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Introduction
Oesophageal cancer originates in the epithelial lining of the oesophagus.1 Around 9400 cases are diagnosed annually (~2% of all UK annual cancer cases), making it the fourteenth most commonly diagnosed cancer type in the UK.2
Aetiology
Anatomy
The oesophagus is the fibromuscular tube that transports a food bolus from the laryngopharynx to the stomach. This tube can be divided into three parts: the upper, middle and lower thirds.3
At the gastro-oesophageal junction, the lower oesophageal sphincter prevents the reflux of acidic stomach contents into the lower part of the oesophagus. This sphincter is physiological as it is not composed of a circular sphincteric muscle. Instead, the sphincter functions due to various anatomical factors at the gastro-oesophageal junction (e.g. the diagonal small entry point into the stomach and mucosal folds occluding the lumen).3 The sphincter is therefore vulnerable to malfunction.
Layers of the oesophagus
The oesophageal wall has four main layers:
- Mucosa: composed of non-keratinised stratified squamous epithelium, lubricated to help food travel down the oesophagus towards the stomach more easily. This is the innermost layer of the oesophagus
- Submucosa: contains mucous-secreting glands
- Muscularis: muscular layer containing both voluntary striated muscle in the upper and middle parts of the oesophagus and involuntary smooth muscle in the middle and lower parts. These muscles produce the rhythmic contractions that propel the food towards the stomach (peristalsis)
- Adventitia: composed of connective tissue that forms the outermost layer of the oesophagus4
Histological classification of oesophageal cancer
There are broadly two different histological types of oesophageal cancer that account for >95% of cases.5
Adenocarcinoma
- Most common histological subtype in the developed world
- Affects the lower third of the oesophagus
- Develops from glandular (adenomatous) cells
- Associated with Barrett’s oesophagus, obesity and gastro-oesophageal reflux disease (GORD)
Squamous cell carcinoma
- Most common histological subtype in the developing world
- Affects the upper two thirds of the oesophagus
- Develops from squamous cells
- Associated with smoking and alcohol use
Risk factors
Modifiable
Modifiable risk factors include:
- Smoking
- Alcohol
- Obesity
- Consuming drinks and foods at high temperatures
- Low-socioeconomic status
Non-modifiable
Non-modifiable risk factors include:
- Older age (peak incidence 80-84 years old)
- Male sex
- Gastro-oesophageal reflux disease (GORD)
- Barrett’s oesophagus
- Achalasia
- Hiatus hernia
- Family history of oesophageal cancer/hereditary cancer syndromes1
Clinical features
History
Typical symptoms of oesophageal cancer include:
- Progressive dysphagia (difficulty swallowing): the most common presenting symptom. Initially, there is difficulty swallowing solids and then liquids with further lumen obstruction
- Odynophagia (painful swallowing): occurs due to tumour invasion outside of the oesophagus, into the airway or mediastinum
- Unintentional weight and appetite loss: associated with poor survival
- Vomiting/regurgitation: undigested food is regurgitated due to oesophageal obstruction
- Dyspepsia/retrosternal chest pain: due to underlying gastro-oesophageal reflux
- Hiccups: occurs as the tumour locally invades into the phrenic nerve (supplying the diaphragm)
Clinical examination
Typical clinical findings of oesophageal cancer include:
- Vocal hoarseness: occurs as the tumour locally invades into the recurrent laryngeal nerve
- Lymphadenopathy: due to the spread of malignant cells to lymph nodes
Differential diagnoses
Differential diagnoses to consider in suspected oesophageal cancer include:
- Benign oesophageal stricture
- Achalasia
- Oesophageal spasm
- Barrett’s oesophagus
- Gastro-oesophageal reflux disease (GORD)
Investigations
Bedside investigations
Relevant bedside investigations include:
- Abdominal examination: to observe clinical signs of oesophageal cancer (e.g. lymphadenopathy)
- Weight/BMI: to quantify and monitor weight loss
Laboratory investigations
Relevant laboratory investigations include:
- Full blood count: may show microcytic anaemia secondary to blood loss, and thrombocytosis
- Urea and electrolytes: baseline before treatment, and may show hypokalaemia in advanced disease when a patient cannot swallow their potassium-rich saliva1
- Liver function tests: baseline before treatment, and may show elevated transaminases in liver metastases
- C-reactive protein: non-specific rise in inflammation
- Genetic testing: microsatellite instability (MSI), mismatch repair (MMR), HER2 and PD-L1 expression testing to determine suitability of targeted immunotherapies and genetic component of disease1
Imaging
Relevant imaging includes:
- Oesophagogastroduodenoscopy (OGD) and biopsy: direct tumour visualisation and collection of tissue samples for histopathological analysis
- Endoscopic ultrasound and fine needle aspiration: most accurate technique for T staging of oesophageal cancer
- CT thorax abdomen pelvis: to assess for local spread, tumour size and staging
- PET scan: improves the node and metastasis components of staging, and for assessing responses to systemic anti-cancer therapies (SACT)1
Oesophagogastroduodenoscopy
OGD is the first line investigation for oesophageal cancer, and it also allows biopsy of suspicious lesions.
Proton pump inhibitors should be stopped two weeks before as they may mask the symptoms of oesophageal cancer.
Diagnosis
Referral criteria
An urgent suspected cancer referral for an upper gastrointestinal endoscopy should be made for:
- Dysphagia OR
- Aged ≥55 years + weight loss + upper abdominal pain, reflux or dyspepsia6
TNM staging
Oesophageal cancer is staged using the tumour nodes metastasis (TNM) system.7
| Tumour (T) | Node (N) | Metastasis (M) |
| TX: unable to assess primary tumour | NX: unable to assess regional lymph nodes | MX: unable to assess presence of distant metastases |
| T0: no evidence of primary tumour | N0: no regional lymph node metastases | M0: no distant metastases |
| T1: carcinoma invades into the mucosa (1a) or submucosa (1b) | N1: 1 or 2 positive regional lymph nodes | M1: distant metastases |
| T2: carcinoma invades into muscularis | N2: 3 to 6 positive regional lymph nodes | |
| T3: carcinoma invades into adventitia | N3: 7+ positive regional lymph nodes | |
| T4: carcinoma invades into adjacent structures outside of the oesophagus |
Histological diagnosis
Diagnosis is confirmed on pathological review of biopsied tumour tissue.
Management
The treatment of oesophageal cancer is determined by the staging of the malignancy and the suitability of a patient for surgery. For almost all oesophageal cancer that is potentially resectable (except T1 disease), a combination of peri-operative chemotherapy (and radiotherapy for squamous cell carcinoma) and resection is recommended. In an advanced setting, chemotherapy or immunotherapy/HER2 directed therapy depends on a cancer’s histological subtype and its molecular biomarkers.
Surgical management
Surgical management is indicated for early-stage, localised disease, without metastases:
- Oesophagectomy
- Endoscopic therapy: an alternative to surgery in patients with superficial adenocarcinomas (early-stage disease)
Oesophagectomy
An oesophagectomy involves removal of part or all of the oesophagus, and can be performed laparoscopically or open.
Neo-adjuvant chemotherapy is given before surgery to reduce the tumour size, improve long-term survival and increase the chance of complete tumour resection.
A repeat CT scan is performed at 6 months post-resection to monitor for further disease spread.
Medical management
Medical management can include:
- Radiotherapy/chemotherapy: can be given as neo-adjuvant and adjuvant treatment, or for symptom management if surgery is not indicated
- Immunotherapy: can be given in patients with identified drug targets (e.g. after PD-L1, MSI or MMR testing)1
- Targeted therapy: trastuzumab (HER2 directed therapy) can be given where HER2 overexpression is detected
Palliative management
- Stenting or balloon dilation: a metallic stent can be inserted to reduce the symptomatic burden of dysphagia or oesophageal obstruction
Complications
Following surgical or medical management, multiple complications can occur.
Surgical complications
- Post-resection oesophageal reflux
- Post-resection anastomotic leak
- Post-operative pneumonia
- Oesophago-aortic/tracheo-oesophageal fistula
Systemic therapy complications
Adverse effects of chemotherapy
- Neutropenic sepsis
- Mucositis
- Diarrhoea
- Cardiac complications
- Peripheral neuropathy
- Nausea and vomiting
- Renal impairment
Adverse effects of radiotherapy
- Oesophagitis
- Skin rash
- Voice change
- Pneumonitis
- Oesophageal stricture
Prognosis
Oesophageal cancer is one of the malignancies with the worst prognosis. The 10-year survival of oesophageal cancer is approximately 12%.2 Its poor prognosis is due to its late symptom presentation, and highly metastatic nature even in the early stage.
Survival is dependent on the stage at which the oesophageal cancer is diagnosed. 5-year survival when oesophageal cancer is diagnosed at stage one is approximately 65%, compared to 5% at stage four.8
Reviewer
Dr Alicia-Marie Conway
Academic Clinical Lecturer in Medical Oncology, ST6, The University of Manchester
Editor
Dr Jamie Scriven
References
- BMJ Best Practice. Oesophageal Cancer. 2024. Available from: [LINK].
- Cancer Research UK. Oesophageal cancer statistics. Available from: [LINK].
- Cancer Research UK. What is oesophageal cancer? 2023. Available from: [LINK].
- Macmillan Cancer Support. The oesophagus. 2019. Available from: [LINK].
- Saltzman JR, Gibson MK. Clinical manifestations, diagnosis and staging of esophageal cancer. UpToDate. 2023. Available from: [LINK].
- NICE CKS. Scenario: Referral for suspected gastrointestinal tract (upper) cancer. 2021. Available from: [LINK].
- Macmillan Cancer Support. Staging and grading of oesophageal cancer. 2019. Available from: [LINK].
- Cancer Research UK. Survival for oesophageal cancer. 2023. Available from: [LINK].
Image references
- Figure 1. Cancer Research UK uploader. License: [CC BY-SA 4.0].
- Figure 2. DrJanaOfficial. License: [CC BY 4.0].
- Figure 3. K.Y.K.Z.K. License: [CC BY-SA 3.0].
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