts. No loss of nuclear
polarity is identified.
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Figure 4 Barrett mucosa with high grade dysplasia. The dysplastic
columnar epithelium shows marked cytological atypia with increased
nuclear:cytoplasmic ratio, nuclear hyperchromatism and loss of nuclear
polarity.
and glandular distortion. High grade dysplasia also typically involves both the deeper glands and surface epithelium
and can present with cribriform architecture with intact
basement membrane. Intraluminal necrotic debris present
in the high grade dysplastic glands usually represent a sign
of synchronous intramucosal or invasive adenocarcinoma
(Odez RD, J Clin Pathol 2006). Endoscopic therapy is recommended for patients with Barrett esophagus with high grade
dysplasia (Shaheen NJ 2016).
There are two main histological types of Barrett dysplasia,
adenomatous (intestinal) type and non-adenomatous (foveolar) type. The adenomatous type dysplasia has histological
features of prominent nuclear stratification with elongated
pencil-shaped nuclei resembling colonic adenoma, is the
most common type of dysplasia in Barrett esophagus. Nonadenomatous (foveolar) type dysplasia represents the dysplasia
of the gastric foveolar component of the Barrett esophagus
(Brown IS, Mod Pathol 2010, Mahajan D, Mod Pathol 2010)
and accounts 6–8% of dysplastic Barrett esophagus in biopsy
materials (Naini BV, AJSP 2016). Foveolar type dysplasia is
characterized by glands with uniform round-oval, basally
located, non-stratified nuclei and abundant pale eosinophilic
cytoplasm typically involves the full thickness of mucosa. Low
grade foveolar type dysplasia has uncrowded glands with preserved glandular architecture and enlarged nuclei of 2–3 times
of mature lymphocyte. High grade foveolar dysplasia shows
presence of back-to back crowded glands with glandular
branching, complexity and occasional villiform pattern; and
enlarged nuclei of 3–4 times the size of mature lymphocyte.
Loss of nuclear polarity, a feature typically only present in high
grade adenomatous type dysplasia can be present in both low
grade and high grade foveolar type dysplasia.
Serrated type dysplasia is a rare form of Barrett dysplasia
(Naini BV, AJSP 2016). Serrated dysplasia in Barrett esophagus
shares similar histological features seen in colonic serrated adenoma. Dysplasia in Barrett esophagus has been described
limited to the crypts without surface involvement as “crypt dysplasia” based on the nuclear and cytological features with clonal
appearance distinctive from the adjacent non-dysplastic crypts
(Lomo LC, AJSP 2006). The concept of crypt dysplasia is not
universally accepted among gastrointestinal pathologists and
some gastrointestinal pathologists prefer to use indefinite for
dysplasia in this setting.
Dysplastic Barrett esophagus has increased risk of developing
adenocarcinoma. The rate of developing adenocarcinoma in
Barrett esophagus negative for dysplasia is 0.1–0.5%/year (HvidJensen F, NEJM 2011). The rate of developing high grade dysplasia/adenocarcinoma for Barrett esophagus with indefinite for
dysplasia is 0.86–1.4%/year, and with low grade dysplasia is 1.7–
1.8%/year (Singh S, Gastrointestinal endoscopy. 2014). Barrett
esophagus with high grade dysplasia has annual rate of 5–8% of
developing adenocarcinoma .
Although histological features are the gold-standard for the
diagnosis for dysplasia for Barrett esophagus and the clinical
follow-ups are based on the absence or presence of dysplasia.
There is considerable intraobserver and interobserver variations even among gastrointestinal pathologists in grading of
Barrett dysplasia. There is a reasonable interobserver agreement
in the categories of negative for dysplasia and high grade dysplasia; but significant discordance in the categories of indefinite
for dysplasia and low grade dysplasia (Kerhof M, Histopathology
2007, Montgomery E, Human Pathol 2001). Diagnosis of dysplasia needs to be confirmed by a second pathologist with
extensive experience in interpretation of Barrett-associated
dysplasia as recommended by AGA clinical guideline (Shaheen
NJ, Am J Gastroenterol 2016).
Adenocarcinoma
Adenocarcinoma is characterized by neoplastic epithelium that
invades through the basement membrane into the surrounding
stroma (Figure 5). Adenocarcinoma can show different degree
of differentiation based on the extent of glandular formation as
well-differentiated, moderately differentiated and poorly differentiated. There are different types of adenocarcinoma based
on the histological pattern, intestinal type adenocarcinoma,
mucinous adenocarcinoma, and signet ring cell type adenocarcinoma. The esophageal adenocarcinoma can be subclassified
based on the depth of invasion as intramucosal adenocarcinoma (invading into lamina propria or muscularis mucosa) or
invasive adenocarcinoma (invading into submucosa, muscularis propria or subserosa).
Intramucosal adenocarcinoma can be further subclassified
into four levels based on the level of invasion as invading into
lamina propria (m1), inner/superficial muscularis mucosae
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Figure 5 Barrett adenocarcinoma. A moderately to poorly differentiated
adenocarcinoma showing neoplastic cells with focal glandular pattern invading
into stroma.
(m2), space between the duplicated muscularis mucosae
(m3) and outer/deep-muscularis mucosae (m4) by Vieth and
Stolte system (Vieth M, Best Pr Res Clin Gastroentero 2005).
Esophageal adenocarcinoma with submucosa invasion can be
further subclassified as three levels based on the level of invasion as into superficial 1/3 of submucosa (sm1), middle 1/3
of submucosa (sm2) and outer 1/3 of submucosa (sm3). This
subclassification requires the presence of entire thickness of
submucosa and use muscularis propria as landmark, is difficult and inaccurate to use for endoscopic resection specimens
typically containing variable thickness of submucosa and lacking muscularis propria as landmark. The Paris endoscopic
classification of superficial neoplasms have recommended
measuring depth of submucosa invasion in microns from the
lower limit of muscularis mucosae on endoscopic resection
specimens (Figure 6) (EndoscopicClassificationReviewGroup,
Endoscopy 2005).
Lymphovascular invasion can be identified in 0% to 12% of
intramucosal adenocarcinoma and 22% to 60% of submucosal
adenocarcinoma (Figure 7) (Estrella JS, AJSP 2011; Badreddine
RJ, Clin Gastro & Hepato 2010). Tumor budding is present in
4% of intramucosal adenocarcinoma and 41% of submucosal
adenocarcinoma; and tumor budding is more frequently present in adenocarcinomas with metastatic lymph node (41%)
than in adenocarcinomas without metastatic lymph node
(10%) (Landau MS, Mod Pathol 2014). Lymphovascular invasion and tumor budding are predictors for lymph node metastasis (Estrella JS, AJSP 2011; Landau MS, Mod Pathol 2014).
Esophageal intramucosal adenocarcinoma has minimal
risk of lymph node metastasis (2%) and endoscopic therapy
is preferred over esophagectomy for Barrett patients with
intramucosal adenocarcinoma (Dunbar KB, AJG 2012).
Esophageal submucosa adenocarcinoma has a higher risk
Figure 6 Submucosal adenocarcinoma. A low power view of
adenocarcinoma invades into deep submucosa (sm3) with 2778 µm
invasion into submucosa based on the measurement on an endoscopic
mucosa resection specimen.
Figure 7 Barrett adenocarcinoma with lymphovascular invasion.
Clusters of adenocarcinoma cells are present with the lymphatic vessels
(arrows).
(ranging from 18% to 33%) of lymph node involvement on
esophagectomy specimens (Estrella JS, AJSP 2011; Badreddine
RJ, Clin Gastro & Hepato 2010). The studies from esophagectomy specimens had shown no significant different rates of
lymph node metastasis between superficial (sm1) and deeper
(sm2 and sm3) submucosa adenocarcinoma (Badreddine RJ,
Clin Gastro & Hepato 2010; Leers JM, Annals Surgery 2011;)
and esophagectomy is the therapy choice for submucosal
adenocarcinoma. However, with the widely accepted practice of endoscopic therapy, it has been shown that a subset
of “low-risk” submucosal invasive adenocarcinoma defined
as superficial submucosal invasion (<500 µm), absence of
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lymphovascular invasion, and histological grade G1/G2
(Manner H, AJG 2008); can be managed by endoscopic
therapy especially in those who are poor surgical candidate
as recommended by AGA Clinical Practice. The “low-risk”
submucosal invasive adenocarcinoma has minimal (2%) risk
of lymph node involvement or distant metastasis (Manner H,
AJG 2008).
Pathophysiology
Barrett’s esophagus was original conceptualized by Norman
Barrett as a congenital condition where gastric type epithelium
was found in the distal esophagus. Even at its initial description, it
was felt to be related to acid peptic disease with ulcer formation
being the clinical significance of the disorder.
BE currently is felt to be the consequence of long-term gastroesophageal reflux disease producing chronic inflammation
and subsequent immune cell infiltration that appears to be
characteristic of metaplasia formation{(Fitzgerald et al. 2014)
#7394}. There does appear to be a dependence on bile as well as
acid reflux to induce metaplastic features in cell culture models
of Barrett’s esophagus
Genomic abnormalities have been studied for decades in
hopes of identifying potential biomarkers for progression of the
disease to cancer. The two most significant tumor suppressor
genes mutated in EAC are TP53 and p16/CDKN2A, though
sporadic mutations have also been identified in various other
genes including APC, BRAF, CDH1, CTNNB1, EGFR, KRAS,
PIK3CA, PTEN, and SMAD4 (Dulak et al. 2013).
Molecular studies suggest that BE can progress to EAC in either
a genome-doubled pathway or a non-genome-doubled pathway
(Figure 8). In the genome-doubled pathway, TP53 inactivation
occurs early, followed by genome doubling resulting in genomic
instability, aneuploidy, and oncogene amplification. In the nongenome-doubled pathway, there is a gradual accumulation of
mutations affecting tumor suppressor genes leading to activation
of oncogenes and the subsequent development of genomic instability (Stachler et al. 2015).
The cancer genome atlas found that the predominant mechanism of genomic evolution in adenocarcinoma is related to
genomic instability with multiple genetic pathways variable
involved (Sanchez-Vega et al. 2018 #57743). Unfortunately, no distinct or predominant mechanism has been found. It is clear that
p53 mutations occur late in the development of neoplasia while
p16 inactivation through mutation, promoter hypermethylation,
deletion, or recombination appears to occur much earlier.
Disease Presentation and Work-up
BE is typically asymptomatic though patients may present
with a long duration of gastroesophageal reflux symptoms.
Similarly, early stage EAC is frequently asymptomatic, but
more advanced stage disease may present with dysphagia, odynophagia, hematemesis, weight loss, and/or fevers. Patients
Figure 8 Genetic aberrations resulting in esophageal adenocarcinoma development. Taken, with permission, from Stachler, M., Taylor-Weiner, A., Peng,
S. et al. Paired exome analysis of Barrett’s esophagus and adenocarcinoma. Nat Genet 47, 1047–1055 (2015).
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may also present with anemia and melena if there is significant
bleeding from the tumor. The presence of dysphagia usually
suggests invasive cancer such as T3/T4 disease, while systemic
symptoms like fever and weight loss indicates metastatic disease (Ripley et al. 2016). Rarely, EAC can present with tracheoesophageal fistula and/or aspiration pneumonia due to tumor
erosion into the bronchial structures (Adler et al. 1985).
Esophagogastroduodenoscopy (EGD) is normally required
for diagnosis. This allows for direct visual assessment of the
esophagus and allows for sampling of the lesion to confirm
the diagnosis. Endoscopically, BE is suspected when salmoncolored mucosa extends at least 1 cm above the gastroesophageal junction (GEJ) into the tubular esophagus and must be
confirmed on histopathology assessment by the presence of
intestinal metaplasia with goblet cells. Accurate description
of the BE segment is vital, and the Prague C[ircumferential]
& M[aximum] criteria is utilized for this purpose, taking into
account the length of BE that is circumferential, as well as
the total length of the segment. For surveillance of Barrett’s
esophagus, biopsies should be obtained according to the
Seattle protocol (Fitzgerald et al. 2001), in which samples
are taken in four quadrants, and separate bottles are utilized
every 1–2 cm.
Since adenocarcinoma of the esophagus is almost always
distal in location, it’s confusion with proximal gastric adenocarcinoma has led to the Siewert classification in an attempt to
distinguish between these two entities as current first line chemotherapy for gastric versus esophageal adenocarcinoma are
quite different (Siewert JR, 2000 #57744). Adenocarcinoma
that are predominantly found in the esophagus are Siewert
Type 1; those at the gastro-esophageal junction are Type 2, and
those predominantly in the stomach are Type 3’s. This has
implications to approach and treatment. Type 3s are usually
treated like gastric cancers and undergo staging laparotomy.
Type 1 and 2 are often treated like esophageal adenocarcinoma
though the precise approach to Type 2 cancers have not been
determined.
In patients with EAC, the endoscopic findings can be quite
varied and range from subtle nodularity in intramucosal cancers to friable, fungating tumors causing complete esophageal
luminal obstruction (8). In lesions that may be amenable to
endoscopic resection, deep biopsies should be avoided as
subsequent scarring can hinder dissection of the lesion.
It is important to note that the vast majority of EAC, which is
diagnosed at late stage (Hur et al. 2013), is diagnosed without a
prior diagnosis of BE (Visrodia et al. 2016). EGD can be
for screening in high risk populations and is most commonly
performed screening procedure at this time. If pursued, documentation of the Prague C&M criteria and obtaining biopsies as
per the Seattle protocol is of paramount
transepithelial sampling with computer-assisted 3-dimensional
analysis (WATS-3D; CDx Diagnostics, Suffern, NY) is a novel
importance. Wide-area
utilized
sampling technique utilizing cytological samples obtained
with a stiff brush, coupled with interpretation by a proprietary artificial intelligence neural network to highlight areas of
dysplasia, assisting pathologists in the interpretation of tissue.
While relatively new to the armamentarium of BE screening, data suggests this technique can increase dysplasia yield
(Codipilly et al. 2022b), and thus guidelines have suggested its
use in an adjunctive manner (in addition to Seattle protocol
biopsies) during BE screening and surveillance (Qumseya et
al. 2019). The precise role of WATS is still being defined given
the lack of long-term outcomes of patients who have neoplastic
disease solely diagnosed by WATS.
Less-invasive modalities are available for screening purposes.
Transnasal endoscopy (TNE) can be performed at the point of
care, though the use is technically more difficult than standard
endoscopy because of the small diameter. TNE uses an ultrathin endoscope inserted through the nasal cavity for visual
inspection of esophageal mucosa. It requires no sedation, and
has good specificity and sensitivity (Honing et al. 2019).
Patients tolerate this procedure well and studies suggest TNE is
preferred to conventional EGD in patients willing to undergo
the procedure (Sami et al. 2019a). If any suspicious lesions are
found, EGD should follow for sampling. However, TNE is not
widely available and often requires more preparation time in
order to provide local anesthesia. Acceptance by primary care
physicians and patients has been a limiting factor.
Barium esophagography may show a mass but can be normal
in early-stage disease. If metastatic disease is suspected, staging
proceeds with computed tomography (CT) of the chest,
abdomen, and pelvis, and/or a positron emission tomography
(PET). More recently, MRI has been combined with PET
imaging with even higher resolution. In addition, newer nuclear
agents that are more specific than standard FDG PET imaging
have been able to image even more metastasis with less false positives. Standard endoscopic ultrasound (EUS) is typically done
to assess for the presence of regional lymphadenopathy and
to sample lymph nodes for most esophageal adenocarcinoma.
For patients with early stage disease such as intra-mucosal cancer, EUS probably has less of a diagnostic role as unsuspected
lymph nodes are uncommon. Endoscopic resection is generally
required to establish the early nature of disease and to exclude
invasion into the submucosal.
Prognosis
Staging of EAC is the most significant predictor of risk and
follows American Joint Committee on Cancer guidelines
(Table 1a and 1b) (Rice et al. 2017). Staging involves depth of
tumor invasion (T), lymph node involvement (N), and metastatic spread (M). Staging may involve CT or PET scan to assess
distal spread of the tumor. As previously described, EUS can be
used to assess for locoregional lymphadenopathy. Risk factors
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Table 1a
adenocarcinoma.
Table 1b Clinical stage groups for esophageal adenocarcinoma.
Cancer staging categories for cancer of esophageal
Category Criteria
T category
TX Tumor cannot be assessed
T0 No evidence of primary tumor
Tis High-grade dysplasia, defined as malignant cells
confined by the basement membrane
T1 Tumor invades the lamina propria, muscularis mucosae,
or submucosa
T1a Tumor invades the lamina propria or muscularis mucosae
T1b Tumor invades the submucosa
T2 Tumor invades the muscularis propria
T3 Tumor invades adventitia
T4 Tumor invades adjacent structures
T4a Tumor invades the pleura, pericardium, azygos vein,
diaphragm, or peritoneum
T4b Tumor invades other adjacent structures, such as aorta,
vertebral body, or trachea
N category
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–2 regional lymph nodes
N2 Metastasis in 3–6 regional lymph nodes
N3 Metastasis in 7 or more regional lymph nodes
M category
M0 No distant metastasis
M1 Distant metastasis
AJCC Stage cTNM staging
0 Tis N0 M0
IA T1 N0 M0
IIA T1 N1 M0
IIB T2 N0 M0
IIIA T2 N1 M0
T3-4a N0-1 M0
IVA T1-4a N2 M0
T4b N0-2 M0
T1-4 N3 M0
IVB T1-4 N0-3 M1
associated with poor survival regardless of stage of the disease
include male gender, older age at diagnosis, visceral obesity,
and first-degree family history of EAC. Patients with stage IV
disease typically have five-year survival rates of less than 5%,
whereas those with Stage I/II disease have five-year survival
rates exceeding 50% (Hur et al. 2013).
Management
Significant advancements over the past 20 years, in particular the
introduction and subsequent refinement of endoscopic resection
coupled with ablative therapies have supplanted the use of
esophagectomy for management of dysplastic BE and early stage
EAC. This has avoided the significant morbidity and mortality
associated with surgery and has improved long-term outcomes
in the patient population. For patients with disease not amenable
to endoscopic therapy, surgical techniques have evolved, and the
safety of these procedures has considerably improved since their
inception. Immunotherapies and targeted molecular therapies
have also provided improved survival for those with metastatic
disease not amenable to surgical resection. The following chapter
has been divided into endoscopic therapy, surgery and chemotherapy, radiotherapy, and biological targeted therapy.
I Endoscopic Therapy
1. Dysplastic BE and T1a Disease – Endoscopic
Eradication Therapy
Endoscopic eradication therapy (EET) is the first line
therapeutic option for patients with BE dysplasia and early
stage (T1a) EAC. EET involves the combination of endoscopic resection with ablation. Of note, the clinical
management is individualized and so not every patient will
require both resection and ablation; patients may need only
one modality for management of their disease, though typically resection and ablation are required in cases of EAC.
It is important to note that guidelines recommend the
endoscopic resection of any nodular disease found within a
segment of BE (Shaheen et al. 2022).
A Endoscopic Resection
Endoscopic resection is used for nodular Barrett’s Esophagus
and early stage EAC. There are two primary resection techniques: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).
1. Endoscopic Mucosal Resection
There are two basic methods in which EMR can be completed: one utilizes a cap with a crescent snare, while the
alternative utilizes a band-ligator similar to that used for
variceal banding.
In cap assisted EMR (cEMR), a hard cap (Olympus
Medical, Center Valley, PA) is fitted onto the end of the
endoscope. Careful assessment of the lesion of interest is
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carried out. A lifting agent, typically comprised of saline, epinephrine, is first injected submucosally under the lesion.
This allows a “lift” of the mucosa from the submucosa. If
poor lifting is noted, this may indicate deeper invasion of the
lesion than expected (though this could also occur in the
setting of fibrosis due to prior procedures or extensive biopsying). A crescent shaped snare (SnareMaster Crescent;
Olympus Medical, Center Valley, PA) is seated on the inner
aspect of the cap, followed by suction of the lesion into the
cap. The snare is closed and the lesion is resected using a
combination of cutting and coagulation current from an
electrosurgical generator (Of note, typically the snare can be
used only once).
With band-ligator EMR (blEMR), a modified banding kit
is used to snare the lesion of interest (Figure 9). There are
two commercially available products, the Captivator EMR
(Boston Scientific, Marlborough, MA) and Duette MultiBand Mucosectomy Device (Cook Medical, WinstonSalem, NC). Assessment of the lesion of interest and
submucosal injection of the lifting agent proceeds as above
for cEMR but suctioning and snaring of the lesion takes
place with the fitted device. The bands are “fired,” and the
lesion can then be resected by passage of an electrical snare
via the working channel, and the process can then continue
utilizing the next band to snare another area of interest.
Of note, specimens are limited to the size of tissue that can be
sucked into the cap. Therefore, the largest lesion resected by
EMR is typically around 15mm, and lesions larger than this
must be resected in piecemeal which can hinder histologic
staging of the underlying tumor.
Endoscopic Submucosal Dissection (ESD)
ESD is a more recently developed endoscopic resection technique, and unlike EMR, allows complete (en bloc) removal of
larger lesions in one piece (Figure 10). Similar to EMR,
during
ESD, careful inspection of the lesion, followed by thermal
marking of the borders, is followed by injection of a lifting
agent (again, usually a combination of saline, epinephrine,
and a viscous agent such as hydroxypropylmethyl cellulose).
The viscous solution is important for ESD since it is important
to visualize the submucosal space for proper dissection. Once
an adequate lift has been achieved, careful dissection takes
place utilizing a variety of electrosurgical knives and devices.
The type of device is usually dependent on the training of
the endoscopist and the reimbursement environment of the
country in which the procedure is performed. Many different knives are available although it appears that scissor type
knives are the easiest to learn and also can perform the entire
resection as well as hemostasis with only one device {Hanada
and Wang, 2021 #57723}. This technique requires specialized
Figure 9 Band-ligation endoscopic mucosal resection. A. A nodular lesion is identified under narrow band imaging in an area of Barrett’s esophagus.
B. Electrocautery is utilized to mark a clear margin around the lesion. C. A submucosal lift is obtained. D. A multiband mucosectomy kit is utilized to snare
the lesion with suction, creating a pseudopolyp that is then banded and resected utilizing electrocautery. E. The post resection bed is visible after removal
of the area of nodular Barrett’s esophagus.
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Figure 10 Endoscopic submucosal dissection. A. A nodular area is noted in Barrett’s esophagus mucosa. B. The margins of the lesion are marked with
cautery. C. Methylene blue saline injection in utilized to lift the lesion. D. Dissection proceeds utilizing the Hook Knife (Olympus USA, Center Valley, PA).
E. The dissection bed after removal of the lesion. F. Pinning of the resected lesion to Styrofoam.
training in third-space endoscopy but once mastered yields
safety profiles similar to EMR. The proceduralist separates,
and ultimately removes, the mucosa and submucosa from
the remainder of the esophageal wall and can send the entire
specimen to pathology for review.
Advantages and Disadvantages of
Endoscopic Resection Techniques
Both cEMR and ESD can result in curative resection of early-stage
disease, obviating the need for esophagectomy which carries its
own significant morbidity and mortality. However, there are several
differences between these two techniques that must be highlighted.
ESD is technically more challenging compared to cEMR, and thus
requires extensive training. ESD may require as many as 250 procedures to gain competence compared to only 25 in cEMR (Yang et al.
2021; Zhang et al. 2020). As such, the ASGE recommends an
intensive, “step-up” program for ESD training whereas EMR competency can be obtained during a typical gastroenterology
fellowship (Maple et al. 2015). ESD is associated with considerably
longer procedure times given the need for careful dissection
(Terheggen et al. 2017). ESD is also associated with a higher risk of
perforation compared to cEMR, though both procedures are safe
given overall complication rates of less than 5% (Maple et al. 2015).
It is unclear if there is a therapeutic benefit favoring one of
these procedures. A retrospective review of patients receiving
EMR against those receiving ESD for dysplastic BE/IMCa demonstrated no difference in remission of intestinal metaplasia
rates at two years, though remission of dysplasia occurred earlier in ESD patients possibly mediated by the removal of larger
areas of BE tissue during resection (Codipilly et al. 2022a).
Regardless, cEMR is recommended for lesions less than 1–1.5
cm in diameter, while ESD is recommended for larger lesions
as it allows en bloc resection and accurate histopathological
staging of the lesion with assessment of both lateral and deep
margins which may ultimately affect further management.
B. Ablation
Endoscopic resection is coupled with different ablation strategies to treat the residual BE segment until eradication of
intestinal metaplasia is achieved. Ablation alone can be used in
the setting of dysplasia without discrete nodularity. Complete
remission of intestinal metaplasia (CRIM) is associated with a
lower risk of dysplasia and advanced neoplasia recurrence
compared with complete remission of dysplasia (CRD) only
(Sawas et al. 2019). As such, the goal for any patient entering a
program for EET should be CRIM, and not CRD alone.
Typically, patients return for assessment of response to therapy
and potential repeat therapies every 3–4 months.
1. Radiofrequency Ablation
Radiofrequency ablation (RFA) is a minimally invasive
procedure during which radiofrequency energy is applied to
the esophageal epithelium causing local coagulative necrosis
(Figure 11. As energy application is limited to the mucosa,
there is minimal to no damage to the submucosa and deeper
structures (Visrodia et al. 2017). RFA requires the use of a
specialized RFA balloon which can provide circumferential
energy (Halo 360 BarrX RFA Ablation Catheter, Medtronic,
Minneapolis, MN) or focal catheter for targeted therapy (Halo
BarrX Focal RFA Catheters, Medtronic, Minneapolis, MN).
The pivotal AIM-Dysplasia trial confirmed the efficacy of
RFA in the management of dysplastic BE (Shaheen et al.
2009). In this multicenter, sham-controlled trial with 127
patients with either low-grade dysplasia (LGD) or HGD,
77.4% of patients in the ablation group achieved CRIM compared to 2.3% in the control group (p<0.001). Moreover,
patients in the ablation group had a reduced risk of disease
progression (3.6% vs. 16.3%, P=0.03) and experienced fewer
cancers (1.2% vs. 9.3%, P=0.045).
Given that the risk of LGD progression is considerably
lower than that associated with HGD, Phoa et al. conducted
a randomized controlled trial to assess the efficacy of
72 1 UPPER GASTROINTESTINAL CANCER
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ablation against endoscopic surveillance in patients with
LGD. This multicenter trial followed 135 LGD patients and
determined that RFA reduced the risk of progression to
HGD/EAC by 25% (p<0.001) and risk of progression to
EAC alone by 7.4% (p=0.03) (Phoa et al. 2014). Furthermore,
88.2% achieved CRIM in the ablation group compared to
0.0% in the surveillance group (p<0.001).
In both trials, RFA was relatively safe and the most
common adverse effects were stricture and bleeding, both of
which were managed either endoscopically or conservatively. Of note, patients did report higher chest pain scores
after the procedure and in clinical practice, patients may
require home-going analgesics for several days after RFA.
Long-term follow-up demonstrates persisting efficacy and
low intestinal metaplasia recurrence rates in patients treated
Figure 11 Radiofrequency ablation (RFA). A. An area of Barrett’s
esophagus (BE) is identified endoscopically. B. Image of the Halo 360
BarrX radiofrequency catheter (Medtronic USA, Minneapolis, MN). C.
Positioning of the catheter over the area of BE prior to balloon
insufflation. D. Post-ablation view of mucosa shows proper
treatment effect. E. Focal Halo BarrX radiofrequency catheter
(Medtronic USA, Minneapolis, MN) attached to endoscope. F. Area of
suspicious BE mucosa is circled. Note the ablation device at the 12
o’clock position. G. Appropriate post-ablation changes.
with RFA for BE-dysplasia or early stage T1a treated with RFA
(Phoa et al. 2016; van Munster et al. 2021; Wolfson et al. 2022).
2. Cryotherapy
Cryoablation is a controlled, localized freezing technique
which induces tissue injury via rapid intracellular freezing
causing cell necrosis (Johnston et al. 1999). Although RFA is
generally considered first line ablative therapy for
management of dysplastic BE, cryoablation is gaining newfound appreciation.
Cryoablation currently has two delivery systems, one via
a cryoablation balloon and one via spray cryotherapy. In
cryoballoon ablation (C2 Cryoballoon System; Pentax
Medical Corporation USA, Montvale, NJ), an inflatable
balloon is passed via the working channel of a therapeutic
endoscope. Within this balloon is a spray port that can be
4 MANAGEMENT OF ESOPHAGEAL DYSPLASIA AND ESOPHAGEAL ADENOCARCINOMA 73
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manipulated with 360° of freedom and also positioned at
any point along the length of the balloon allowing for
targeting of lesions of interest. Under direct endoscopic
visualization, cryogen is sprayed on the inner surface of the
balloon which is in approximation to the lesion on the outer
surface of the balloon for approximately 5–10 seconds
(Canto et al. 2020). The balloon can be repositioned as
needed to target multiple areas.
In spray cryotherapy (truFreeze Spray Cryotherapy
System, Steris Corp., Mentor, OH), liquid nitrogen and/or
argon gas are used to deliver cryogen therapy directly to the
tissue. Given the large amount of gas that is utilized to provide this spray, placement of an orogastric tube connected
to suction is required to vent the insufflated air from the
stomach. The proceduralist then directs the spray catheter
and applies the cryogen directly to the lesion of interest.
Spray cryotherapy utilizes several freeze-thaw cycles to
induce tissue necrosis.
Cryotherapy was initially utilized as a second-line therapy
for patients who did not respond to initial RFA. Assuredly, a
systematic review and meta-analysis in patients receiving
cryotherapy as salvage therapy after RFA failure demonstrated CRIM achievement rates of 45.9% (95% CI: 32.0–
60.5%) (Visrodia et al. 2018).
Retrospective data on a cohort of patients receiving either
RFA (226 patients) or cryoballoon ablation (85 patients) as
primary ablative therapy for EET demonstrated no difference
on CRD or CRIM rates at two years (Agarwal et al. 2021).
Furthermore, cryoablation is safer and better tolerated compared to RFA, inducing less chest discomfort and fewer strictures after therapy (Agarwal et al. 2021; Visrodia et al. 2018).
As such, cryoablation may be a reasonable alternative for
first line ablative management of dysplastic BE/IMCa.
3. Argon Plasma Coagulation and Bipolar Cautery
Argon plasma coagulation (APC) is a noncontact thermal
technique where an ablation probe is introduced via the
working channel of an endoscope and thermal energy is
transferred to the target tissue via ionized argon gas without
any direct contact with the tissue. Bipolar electrocautery is
one of the earlier technologies used to ablate Barrett’s esophagus and utilizes the passage of current through tissue to
induce necrosis. In bipolar cautery, the electrode needs to be
in contact with the mucosa to be effective (Dumot and
Greenwald 2008). Both of these techniques can be utilized to
treat focal areas of residual Barrett’s mucosa, and no data exist
to suggest that one method is superior to the other. Though
currently these are used only to treat residual areas of Barrett’s
esophagus, initially these techniques were used to treat the
entire segment though these procedures were much more
tedious to perform and usually involved non-uniform injury
to the mucosa since the devices are “point” devices developed
to treat small areas of bleeding in the gastrointestinal tract.
precise
Long-term Recurrence after EET
Surveillance intervals once CRIM is achieved following RFA
are currently not evidence based. Two large, multicenter, retrospective reviews assessed recurrence of BE following CRIM
and found cumulative intestinal metaplasia recurrence rates
ranging from 19–33% within two years of achieving CRIM
(Gupta et al. 2013; Sami et al. 2019b).
Notably, the majority (approximately 75%) of recurrences
develop at the gastroesophageal junction (GEJ) while the
remainder are found in the tubular esophagus (Sami et al.
2019b). Increased risk of recurrence was found in patients with
baseline dysplasia or intramucosal carcinoma, long-segment
BE (> 3 cm), and RFA treatment performed at low volume centers (Krishnamoorthi et al. 2016).
Consequently, most proceduralists surveil CRIM patients
every 3–6 months for the first year, then extend surveillance
intervals depending on the histological and clinical scenario.
T1b Disease
T1b disease, that is, disease that invades no deeper than the
submucosa, has traditionally been managed with surgical
resection allowing for lymph node dissection to assess for
locoregional metastasis. However, recent evidence indicates
that in patients with low-risk T1b (that is, patients with en
bloc tumor resection, R0 margins, absence of lymphovascular
invasion, and well or moderately differentiated disease), EET
may carry comparable outcomes as surgery though with less
peri-procedural complications. Studies have demonstrated
that these low-risk T1b patients treated endoscopically have
similar cancer-free survival, remission, recurrence, and
remission rates compared to low-risk T1b patients treated
surgically (Ballard et al. 2016; Manner et al. 2008). Recent
guidance from the American Gastroenterology Association
suggests that low risk T1b patients should be offered endoscopic therapy as a potential curative therapy (Motomura D
2021). As such, it is reasonable to “consider” the use of EET in
low-risk T1b lesions, though in clinical practice multidisciplinary management is strongly recommended to develop a
strategy for individual patients based on their comorbidities
and expectations.
Palliative Management
In patients with heavy disease burden and incurable disease,
palliation is an important aspect of care to improve quality of
life. While non-curative intent esophagectomy can be pursued
in selected patients, this is rarely done given the complexity and
morbidity of this surgery. For patients with considerable dysphagia, as well as those with slow, oozing blood loss from a
tumor, endoscopic stenting can relieve obstruction or provide
tamponade in patients with inoperable esophageal cancer
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