ESOPHAGEAL CANCER

Summary

Esophageal cancer (EC) is the eighth most common type of cancer worldwide and affects predominantly male individuals (3:1). The two
main forms are esophageal adenocarcinoma and squamous cell carcinoma. Adenocarcinomas are considered the fastest-
growing neoplasms in Western countries, while squamous cell carcinoma is still most common in the resource-limited countries.
Development of EC is associated with a number of risk factors. Adenocarcinoma, which usually affects the lower third of
the esophagus, may be preceded by gastroesophageal reflux disease and associated Barrett esophagus. Other risk factors are smoking
and obesity. Major known risk factors for squamous cell carcinoma include carcinogen exposure (e.g., in form of alcohol and tobacco)
and a diet high in nitrosamines, but low in fruits and vegetables. Initially, EC is usually asymptomatic, so locally advanced disease is
common at time of diagnosis. Weight loss and dyspepsia can precede the primary symptom progressive dysphagia. Late stages may be
characterized by cervical adenopathy, hoarseness or persistent cough, and signs of upper gastrointestinal bleeding, such
as hematemesis or melena. Esophagogastroduodenoscopy is used for direct visualization and allows biopsy of the lesion for
histopathological confirmation. Staging of the tumor includes transesophageal endoscopic ultrasound, CT scans of chest and abdomen,
and bronchoscopy. Curative surgical resection may be considered for locally invasive cancers, but in about 60% of patients EC is
already unresectable at time of diagnosis. In those cases, treatment options includes chemotherapy, radiation, and palliative stenting.
Prognosis is generally poor due to the aggressive nature of EC and oftentimes late diagnosis.

Epidemiology

Sex: ♂ > ♀ (3:1)  [1]

Incidence: an estimated 18,440 new cases of esophageal cancer will be diagnosed in 2020 in the United States  [1]

Median age of onset: between 60 and 70 years of age

Adenocarcinoma: most common type of esophageal cancer in the US   [2]

Squamous cell carcinoma (SCC): most common type of esophageal cancer worldwide 

Adenocarcinoma is more common in the US of America.

ETIOLOGY

Adenocarcinoma  [4]
 Exogenous risk factors
o Smoking (twofold risk)
o Obesity
Endogenous risk factors
o Male sex
o Older age (50–60 years)
o Gastroesophageal reflux
o Barrett esophagus
Localization: mostly in the lower third of the esophagus
The most important risk factors for esophageal adenocarcinoma are gastroesophageal reflux and associated Barrett
esophagus.

Squamous cell carcinoma (SCC)  [4][5]

Exogenous risk factors
o Alcohol consumption
o Smoking (ninefold risk)
o Diet low in fruits and vegetables
o Hot beverages
o Nitrosamines exposure (e.g., cured meat, fish, bacon)  [6]

o Caustic strictures
o HPV  [7]

o Radiotherapy
o Betel or areca nut chewing
o Esophageal candidiasis  [8][9]

Endogenous risk factors
 o Male sex
o Older age (60–70 years)
o African American descent
o Plummer-Vinson syndrome
o Achalasia
o Diverticula (e.g., Zenker's diverticulum)
o Tylosis
Localization: mostly in the upper two-thirds of the esophagus
The primary risk factors for squamous cell esophageal cancer are alcohol consumption, smoking, and dietary factors
(e.g., diet low in fruits and vegetables).
Comparison of the mucous membrane of a normal distal esophagus to one affected by Barrett metaplasia: In reflux esophagitis, stomach acid
damages the stratified squamous epithelium of the distal esophagus, which then becomes replaced by columnar epithelium and goblet cells.

Clinical Features
Early stages  [10]

Often asymptomatic
May manifest with swallowing difficulties or retrosternal discomfort

Advanced stages  [10]

General signs
o Weight loss 
o Dyspepsia
o Signs of anemia 
Signs of advanced disease
o Progressive dysphagia (from solids to liquids) with possible odynophagia
o Retrosternal chest or back pain
o Cervical adenopathy 
o Hoarseness and/or persistent cough 
o Horner syndrome
Signs of upper gastrointestinal bleeding 
o Hematemesis
o Melena
Initially, esophageal cancer is often asymptomatic. It typically becomes symptomatic at advanced stages.
Diagnostics

Esophagogastroduodenoscopy
Best initial and confirmatory test 
[11]

Direct visualization of the tumor 

Allows biopsy of any suspicious lesions
Barium swallow
Overview
o Sensitive, but does not allow confirmation or staging of a malignancy
o Inferior to endoscopy 
Indications
o Severe stricture that inhibits endoscopic evaluation
o Suspected tracheoesophageal fistula
Findings: asymmetrical and irregular borders of the esophagus with characteristic stenosis and proximal dilatation
(apple core lesion) 
Staging  [11]

Chest and abdominal CT 

o To identify the location and content of the lesion and to exclude distant metastases
o In case CT scan does not show metastatic disease, a PET scan can be added to increase
diagnostic accuracy
Transesophageal endoscopic ultrasound
o Used to determine the infiltration depth and register regional lymph node disease
o Should be combined with FNA to increase sensitivity and specifity for the identification of lymph
node disease
Bronchoscopy: for staging of lesions at or above the carina to rule out airway involvement
Laparoscopy: in some cases, to increase accuracy of detecting small liver metastases
Siewert classification of adenocarcinoma of the esophagogastric junction 
 This classification was proposed by Siewert and is applied in clinical practice. 
 Recent guidelines suggest that tumors located ≤ 2 cm below the z-line (i.e., Siewert types I and II) should be treated as
esophageal cancer.  [12]

}
 Overview of Siewert classification

Type Localization Comments and surgical approaches

 Tumor invades the gastric

cardia from proximal to z-line

Siewert  Center of the tumor located 1–5 cm above the z-line (associated  Surgical approach

type I with Barrett mucosa) o Transthoracic esophagectomy

o Partial gastrectomy

o Lymphadenectomy

Siewert  Tumor invades the gastric cardia from distal to

 Center of the tumor located 1 cm above or 2 cm below the z-line
type II
the z-line

 Surgical approach

o Transhiatal esophagectomy

o Total gastrectomy

o Extended lymphadenectomy
pTNM staging for esophageal squamous cell carcinoma
 pTNM staging for esophageal squamous cell carcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

Curative  High-grade dysplasia, but  None  None

intent  Tis,
 Stage still confined
N0,
0 by basement
M0
membrane

 T1a,  Lamina
 Stage
N0, propria or muscularis
IA
M0 mucosae

 Stage  T1b,

IB N0,  Submucosa

M0

 T1,  Lamina

N0, propria, muscularis

M0 mucosae,

or submucosa
 pTNM staging for esophageal squamous cell carcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

 T2,

N0,

M0
 Muscularis propria
 T2,

N0,

M0

 T3,  Adventitia
 Stage
N0,
IIA
M0

 T3,

N0,

M0

 Stage  T3,

IIB N0,
 pTNM staging for esophageal squamous cell carcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

M0

 T3,

N0,

M0

 T3,

N0,

M0

 Lamina  1–2 regional lymp
 T1,
propria, muscularis h
N1,
mucosae, node metastase
M0
or submucosa s

Intermediate  Stage  T1,  3–6 regional lymp

intent
IIIA N2, h

M0 node metastase
 pTNM staging for esophageal squamous cell carcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

 1–2 regional lymp
 T2,
h
N1,  Muscularis propria
node metastase
M0
s

 Stage  T4a,  0–2 regional lymp

 Pleura, pericardium,
IIIB N0 h
diaphragm, peritoneu
–1, node metastase
m, or azygos vein
M0 s

 1–2 regional lymp
 T3,
h
N1,  Adventitia
node metastase
M0
s

 T2–3,  Muscularis propria or  3–6 regional lymp

 pTNM staging for esophageal squamous cell carcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

N2,
adventitia
M0
h

Palliative node metastase
 T4a,  Pleura, pericardium,
intent s
N2, diaphragm, peritoneu

M0 m, or azygos vein

 T4b,  0–6 regional lymp
 Stage  Trachea, vertebral body,
N0 h
IV other adjacent
–2, node metastase
A structures, or aorta
M0 s

 T1–4,  Any structure  ≥ 7 regional lymph

N3, node metastase

M0 s

 Stage  T1–4,  Any number  Yes

IVB N0
 pTNM staging for esophageal squamous cell carcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

–3,

M1

pTNM staging for esophageal adenocarcinoma

pTNM staging for esophageal adenocarcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

 High-grade dysplasia, but

 Stage 0  Tis still confined by basement

membrane

Curative
 Stage  T1a,  None  None
intent  Lamina propria or muscularis
IA N0,
mucosae
M0
 Stage

IB  T1b,  Submucosa
 pTNM staging for esophageal adenocarcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

N0,

M0

 T1, N0,  Lamina propria, muscularis

M0 mucosae, or submucosa
 Stage

IC
 T2, N0,

M0
 Muscularis propria
 Stage  T2, N0,

IIA M0

 T1, N1,  Lamina propria, muscularis  1–2 regional lymph

M0 mucosae, or submucosa node metastases

 Stage

IIB
 T3, N0,
 Adventitia  None
M0

Intermediate  Stage  T1, N2,  Lamina propria, muscularis  3–6 regional lymph

 pTNM staging for esophageal adenocarcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

M0 mucosae, or submucosa node metastases

IIIA
 T2, N1,  1–2 regional lymph
 Muscularis propria
M0 node metastases

 T4a,
 Pleura, pericardium,
N0–  0–2 regional lymph
diaphragm, peritoneum,
1, node metastases
intent or azygos vein
M0

 Stage
 T3, N1,  1–2 regional lymph
IIIB  Adventitia
M0 node metastases

 T2–3,
 Muscularis propria or
N2,
adventitia
 3–6 regional lymph
M0
node metastases
Palliative  Stage  T4a,  Pleura, pericardium,

intent IVA N2, diaphragm, peritoneum,

 pTNM staging for esophageal adenocarcinoma

Stage AJCC/UICC TNM Tissue invasion Lymph node metastases Distant metastasis

M0 or azygos vein

 T4b,
 Trachea, vertebral body,
N0–  0–6 regional lymph
other adjacent structures,
2, node metastases
or aorta
M0

 T1–4,
 0–≥ 7 regional lymph
N3,  Any structure
node metastases
M0

 T1–4,
 Any number of
N0–
 Any structure regional lymph  Yes
3,
node metastases
M1

Adenocarcinoma  [13]

Carcinoma arises in context of Barrett esophagus (columnar epithelium with goblet cells) and high-grade dysplasia

 Gland-forming tumors with different possible growth patterns (tubular, papillary, tubulopapillary)
Mucinous differentiation possible

Squamous cell carcinoma  [13]

Breakdown of uniform tissue structure

Squamous cell carcinoma clusters with circular keratinization
Lymphocytic infiltration between the carcinoma clusters
TREATMENT
Curative
Indication
o Locally invasive disease that has not invaded surrounding structures
o High-grade metaplasia in Barrett syndrome
Methods
o Neoadjuvant chemoradiation: as definitive treatment in patients with proven complete response (e.g.,
during endoscopy)
o Surgical resection
 Endoscopic submucosal resection for removal of superficial, epithelial lesions 
[14][15]

 Subtotal or total esophagectomy with gastric pull-through procedure or colonic interposition 

Palliative
Indication: patients with advanced disease (majority of patients)
Methods
o Chemoradiation
o Stent placement  
o Other endoscopic treatments (e.g., laser therapy) 
Cancer-associated complications 
Esophageal stenosis
Tracheoesophageal fistula → passage of food and fluid into the respiratory tract → ↑ risk of aspiration pneumonia
Treatment-associated complications
Surgical complications
o Anastomotic leak or stricture
o Recurrent laryngeal nerve injury
Functional gastrointestinal disorders
o Dysphagia
o Reflux
o Dumping syndrome
We list the most important complications. The selection is not exhaustive.

PROGNOSIS
Prognosis is generally poor due to an aggressive course (due to an absent serosa in the esophageal wall) and typically late diagnosis.

5-year survival rate of esophageal cancer  [17]

SEER stage 5-year survival rate

Localized  47%

Regional  25%
 Distant  5%

Combined  20%