Oesophageal Cancer

For the purposes of pathology, adenocarcinoma of the gastro-oesophageal junction seems to be a distinct entity and is discussed here

Most oesophageal malignancies are squamous cell carcinoma or adenocarcinoma, with a small number of other carcinomas that do not fall into either category and are rare. These include:

  • Neuroendocrine tumours (usually small cell carcinoma or carcinoid)
  • Sarcoma (usually leiomyosarcoma) or benign mesenchymal tumours (leimyoma)
  • Lymphoma is very rarely associated with the oesophagus, but may cause extrinsic compression from a mediastinal mass
  • Primary melanoma of the oesophagus is rare


Squamous cell carcinoma has an extreme variation in incidence, from about 5/100,000 in western countries such as Australia to over 100/100,000 in China and Persia. It is five times more common in men in Australia than women. The Normandy region of France is an exception, with rates of about 20/100,000. The usual age of diagnosis is 65, with virtually no diagnoses before age 30. The rate of SCC is increasing slowly in low risk areas and decreasing slowly in high risk areas.
Adenocarcinoma of the oesophagus has increased rapidly in recent years. In the United States there is a yearly increase in oesophageal adenocarcinoma of about 10% per year. The incidence is around the same as for squamous cell carcinoma, or has surpassed it. Adenocarcinoma is also seen more commonly in men. It is an uncommon diagnosis in high-SCC risk areas such as China, South Africa or Iran.
Other carcinomas, such as small cell neuroendocrine carcinoma or melanoma, are extremely rare with a handful of reported cases. The oesophagus is an uncommon site of metastatic spread of disease, aside from local invasion by mediastinal or lung metastases.
Leiomyoma is the most common mesenchymal tumour of the oesophagus, and is still exceedingly rare. Sarcomas account for < 0.5% of all oesophageal tumours.

Aetiology and Pathogenesis


Squamous cell carcinoma has a well studied set of risk factors:

  • In Western countries, about 90% of oesophageal malignancies can be attributed to use of tobacco and alcohol. Acetylaldehyde is thought to be the primary carcinogen in tobacco smoke for the development of oesophageal (and other head and neck) cancer.
  • In China, nutrition and lack of trace elements seems to be an important risk factor
  • Hot drinks may lead to oesophagitis and development of malignancy, particularly in South America
  • The HPV genome is found in 20-40% of oesophageal SCC in China; it is rarely seen in Western countries.

Adenocarcinoma has a different set of risk factors:

  • Barrett's Oesophagus, intestinal metaplasia of the distal oesophagus, is closely linked with adenocarcinoma
    • Metaplasia occurs following repeated insults to the squamous epithelium
    • The most common cause of this is gastro-oesophageal reflux disease
    • Patients with intestinal metaplasia have about a 10% lifetime risk of developing adenocarcinoma of the oesophagus
  • Tobacco exposure accounts for about 40% of adenocarcinomas
  • Obesity (BMI > 30) is associated with a 16-fold increase in risk compared with people possessing a low BMI (< 22)
  • Alcohol and helicobacter pylori appear to have no effect

Small cell/neuroendocrine tumours of the oesophagus are associated closely with smoking.


Squamous cell carcinoma is thought to follow the classical multistep carcinogenesis paradigm. The initial lesion is thought to begin as basal cell hyperplasia, where the basal layer of the epithelium becomes abnormally thickened; this condition is associated with a relative risk of 2 for development of oesophageal SCC. This proceeds to intraepithelial neoplasia (carcinoma in situ); associated with a 50-60 fold increase in risk of invasive disease.
Adenocarcinoma is associated with Barrett's oesophagus, itself associated with chronic gastro-oesophageal reflux disease and obesity. The reflux of acid and enzymes from the stomach and duodenum is presumed to cause chronic inflammation in the lower oesophagus which leads to the development of intestinal metaplasia. The development of intraepithelial neoplasia (carcinoma in situ) within Barrett's oesophagus predicts strongly for invasive malignancy.

Natural History

Squamous cell carcinoma, as described above, is thought to develop from abnormal areas of basal cell hyperplasia, which then progresses to intraepithelial neoplasia before becoming an invasive tumour. Lymphatic spread is very common once tumours have penetrated the muscularis mucosae; 50% of patients will have lymph node metastases if this has occurred. The extensive, anastamosing submucosal lymphatic plexus allows distant tumour spread to multiple regional nodes. For the upper third of the oesophagus, cervical and mediastinal nodes are most commonly affected; the middle third may spread to cervical, mediastinal or abdominal nodes; the lower third will usually only spread to mediastinal and abdominal nodes. Haematogenous spread is common; the lungs and liver are frequently affected but most other viscera may also be involved.
Adenocarcinoma has a similar pattern of spread to squamous cell carcinoma, but typically involves the lower third of the oesophagus due to its association with Barrett's oesophagus. Spread therefore usually occurs to mediastinal and gastric lymph nodes.

Clinical Presentation


The most common presenting symptoms for locally advanced squamous cell carcinoma and adenocarcinoma are of dysphagia, weight loss and regurgitation. Non-invasive disease, including Barrett's oesophagus, and superficial invasive disease (T1) are typically silent and are found incidentally on gastroscopy for other reasons (often dyspepsia).


Patients may appear gaunt from weight loss, but there are usually no other significant findings unless metastatic disease has developed. In this case, the liver may be enlarged and there may be a pleural effusion.


Bloods should include liver function tests, which will help to determine nutritional status (albumin) as well as the likelihood of liver metastases. Full blood count for detection of anaemia may be helpful.


CT of the chest and abdomen is mandatory for staging purposes.
Endoscopic ultrasound is a very useful test for evaluating the stage of disease, but is limited by poor availability outside of major capital cities.

Tumour Features

Squamous Cell Carcinoma

Macroscopic Features

There are three usual patterns of carcinoma seen macroscopically:

  • Fungating carcinoma is typically exophytic with loss of mucosa on the surface
  • Ulcerative carcinoma is typically intramural with loss of mucosa
  • Infiltrative carcinoma grows through the wall of the oesophagus but causes minimal disruption of the mucosa; this is the least common type

The tumour surface is typically ulcerated and red. The cut surface is usually tan.


The microscopic appearance depends on the histological grade of the tumour. Well differentiated tumours have larger cells that resemble keratinocytes; as the tumour becomes less well differentiated there is an increase in the number of basal-like cells and an increase in the number of mitotic figures. There is no standardised grading system for oesophageal SCC. Features common to SCC include intercellular bridging and keratin formation.


Oesophageal SCC is usually positive for CK5, CK6, CK10 and CK14. It is negative for CK7 and CK20. Positivity for p16 is seen in cases associated with HPV.


Inactivation of TP53 is an early event in the development of oesophageal SCC, but mutations in this gene do not mimic those seen in lung cancer. Other genetic abnormalities are still under investigation.



Adenocarcinomas have a broad range of appearances; a stenotic lesion in the distal third of the oesophagus is most common. Tumours are usually infiltrative and may be surrounded by pink Barrett's mucosa. Their surface is usually flattened.


H&E staining usually shows well or moderately differentiated adenocarcinoma with tubular or papillary growth patterns; diffuse patterns are seen in higher grade disease. Mucinous tumours are uncommon.


Unlike SCC, adenocarcinomas are usually positive for CK20 and about half are positive for CK7.


TP53 is less commonly deactivated (directly) in adenocarcinoma, with about 60% of tumours showing loss of this gene.

Other Tumours

Other tumour appearances are described in their relevant sections.

Staging / Classification

Oesophageal cancer, both squamous cell and adenocarcinoma, is staged with the TNM system.

T Stage

Stage Features
T0 No evidence of primary tumour
Tis Carcinoma in situ/ intraepithelial neoplasia
T1a Tumour invades mucosa (not through muscularis mucosae)
T1b Tumour invades submucsoa (not into muscularis propria)
T2 Tumour invades into muscularis propria
T3 Tumour invades into adventitia
T4a Tumour invades pericardium, pleura or diaphragm
T4b Tumour invades other local organs

N Stage

Regional lymph nodes include paraoesophageal, paratracheal, other mediastinal, and coeliac nodes. They do not include supraclavicular nodes.

Stage Features
N0 No evidence of nodal metastases
N1 1-2 lymph nodes involved
N2 3-6 lymph nodes involved
N3 7+ lymph nodes involved

M Stage

Stage Features
M0 No distant metastases
M1 Distant metastases

Final Stage

Stage T N M
0 Tis N0 M0
IA T1 N0 M0
IB T2 N0 M0
IIA T3 N0 M0
IIB T1-2 N1 M0