14 
Neoplastic Disease of the Esophagus
BENIGN LESIONS OF THE ESOPHAGUS
Benign tumors of the esophagus are rare, accounting for less than 10%
of all esophageal tumors and occurring with a prevalence of 0.5%.
However, autopsy studies indicate that benign lesions occur in 8% of
the adult population and may account for the higher frequency of
individuals that remain undiagnosed and asymptomatic. Esophageal
carcinoma is 50 times more prevalent than benign lesions. Since the
advent of computed tomography (CT), tumors have been discovered
more frequently (Fig. 14.1). Benign esophageal lesions can be classified
either histologically according to their involvement in the epithelial or
subepithelial tissue layers or by endoscopically visualized characteristics
such as flat, raised, or cystic features.
The histologic frequency of epithelial lesions occurs most commonly
to least, including glycogenic acanthosis, heterotopic gastric mucosa,
squamous papilloma, hyperplastic polyp, ectopic sebaceous gland, and
xanthoma. Subepithelial lesions occur most frequently with hemangioma,
leiomyoma, and granular cell tumor. (Leiomyomas are the most common
subepithelial lesions and are described in another section). (Gastro-
intestinal stromal tumors [GISTs] are benign and malignant and leio-
myosarcomas are malignant; these subepithelial lesions are described
in rare malignant lesions of the esophagus.) The benign lesions in this
section are categorized by endoscopic features.
Clinical Picture
Benign lesions of the esophagus are rarely symptomatic. They are usually
found incidentally at the time of upper endoscopy or barium esopha-
graphy that is performed for another reason. They are unlikely to be
malignant or a precursor to malignancy. They have been classified as
raised, flat, or cystic.
Diagnosis, Treatment, and Management by Lesion
Benign esophageal lesions can be classified as raised, flat, or cystic. Most
can be diagnosed based upon their endoscopic appearance, findings
on routine biopsy, and, in the case of submucosal lesions, by endoscopic
ultrasound (EUS).
Raised Lesions
Schwannomas are rare benign tumors derived from Schwann cells in
the peripheral nerves. Microscopically, they are diagnosed by lymphoid
cuffing, nuclear atypia, and the presence of spindle-shaped cells. Rarely
do they cause dysphagia, and malignant schwannomas are highly unusual.
Small lesions may be enucleated and larger ones may be surgically
resected.
Lymphangiomas arise from lymphatic tissue malformations. They
are rare in the esophagus, occurring most frequently in patients younger
than 2 years of age. Endoscopy reveals translucent yellow compressible
mass structures less than 0.5 cm. Biopsy may be negative, as they are
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Neil R. Floch
submucosal, but EUS is diagnostic. Histology reveals dilated endothelial
cavities with eosinophilic material lined by flat endothelial cells. Treat-
ment is with observation unless they grow to 4 to 5 cm. They are resected
by band-assisted mucosectomy, endoscopic submucosal dissection (ESD),
or by using a CO2 laser.
Esophageal hemangiomas occur in 0.04% of autopsies. Most are
cavernous and rarely involve capillary lesions. Usually they occur alone,
but multiple lesions are seen in disorders such as Osler-Weber-Rendu
disease, Klippel-Trénaunay syndrome, or congenital blue rubber bleb
nevus syndrome. They are found incidentally on endoscopy and are
nodular, soft, and bluish-red; they blanch when compressed. These
lesions have been confused with Kaposi sarcoma. Rarely, they may bleed
or cause dysphagia, which is the only reason to resect them endoscopi-
cally or surgically.
Fibrovascular polyps arise from nodular mucosa and take up 0.5%
to 1.0% of all benign esophageal lesions; most are located proximally
and 75% occur in men. They are most common in the upper esophagus
and are usually attached to the cricopharyngeus. They are a conglomer-
ate of fibrous, vascular, and adipose tissues with a squamous epithelium.
Histologically they are inclusive of different fibromas, fibrolipomas,
myomas, and lipomas. They are rare, accounting for 0.5% to 1% of all
benign esophageal lesions. Fibrovascular polyps rarely cause symptoms
of dysphagia, chronic cough, nausea, and vomiting. They can grow to
20 cm and prolapse into the larynx, causing airway obstruction. Gastric
prolapse can result in ulceration and bleeding. If fibrovascular polyps
are symptomatic, they are removed. They usually have stalks that are
vascular and can be detected by EUS. Lesions can be removed endo-
scopically if an Endoloop is used to ligate the nutrient vessels.
Approximately 10% of granular cell tumors arise in the gastro-
intestinal (GI) tract; the esophagus is involved in 65% of such cases.
Granular cell tumors of the esophagus are rare, occurring in 0.033%
of all individuals at endoscopy and composing 1% of benign esophageal
tumors. Approximately 60% of those affected are men. Endoscopic
exam reveals sessile yellowish-white lesions with normal mucosa with
a thick consistency. Of all, 90% are solitary with histologically large
polygonal cells containing eosinophilic granules. They are believed to
be of neural origin, as they resemble Schwann cells under electron
microscopy and are positive for S100 protein. Deeper tunneling biopsies
are needed to diagnose these deeper lesions. The larger the lesion, the
faster the growth and the higher the malignant potential. Lesions of
4 cm and greater compose all of the 4% of malignant lesions that dem-
onstrate infiltrative growth. These lesions must therefore be removed,
which is usually possible with the techniques of classic biopsy, endoscopic
mucosal resection or submucosal tunnel endoscopic.
Esophageal adenomas usually arise in segments of Barrett esophagus.
They are dysplastic, polypoid, or nodular lesions that may reach 1.5 cm
and may be multiple. They may be found in conjunction with esophageal
adenocarcinoma; therefore adjacent areas must be biopsied along with
73
74 SECTION I Esophagus

Pedunculated
lipoma in
esophagus

Laryngoscopic view

Intramural
leiomyoma

Esophagoscopic view

Fig. 14.1  Benign Neoplasms.

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 CHAPTER 14  Neoplastic Disease of the Esophagus
narrow-band imaging and chromoendoscopy. If surrounding Barrett
is detected, patients are treated as having Barrett esophagus with dys-
plasia. If there is no Barrett, lesions smaller than 1 cm are removed
endoscopically and those greater than 1 cm with high-grade dysplasia
(HGD) undergo mucosal resection or surgery.
Inflammatory fibroid polyps are composed of many lesions with
reactive blood vessels, fibroblasts, and inflammatory cells such as ham-
artomas, inflammatory pseudopolyps, and eosinophilic granulomas.
They are extremely rare, at 3 per million cases, and less likely to be
found in the esophagus than any other section of the intestine. They
are believed to be caused by acid reflux.
Inflammatory fibroid polyps are benign, incidentally found, reactive
and inflammatory, with a connective tissue stroma and eosinophilic
infiltrate. They occasionally cause dysphagia and hemorrhage and may
grow to 9 cm, at which point endoscopic snare removal or surgery is
warranted.
Esophageal papillomas are rare, with an incidence up to 0.04%,
benign epithelial with microscopic fingerlike projections of squamous
cells, connective tissue, and blood vessels. The cause of these lesions is
unknown but believed to be an underlying inflammatory condition.
Approximately 70% are located in the distal third of the esophagus and
associated with reflux, esophagitis, or mechanical manipulation. Sub-
stances such as benzopyrene and nitrosamines may be a cause as well.
Human papillomavirus (HPV) is associated in up 5% to 46% of cases
and may be a cause. Sexual transmission may be the route of spread,
as serotypes 6 and 11 are commonly found in the human oropharynx
and genital tract. HPV is documented to be associated with cancer of
the larynx and cervix. HPV is also involved with esophageal squamous
cell carcinoma, along with papillomas. Malignant transformation related
to HPV infection has not been proven.
Esophageal papilloma is most common in individuals in their 50s,
with a mostly equal gender frequency. Most lesions are solitary, but
rarely up to 10 are found. Endoscopy reveals small whitish-pink wart-
like exophytic projections with a differential diagnosis of verrucous
squamous cell carcinoma, granulation tissue, and papillary leukoplakia.
Papillomas are found more frequently in patients with tylosis, acantho-
sis nigricans, and Goltz syndrome. Large lesions can cause dysphagia,
but most may be endoscopically resected with forceps when they are
1 cm or less in size; mucosal resection can be performed when they
are larger.
Flat Lesions
Heterotopic sebaceous glands are found in ectodermal tissues such as
the genitalia, parotid gland, palms, soles, eyelashes, lips, mouth, and
tongue; they are rare in the esophagus. They are unlikely congenital,
resulting from heterotopic mucosa or reactive metaplasia of the esopha-
gus. Endoscopy reveals yellowish-gray plaquelike lesions occurring in
clusters of up to 100 in one area. Histology reveals groups of sebaceous
cells in the lamina propria. Lesions may be observed as they have no
malignant potential.
Glycogen acanthosis occurs in 3.5% to 15% of all endoscopies and
30% of barium esophagrams. There are multiple round protrusions 2
to 15 mm in size in the midesophagus. The pathogenesis is unclear but
has been associated with Cowden disease. Most lesions present in patients
in their 40s and 50s, mainly in men, and increase in number and fre-
quency with age. Endoscopic mucosal biopsies reveal plaques of hyper-
plastic squamous epithelium with glycogen in the cells.
Esophageal parakeratosis on endoscopy appears as whitish mem-
branous linear plaques. Histologically they manifest epithelial acanthosis,
basal hyperplasia, and parakeratosis covered by nonnucleated squamous
cells. Esophageal parakeratosis has been associated with esophageal and
head and neck carcinoma but is not premalignant and represents 40%
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75
of new squamous cell cancers (SCCs) of the head and neck. It is also
associated with submucosal fibrosis in smokers and betel nut chewers.
Esophagitis dissecans superficialis is a rare condition involving
sloughing of mucosal epithelium and characterized by tubular casts
within the esophageal lumen. It occurs with pemphigus vulgaris in 5%
of patients or as a complication of rigid endoscopy with esophageal
dilation, ingestion of oral bisphosphonates, and celiac disease.
An esophageal inlet patch is heterotopic gastric mucosa of the upper
esophagus (HGMUE) occurring with a prevalence of 5% of adults by
autopsy and 11% at endoscopy. These lesions are most commonly found
in individuals their 50s and are most often located in the proximal 3 cm
of the esophagus. Patches range from 2 mm to 4.5 cm in size and can
occur alone or be multiple. They are red, velvety, and flat but rarely raised
or polypoid. Microscopically they have fundic-type of gastric mucosa
with some parietal cells and evidence of an inflammatory infiltrate.
The origin of the esophageal inlet patch is unclear; it is unknown
whether they develop from “heterotopic” gastric mucosa or are embry-
onic. They are frequently found in children and their prevalence does
not increase with age. Immunohistochemical analysis reveals that the
cells are reactive to glucagon, which is an embryonic finding that is not
noted in mature gastric cells. Controversy exists as to their origin, which
may be the failure to replace the columnar lining of the esophagus with
squamous epithelium during maturation as well as the belief that inlet
patches are more similar to Barrett mucosa, which has been believed
to be an acquired lesion. Trauma to the lining with rehealing by squa-
mous mucosa has also been suggested.
Clinical problems have been attributed to the inlet patches by asso-
ciation. Tracheoesophageal fistula has occurred at the site of an inlet
patch secondary to acid production with perforation. Patients with
strictures, rings, and webs that have a patch frequently have dysphagia.
Patches have been suggested as a cause of Plummer-Vinson syndrome.
Helicobacter pylori grows in the patch in 19% to 73% of those that are
H. pylori–positive in the stomach, indicating that the esophagus may
be a reservoir. Barrett esophagus has been found in the distal esophagus
of 20% of individuals with a patch. Esophageal and laryngeal adeno-
carcinoma has been found arising from inlet patches in the upper
esophagus. Symptoms of globus, cough, and laryngopharyngeal reflux
have been associated with patches, and improvement in globus symp-
toms has occurred after argon plasma ablation. Diagnosis is made on
endoscopic visualization and confirmed by biopsy. Patches are benign
and are treated only if symptomatic. Risk factors for malignancy are
unclear. Endoscopic ablation and treatment a PPI can result in replace-
ment with squamous mucosa.
Cystic Lesions
Cystic lesions of the esophagus occur in 1 in 8200 patients and most
commonly are bronchogenic or originate from the GI tract. Broncho-
genic cysts are lined by columnar cells and contain a milky-white sub-
stance, smooth muscle, hyaline cartilage, and seromucous glands.
Enterogenous cysts are lined with columnar, bowel, or cuboidal cells
or gastric mucosa and contain green mucus. They occur secondary to
abnormal embryonal budding; they are located periesophageally or
may be intrapulmonary and average 4 cm in size. Endoscopy and barium
esophagraphy reveal protruding masses with normal mucosa, but EUS
must be performed to confirm their presence. If dysphagia is present
from a large cyst, surgical resection is indicated. These lesions do not
have malignant potential.
Duplication cysts are congenital and are found in 1 in 8000 live
births. They are rarely found in the esophagus, where they are located
within the esophageal wall and are covered by two muscle layers covered
by squamous epithelium. The cysts contain gastric mucosa in 33% of
cases but they may also contain pancreatic mucosa. They are usually
76 SECTION I Esophagus
located to the right side of the esophagus. There is no cyst-esophageal
communication in 80%, but 20% are parallel with esophagus and do
communicate. They usually cause symptoms, resulting in 80% being
diagnosed in patients younger than 2 years of age. Compression of
adjacent structures causes dysphagia in 70%, epigastric pain in 20%,
and mediastinal pain in 10% as well as respiratory symptoms and occa-
sional hematemesis. Symptoms are an indication for surgical resection.
Malignancy is rare.
Course and Prognosis
Benign lesions of the esophagus are rarely malignant or have malignant
potential. Only in rare instances do lesions transform; therefore most
patients have a normal life expectancy with minimal symptoms. Man-
agement of benign lesions is dependent on accurate diagnosis to rule
out other potentially malignant lesions. Symptomatic lesions may warrant
resection, but most benign lesions can be observed. Few lesions have
the potential to progress to malignancy, although they may be markers
for an increased risk of malignancy. In themselves, however, they do
not have malignant potential.
Esophageal schwannomas have a low risk, but symptomatic lesions
should be enucleated or removed by partial esophagectomy. When
esophageal parakeratosis is found, patients should be referred to a head
and neck specialist for a careful exam of the proximal esophagus, mouth,
and pharyngeal structures because the findings can be associated with
head and neck malignancies. Esophageal papilloma should be removed
because of their association with esophageal squamous cell carcinoma.
Esophageal adenomas are almost always found in areas of Barrett
esophagus, and such patients should be treated similarly to any other
individual with Barrett esophagus. Granular cell tumors have a malignant
potential, and all lesions larger than 1 cm should be resected either
with biopsy forceps or endoscopic mucosal resection. Inlet patches and
duplication cysts have a low likelihood of malignant transformation
and do not warrant treatment or surveillance.
BENIGN NEOPLASMS OF THE
ESOPHAGUS: LEIOMYOMAS
Esophageal leiomyomas account for 0.6% of all esophageal neoplasms.
Leiomyomas are the most common benign tumor of the esophagus,
accounting for two-thirds of all benign esophageal tumors. They typi-
cally occur in individuals aged 20 to 50 years; 80% are intramural, 33%
occur in the middle, and 56% are found in the distal third of the esopha-
gus. In 13% of patients, intraluminal leiomyomas are annular or com-
pletely encircle the esophagus. Leiomyomas may extend into the stomach
as well. Half the tumors are smaller than 5 cm. They are usually firm,
encapsulated, rubbery, and elastic and typically are not pedunculated
because they are muscular in origin and are covered by the mucosa.
They are usually isolated but may appear in multiples in 5% of such
cases. Malignant degeneration of leiomyomas is extremely rare. Patho-
logic examination of cells reveals a positivity for smooth muscle actin
and negativity for the proteins CD34 and CD117. Leiomyomatosis with
multiple leiomyomas along the entire esophagus is associated with Alport
syndrome. Esophageal leiomyomas are also associated with multiple
endocrine neoplasia (MEN) type 1.
Clinical Picture
Esophageal leiomyomas rarely cause symptoms in those with an average
tumor size of 0.4 cm. The majority of leiomyomas have been discovered
incidentally during evaluation for dysphagia or in the course of autopsy.
Large tumors that average 5.2 cm may be symptomatic. The most
common presenting symptoms for these leiomyomas are dysphagia
(71%), pain (50%), weight loss (15%), and nausea or vomiting (12%).
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Other symptoms include odynophagia, reflux, regurgitation, respiratory
symptoms, shoulder pain, chest pain, hiccups, and anorexia. Larger
pedunculated tumors may occlude the esophageal lumen, causing dys-
phagia, or may be aspirated into the trachea. Bleeding into the lumen
may occur from ulceration of lesions such as angiomas.
Diagnosis
A large endoluminal tumor may be visualized on barium esophagraphy
as a concave mass with smooth borders. CT is 91% sensitive and excel-
lent for the visualization of smaller lesions. If obstruction has occurred,
proximal dilation of the esophagus may be detected. Endoscopy is most
sensitive and may determine the presence, location, and integrity of
the mucosa. The lesions are identified as mobile submucosal masses.
Endoscopy should be performed to rule out malignancy. Normal mucosa
over a leiomyoma frequently rules out malignancy. In patients with
leiomyoma, biopsy is contraindicated because it may cause infection,
bleeding, or perforation. It also increases the risk for a mucosal tear at
surgical excision. Brush cytology should be performed to establish a
diagnosis. If an ulcer is identified on endoscopy, biopsy should be
performed.
The best method of classification is EUS, which is capable of delin-
eating five layers of the esophageal wall. These layers are detected by
alternating hyperechoic and hypoechoic transmissions. The superficial
or inner, layer is hyperechoic and the remaining layers alternate as
described; deep mucosa (second layer), submucosa (third layer), and
muscularis propria (fourth layer). Periesophageal tissue is seen as the
fifth layer. Ultrasound is limited in determining the nature of the tumor
and whether it is malignant.
Treatment and Management
Most patients without symptoms can be managed periodically with
barium swallow because of the benign nature of the lesions. Surgical
excision should be performed for symptomatic lesions, those greater
than 5 cm, those increasing in size, or lesions with mucosal ulceration.
Resection is the definitive method to confirm that a tumor is benign
or malignant.
Traditionally transthoracic excision by thoracotomy was the most
common approach, as lesions of the middle third of the esophagus are
accessed through a right thoracotomy whereas those in the distal third
are addressed with a left thoracotomy. Enucleation of the mass with
primary closure is the preferred technique. Benign tumors larger than
8 cm may require esophagectomy with gastric pull-up, using thora-
cotomy, thoracoscopy, or laparoscopy.
Lesions may preferably be removed by combined esophagoscopy
and thoracoscopy or laparoscopy. Endoscopic removal is being performed
but remains experimental. Initial studies indicate that endoscopic sub-
mucosal tunnel dissection (ESTD) is safe and effective and has advantages
over ESD, such as shorter operating times, hospital stays, and time
needed for healing. There is no significant difference in the incidence
of complications when both techniques are compared.
Course and Prognosis
Results of leiomyoma enucleation are excellent, and recurrence is rarely
reported. Symptoms resolve with tumor excision. Overall the prognosis
is excellent because the lesions are benign. Minimally invasive techniques
result in minimal morbidity and rare mortality.
MALIGNANT NEOPLASMS: UPPER AND MIDDLE
PORTIONS OF THE ESOPHAGUS
Both carcinomas and SCCs occur in the upper third of the esophagus.
Carcinomas are more common in women (Fig. 14.2), but the upper
 CHAPTER 14  Neoplastic Disease of the Esophagus 77

Esophagoscopic
view

Ulcerated
carcinoma

Nodular carcinoma
obstructing mouth
of esophagus

Squamous cell carcinoma

Esophagoscopic view

Ulcerative, Fungating
infiltrative carcinoma
carcinoma

Fig. 14.2  Malignant Tumors: Upper and Middle Portions of the Esophagus.

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78 SECTION I Esophagus
third of the esophagus is the least common site for them to occur, as
5% to 6% of esophageal cancers arise in the cervical portion. Anatomi-
cally, this area is 6 to 8 cm long, beginning at the hypopharynx and
commencing at the thoracic inlet or suprasternal notch. At the time of
diagnosis, most patients with cancer of the cervical esophagus have
locally advanced disease with extension to the hypopharynx. There is
an association in up to 14% between SCC of the head and neck located
in the oral cavity, oropharynx, hypopharynx, larynx, lung, or esophagus
with synchronous or metachronous SCC of the esophagus. Cervical
esophageal adenocarcinoma and SCC share common risk factors of
smoking and/or alcohol usage.
Clinical Picture
Most commonly patients with cervical esophageal cancer will present
with weight loss and dysphagia. Up to 24% will have hoarseness at the
time of presentation which results from recurrent laryngeal nerve involve-
ment by the tumor. Dysphagia may be the first symptom, and its pres-
ence should initiate a thorough evaluation. Aspiration may be a late
symptom.
Diagnosis
Evaluation should include flexible laryngoscopy and esophagoscopy to
evaluate the upper respiratory and GI tracts and to determine the loca-
tion of the lesion and local disease spread and to exclude a synchronous
malignancy of the head and neck. If a lesion is encountered, biopsy
should be performed. CT or magnetic resonance imaging (MRI) may
show the soft tissue lesion more accurately. Determination of the need
for resection or radiation therapy (RT) may be made on the basis of
this test. Preoperative bronchoscopy with biopsy and brush cytology
may be performed as the last procedure in the staging workup in patients
with locally advanced nonmetastatic disease of the cervical esophagus.
Bronchoscopy is superior to CT in that it may reveal airway invasion
in up to 10% of patients, excluding surgery as the most appropriate
treatment option.
Treatment and Management
Treatment of SCC of the esophagus is similar to treatment of SCC of
the head and neck. Locally advanced malignancy of both SCC and
adenocarcinoma is usually treated with a combination of radiation and
chemotherapy with the advantage of organ preservation with the same
overall survival, local failure-free survival (FFS), and distant FFS as
proximal esophageal surgical excision. Major morbidity is avoided
without surgery. The recommended treatment is usually cisplatin che-
motherapy given with RT.
Surgery is an option for individuals found to have a malignancy at
an early stage of the disease or for patients who fail chemotherapy and
radiation. Cervical esophageal SCCs are usually difficult to resect and
often require removal of part or all of the pharynx, larynx, and thyroid
as well as the proximal esophagus. The most aggressive resection is a
complete pharyngo-laryngo-esophagectomy (PLE) requiring cervical,
abdominal, and thoracic incisions and a tracheostomy. A gastric pull-up
or jejunal interposition with a pharyngeal anastomosis reestablishes GI
continuity. Myocutaneous flaps or skin grafts may be necessary to close
the resected areas and spaces. Bilateral radical dissections are performed
to remove lymph nodes in the neck and superior mediastinum. Surgical
resection is contraindicated if there is involvement of the prevertebral
fascia, posterior larynx, membranous trachea or encasement of major
neurovascular structures.
Course and Prognosis
The 2-year results of cervical esophageal cancer treated primarily with
RT versus surgery with or without follow-up treatment with chemo-
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therapy or surgery for local FFS, distant FFS, and overall survival were
70% versus 69%, 74% versus 63%, and 49% versus 51%, respectively.
Although results were similar, the mortality of RT versus surgery was
significantly better, 4% versus 13% for surgery. Patients who undergo
complete resection usually succumb to metastatic disease. Unfortunately
80% of patients fail after radiation, and 20% require palliation to control
local disease.
MALIGNANT NEOPLASMS: LOWER END OF
THE ESOPHAGUS
Malignancy of the esophagus accounts for 5% of all GI cancers (Fig.
14.3). Squamous cell carcinoma is the most common esophageal malig-
nancy worldwide. Adenocarcinoma is the most common malignancy in
Western countries and has continued its 20-year increase in incidence,
especially in white men in the sixth decade of life. The black/white male
ratio is 3: 0 for adenocarcinoma; the reverse is true for SCC. The inci-
dence of superficial esophageal cancers limited to the mucosa or sub-
mucosa has increased globally; this be attributed to more aggressive
endoscopic surveillance in patients with Barrett esophagus. It is not
surprising that now 85% of cancers occur in the middle to distal esopha-
gus. Recommendations of routine surveillance and aggressive surgical
treatment for patients with HGD have been instituted to discover and
treat esophageal cancer early.
Patients with achalasia, caustic strictures, Barrett esophagus, or gas-
troesophageal reflux disease (GERD) are predisposed to adenocarcinoma;
those who drink alcohol, smoke, or have tylosis or Plummer-Vinson
syndrome are predisposed to SCC. Unfortunately, despite best attempts,
only 5% of patients seek treatment while they have local disease. Five-
year survival ranges from 16% to 32% of patients.
Adenocarcinoma is thought to develop from metaplastic columnar
mucosa or Barrett esophagus, which occurs in the distal esophagus in
patients with GERD. Distal esophageal and proximal gastric malignan-
cies are similar. Bile, pancreatic juice, pepsin, and gastric acid may cause
a transformation of squamous cells to columnar cells. In time, meta-
plastic cells may be transformed from dysplastic to malignant. Barrett
mucosa is almost always present in those with adenocarcinoma. Heli-
cobacter pylori infection may be protective for adenocarcinoma but can
cause gastritis, ulcers, and lymphoid tumors. Adenocarcinomas and
SCCs invade the mucosa and submucosa, spreading quickly up the
length of the esophagus. Other uncommon lower-end esophageal malig-
nancies include adenosquamous carcinoma, small cell cancer, and
lymphoma.
Clinical Picture
Early adenocarcinomas that develop from Barrett esophagus in the
distal esophagus may be completely asymptomatic and be discovered
only at the time of endoscopy. Most patients with tumors have initial
symptoms of dysphagia, odynophagia, and weight loss. Presentation
with luminal obstruction indicates a poor prognosis, as does progressive
dysphagia. As a tumor invades, there may be pain, hoarseness from
recurrent laryngeal nerve involvement, superior vena cava syndrome,
malignant pleural effusions, hematemesis, or bronchotracheoesophageal
fistulas.
Diagnosis
Diagnosis is not limited to determining the presence of malignancy
and must include determination of its extent. History and physical
examination suggest the disease, but diagnosis is usually made by upper
endoscopy with biopsy. Early lesions include plaques, nodules, or ulcer-
ations. The visual characteristics of more advanced tumors are usually
highly suspicious and include: ulcerated or circumferential masses of
 CHAPTER 14  Neoplastic Disease of the Esophagus 79

Adenocarcinoma of cardiac end of stomach infiltrating esophagus submucosally

Esophagoscopic view

Primary carcinoma of lower end of esophagus

Fig. 14.3  Malignant Tumors: Lower End of the Esophagus.

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80 SECTION I Esophagus
very large ulcers of the esophagus. The biopsy is diagnostic in over
90% of cases.
Investigations may include barium esophagraphy to determine
mucosal extent, EUS with or without fine-needle aspiration (FNA) to
determine depth of invasion, CT or MRI to determine local invasion
and lymph node involvement, bronchoscopy to determine invasion of
the airway, and positron emission tomography (PET) to detect distant
metastases. Diagnostic mediastinoscopy, laparoscopy, or thoracoscopy
may determine metastasis to the lymph nodes.
Once the diagnosis of esophageal cancer has been established, staging
is performed, as it is the best predictor of survival. The tumor-node-
metastasis (TNM) classification of the American Joint Committee on
Cancer (AJCC) and the Union for International Cancer Control (UICC)
for esophageal cancer is used universally (eighth edition, 2017). These
are the most current staging systems. (Visit http://www.annalscts.com/
article/view/14237/14430 [Accessed August 2018].)
Local and distant disease presence must be assessed. Local disease
assessment is performed best with the use of EUS as it is superior to
CT for determining depth of tumor wall invasion, lymph node involve-
ment, and characteristics of adjacent structures. US has the added benefit
of facilitating endoscopic-guided FNA of lymph nodes and mediastinal
lesions. US is capable of delineating four layers of the esophageal wall
and has 90% and 85% accuracy, respectively, for measuring tumor and
lymph node status. Assessment of distant metastases is performed by
obtaining a contrast-enhanced CT of the neck, chest, and abdomen.
Whole-body integrated fluorodeoxyglucose (FDG) PET/CT may also
be used as well as EUS, and exploratory laparoscopy. FDG-PET/CT
scans are more sensitive than CT scans and more successful at detecting
metastases. EUS with needle biopsy of the liver or aspiration of abdomi-
nal ascites may also be performed. Laparoscopy and laparoscopic US
may be superior to CT and EUS and can avoid noncurative laparotomies
in 11% to 48% of patients. However, it is usually reserved for suspected
clinical T3/T4 adenocarcinoma in the abdominal esophagus when the
lesion is potentially resectable or metastatic disease cannot otherwise
be ruled out.
Treatment and Management
Over the past several decades the incidence of adenocarcinoma of the
distal esophagus has increased as squamous cell carcinoma has decreased,
but the operative treatment of both has remained the same. Esophageal
cancer tends to spread early and rapidly, as two-thirds of patients have
lymph node metastases at presentation. Aggressive multimodal therapy
is necessary to achieve control. If cure is not possible, palliation with
attempts at maintaining nourishment and quality of life is paramount.
The TNM classification aids in determining the feasibility of surgical
resection and treatment options.
Use of the two major treatment options for early esophageal cancer—
surgical esophagectomy and endoscopic resection (ER)—is dependent
on procedural risk. Choice depends on submucosa or muscularis mucosa
invasion (M3 tumors) and lymphovascular invasion, which increase
the risk for lymph node metastases. Signs of submucosal growth include
poor lifting and inability to suction during ER. Determining factors in
treatment include lesion size, lymphovascular invasion, histologic grade,
Barrett mucosa, varices, comorbidities, age, treatment availability, and
patient desire.
Cure is maximized in submucosal (T1b) cancers treated with esopha-
gectomy. In otherwise healthy patients with M1 or M2 tumors and
well-differentiated M3 tumors without lymphovascular invasion, esopha-
gectomy is best. ER is an alternative in poor surgical candidates in
experienced centers. If lymphatic invasion is present, PDT or radiofre-
quency ablation (RFA) therapy may be used in conjunction with ER.
Esophagectomy should be performed for persistent positive margins
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after ER, recurrence, and long lesions not amenable to ER. RT and/or
chemoradiotherapy is performed for otherwise ER candidates who have
varices, had previous perforation, or have severe cervical spine disease
that make them poor candidates.
Other than superficial early esophageal cancers, total esophagectomy
to obtain free margins and to clear all mediastinal lymph nodes is the
standard first line of therapy and may be the only modality necessary
for those with T1-2 N0 M0 disease. More recently, surgical resection
has been extended to localized T1 to T3 lesions and certain T4a lesions
that may have invaded structures such as pleura, pericardium, or the
diaphragm. The mortality rate associated with surgery is 3%.
Lesions of the thoracic esophagus are usually removed by a total
thoracic esophagectomy with cervical esophagogastrostomy. A radical
two-field lymph node dissection is performed with placement of a
feeding jejunostomy. The tri-incisional approach consists of a right
posterolateral thoracotomy or thoracoscopy with a laparotomy or lapa-
roscopy. An en bloc excision with gastric dissection and mobilization
is performed. There is complete dissection of abdominal and mediastinal
lymph nodes and a left neck incision and cervical anastomosis. Cancers
of the GEJ are approached by total esophagectomy with cervical esopha-
gogastrostomy with a partial gastrectomy or a minimally invasive Ivor-
Lewis procedure, with a thoracic esophagogastrostomy. Randomized
trials do not support any one technique over another.
In patients with T1N0 esophageal or GEJ adenocarcinoma or SCC,
surgery alone is strongly supported as the only treatment needed, but
chemoradiotherapy is an alternate option for patients who are not
surgical candidates. The type of chemotherapy remains low-dose weekly
carboplatin plus paclitaxel. An alternate option is two treatments of
cisplatin plus fluorouracil (FU). Neoadjuvant chemoradiotherapy, com-
bined with surgery for patients with clinical stage T2N0 tumors dem-
onstrated a survival benefit in three clinical trials in patients with
adenocarcinoma. Resection alone is considered for those with 2N0 SCCs.
In patients with surgically resected T2N0 adenocarcinomas that are
poorly differentiated, have lymphovascular or perineural invasion, arising
in patients at or younger than 50 years of age, adjuvant chemotherapy
or chemoradiotherapy are options. These options are considered only
in SCC if the margins are positive. In resected T3 or pT4 adenocarci-
nomas, independent of node status, in patients who are not treated
with neoadjuvant therapy, postoperative adjuvant therapy is recom-
mended. Chemoradiotherapy is given for nonsurgical candidates.
Chemoradiation alone for complete responders with SCC is an option
but is known to have a higher rate of locoregional control.
For patients who are potential surgical candidates who have SCC
and an endoscopically documented complete response, definitive chemo-
radiotherapy is also an option, but surgery is recommended if the patient
remains a candidate. In the similar situation with adenocarcinoma,
surgical resection remains recommended.
Palliation of metastatic disease is reserved for those with any T, any
N, M1 disease. Chemotherapy is the treatment of choice, but radiation
may be added. Endoscopic metal stents, photodynamic tumor ablation
with laser, metalloporphyrin, and brachytherapy may be used for pal-
liation of obstruction. Radical surgery to bypass obstruction is rarely
performed.
Other tumors of the esophagus are usually treated by surgery. Most
patients with small cell carcinoma have metastatic disease at presenta-
tion and rarely survive a year. Therapy is palliative, but surgery and
chemoradiation may result in a rare cure. Melanomas of the esophagus
have a worse prognosis than cutaneous disease because they are dis-
covered late. Surgery is performed but rarely helpful. Results after surgical
excision of salivary tumors are worse than after excision of head and
neck tumors. Lymphomas develop after direct spread from other organs.
Primary lymphomas usually develop in patients with immune disorders.
 CHAPTER 14  Neoplastic Disease of the Esophagus
Sarcomas may develop, but not from the degeneration of benign tumors
and are removed by surgery. Metastatic lesions of the breast and lung
and melanomas are most common and are treated by palliation.
Course and Prognosis
Patient survival depends directly on disease stage. Five-year survival
rates for esophageal cancer are 78.9% for stage I, 37.9% for stage IIA,
27.3% for stage IIB, 13.7% for stage III, and 0% for stage IV.
RARE MALIGNANCIES OF THE ESOPHAGUS:
GASTROINTESTINAL STROMAL TUMORS
AND LEIOMYOSARCOMAS
The two most common types of malignancies of the esophagus are
squamous cell carcinoma and adenocarcinoma. Less commonly, esopha-
geal leiomyosarcoma accounts for less than 1% of all malignant esopha-
geal tumors, and only 165 cases have been reported. Leiomyosarcomas
grow slowly and metastases occur late, giving them a better prognosis
than squamous cell tumors and carcinoma. Esophageal GISTs are the
most common mesenchymal neoplasms in the digestive tract, but
esophageal GISTs are extremely rare. GISTs develop from the interstitial
cells of Cajal, which are located in the muscle layer. The cells overexpress
the tyrosine kinase receptor KIT.
Clinical Picture
Esophageal GISTs accounts for only 1% of all neoplasms found in the
GI tract. Their clinical, endoscopic, and radiographic appearance is
similar to that of leiomyomas. The esophagus lacks a serosa layer and
has a limited blood supply, making GISTs in this location more difficult
treat with surgical resection. Mesenchymal tumors are most commonly
located from the middle to the distal esophagus. They are usually
asymptomatic until they grow to a large size and cause dysphagia. The
majority of mesenchymal tumors located in the esophagus are leio-
myomas and occur most commonly in men. Leiomyosarcomas are
significantly less common. The treatment of GISTs and leiomyosarcomas
of the esophagus depends upon the preoperative diagnosis, tumor loca-
tion, size, presence of metastases, and complications such as obstruction,
perforation, or hemorrhage.
Diagnosis
Diagnosis of leiomyosarcoma is usually made incidentally at the time
of a barium esophagram or endoscopy. The lesions are round and sub-
mucosal, with intact mucosa. They have a rubberlike consistency and
do not ulcerate or bleed. A TNM classification system is used for soft
tissue sarcomas of the abdominal viscera, but there are no prognostic
stage groupings.
GISTs enhance more than leiomyomas on contrast CT and FDG-PET.
Definitive diagnosis is made and differentiated from leiomyomas by
EUS-guided FNA with immunohistochemical staining for KIT. Lesions
that are well circumscribed, submucosal, larger than 2 cm, enlarging,
or FDG-enhancing are suspicious for a GIST. Preoperative biopsies may
preclude surgery for chemotherapy treatment or nonresectable, meta-
static disease.
Treatment and Management
ER of leiomyosarcoma submucosal lesions is recommended as it is
difficult to distinguish between a well-differentiated leiomyosarcoma
and leiomyoma histologically. Resection by endoscopic snare polypec-
tomy is performed on lesions less than 2 cm in size that are polypoid,
have a round protrusion, and are elevated. Larger or flat lesions must
be enucleated with an electrocautery snare and coagulated after removal
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81
of the overlying mucosa. Small lesions are rarely found to be malignant.
Alternatively, small asymptomatic lesions may be followed with EUS
at 6 months, 1 year, and less frequently if no changes are found. Surgical
excision is reserved for lesions that become symptomatic, grow bigger
than 1 cm, develop structural changes, or when there is suspicion of a
malignancy. Despite stability, lesions greater than 2 cm should be excised.
Local excision is usually adequate to remove all lesions. Total or partial
esophagectomy may be required.
An algorithmic approach to management of gastric GISTs based
upon size and EUS appearance has been proposed, but one does not
exist for esophageal lesions. The recommended treatment is surgical
resection, including the pseudocapsule with negative margins preceded
by neoadjuvant treatment with imatinib. Neoadjuvant imatinib is given
to decrease the size of the tumor and prevent locoregional recurrence.
Patients with locally advanced tumors that may not be completely
resected are good candidates for neoadjuvant imatinib. GISTs of the
esophagus, especially located at the LES may undergo imatinib treat-
ment in order to reduce the tumor burden and allow for a segmental
resection instead of total esophagectomy. Patients are treated for 6 to
12 months with periodic barium esophagram or CT to evaluate changes
in tumor size.
Despite the very small risk of metastases, controversy exists as to
whether GISTs less than 2 cm in size should be observed, resected, or
resected only if they increase in size. Follow-up with EUS is recom-
mended for nonoperative lesions. Canadian guidelines, for example,
recommend excision of all GISTs irrespective of size because of metastatic
risk. GISTs 2 cm or greater in size are surgically excised. Lesions greater
than 2 cm or located near the GEJ despite imatinib may require esopha-
gectomy. ER or enucleation may result in positive margins, tumor spill-
age, and perforation and is therefore not recommended. The prognosis
for negative margins of lesions larger than 10 cm has an uncertain
benefit. Although positive margins may lead to increased locoregional
recurrence, factors such as size and tumor grade are more significant.
GIST prognosis is influenced by size, mitotic rate, tumor site, and the
completeness of resection. Lymphadenectomy is unnecessary because
nodal metastases are rare. The abdomen, peritoneum, and liver should
be examined for possible metastases. Rupture of the tumor yields a
worse prognosis. Recurrences may be treated with imatinib with or
without a reexcision. Most GISTs are completely excised but only 50%
remain recurrence-free at 5 years.
Tyrosine kinase inhibitors (TKIs) of which imatinib is the first line
therapy, are used to help decrease the growth of GIST cells after surgery.
imatinib is indicated for use as adjuvant therapy for primary GISTs
3 cm or larger. Patients with very low/low-risk GISTs do not need to
receive it. One year of imatinib reduces GIST recurrence in the first
year, but the best results occur after 3 years of treatment. The longest
studies reveal a median survival of advanced GISTs of 60 months. The
median time that tumors progress is 2 years, and the most common
sites for metastasis to occur are the peritoneum and liver, which is the
most common site in 67% of patients with recurrent disease. Despite
an 80% control rate of tumor growth, metastatic GISTs are treated with
imatinib because complete responses are rare. Imatinib treatment reduces
the tumor bulk in order to prevent resistance to the drug from muta-
tions in the KIT gene.
Metastases resection is best after 3 to 9 months of imatinib treat-
ment as there is little tumor reduction seen thereafter. Up to 30% of
patients may have resectable disease. Surgical resection of metastases
is beneficial for patients who have localized progression, stable disease,
or partial responses. Patients with multifocal disease progression are
poor surgical candidates. Five-year survival is 27% to 34% when only
the lesion is resected. Resection combined with imatinib results in the
longest survival. It is less important for the tumor to shrink in size than
82 SECTION I Esophagus
to reduce its density and vascularity. The National Comprehensive Cancer
Network (NCCN) and European Society for Medical Oncology (ESMO)
both recommend continual lifelong treatment with imatinib after metas-
tases are resected.
Course and Prognosis
Patients with a surgically resected leiomyosarcoma have a 5-year survival
of 30% to 40%, which is influenced by tumor grade and size. Generally
outcomes for leiomyosarcomas of the GI tract are less favorable than
for GISTs arising in similar locations.
No consensus exists on the follow-up treatment of GISTs. Regular
follow-up may detect recurrences at an earlier stage and may lead to
improved postrecurrence progression-free and overall survival. NCCN
guidelines are as follows: For patients with a completely resected GIST
tumor, history and physical every 3 to 6 months for 5 years, then yearly.
Also a CT scan every 3 to 6 months for 3 to 5 years, then yearly. For
patients with locally advanced or metastatic disease, receiving imatinib,
history and physical and abdominal/pelvic CT scan every 3 to 6 months.
Very low risk GISTs do not need routine follow-up, although recurrence
may rarely be seen. MRI is a reasonable alternative to CT scans when
there is concern for x-ray exposure in low-risk lesions.
Follow-up for a completely resected leiomyosarcoma includes a
physical examination with an abdominal/pelvic CT or MRI scan every
3 to 6 months for 3 years and then every year. For patients with positive
margins, CT or MRI should be continued every 6 months for 2 more
years. Some centers recommend including a chest CT as well as one of
the abdomen/pelvis to rule out lung metastases, which are a high risk.
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