1

What is Barrett’s oesophagus?

Barrett’s oesophagus (also known as columnar-lined oesophagus) is a condition where any portion of the normal squamous epithelium has been replaced by metaplastic columnar epithelium that is visible macrosopically.

It is a complication of chronic gastro-oesophageal reflux disease (GORD), where spillage of acidic gastric secretions above the gastro-oesophageal junction (GOJ) cause the normal oesophageal squamous epithelium to be replaced by intestinal secretory columnar epithelium in order to withstand the erosive actions of gastric acid.

Barrett’s oesophagus usually involves the lower oesophagus but can be of any length above the GOJ.

It is considered an important risk factor for developing adenocarcinoma of the oesophagus.

2

What is the epidemiology of Barrett’s oesophagus?

Barrett’s oesophagus is estimated to affect 1.6-7% of the general population, with an average age of 55-65 at the time of presentation.

It is more common in males (male: female ratio 2:1) and the Caucasian population.

Other risk factors that have been linked to its development include GORD, obesity, alcohol and smoking.

3

What are the principles of diagnosing Barrett’s oesophagus?

Normal findings on oesophagogastroduodenoscopy (OGD) include:

a)

squamocolumnar junction (SCJ) – which represents the interface of squamous epithelium (pale glossy appearance) and columnar epithelium (salmon-red colour and coarse texture). It is also known as the Z-line;

b)

gastro-oesophageal junction (GOJ) – which represents the most proximal extent of the gastric folds;

c)

the SCJ and GOJ are located at the same level, hence the absence of columnar-lined oesophagus.

The diagnosis of Barrett’s oesophagus requires the presence of:

a)

columnar epithelium of any length visible endoscopically above the GOJ (Figure 1);

b)

intestinal metaplasia in biopsies taken from the columnar-lined oesophageal segment.

The presence of specialised intestinal metaplasia (SIM), with mucin acid-secreting goblet cells, is required for the diagnosis of Barrett’s oesophagus and should be proven in at least eight biopsies by an expert histopathologist (Figure 2).

The presence of metaplasia is fundamental because there are no data linking oesophageal adenocarcinoma to columnar-lined oesophagus when intestinal metaplasia is absent.

Short segment Barrett’s oesophagus is present if the distance between the GOJ and SCJ is <3cm and long segment Barrett’s oesophagus if the distance is >3cm.

The length of Barrett’s oesophagus can also be described by the Prague classification (Figure 3), which measures for the presence of a complete circumferential lesion (Prague C) and the maximal extent of the lesion (Prague M).

In high-grade dysplasia, the spacing of four quadrant biopsies should be every 1cm because larger intervals (>2cm) are associated with an increased false-negative rate.

Any mucosal abnormality, including ulcer or nodularity is best assessed by endoscopic resection and extensive histopatholgical evaluation.

Mucosal nodularity is shown to be associated with a much higher frequency of malignancy and with spread to the regional lymph nodes.

4

What are the predictors of progression from Barrett’s oesophagus to adenocarcinoma?

The progression from Barrett’s oesophagus to adenocarcinoma (0.5% per year) is multi-factorial and usually occurs through stages:

a)

metaplasia;

b)

low-grade dysplasia (LGD);

c)

high-grade dysplasia (HGD);

d)

carcinoma in situ;

e)

invasive carcinoma.

Dysplasia is defined as the presence of neoplastic epithelium that has not penetrated the basement membrane.

The risk of developing high-grade dysplasia is increased by:

a)

presence of low-grade dysplasia;

b)

Barrett’s oesophagus for >10 years;

c)

longer segment of columnar epithelium;

d)

presence of chronic oesophagitis;

e)

smoking (current or past).

High-grade dysplasia is associated with a 30% risk of developing adenocarcinoma.

The Factors Influencing the Barrett’s – Adenocarcinoma Relationship (FINBAR) study suggested that GORD chronicity and frequency of acute episodes rather than their severity appear to be better predictors for neoplastic progression.

5

What are the principles of management of Barrett’s oesophagus?

Surveillance.

Medical treatment.

Endoscopic ablative therapies.

Endoscopic mucosal resection.

Surgery.

6

What are the principles of the surveillance programme for Barrett’s oesophagus (Table 1)?

The grade of dysplasia determines the appropriate surveillance interval.

In patients with metaplastic changes only (in the absence of dysplasia), routine surveillance is of doubtful value.

Surveillance programmes for dysplasia have been shown to be associated with a survival benefit from multiple retrospective studies. No randomised controlled trails, however, have been performed.

7

What are the principles of medical management for Barrett’s oesophagus?

Medical management is directed at treating the underlying GORD rather than Barrett’s oesophagus itself, including:

a)

dietary changes;

b)

weight-lowering strategies;

c)

acid suppression medications, usually proton-pump inhibitors.

The use of antacid therapy (such as Gaviscon^®) has not been demonstrated to significantly lower the risk of progression to dysplasia or carcinoma.

8

What are the principles of non-medical management for Barrett’s oesophagus?

Photodynamic therapy – which uses a laser beam-activated polymer (Photofrin^®), under OGD direct vision, to ablate the precancerous lesion in the Barrett’s epithelium. Complications include scarring, dysphagia, dyspnoea and chest pain.

Radiofrequency ablation – which delivers energy via an electrode mounted on a balloon endoscope to cause charring of the Barrett’s epithelium. Complications, including scarring and strictures, seem to be less prominent when compared to photodynamic therapy.

Endoscopic mucosal and submucosal resection – large areas of mucosa can be removed by suction into a plastic cap (mucosal resection) or by injecting a separating fluid under the mucosa and knife resection (submucosal resection).

Surgery:

a)

anti-reflux surgery – should be considered for non-responders to medical therapy;

b)

oesophagectomy and reconstruction – should be considered in specific cases of high-grade dysplasia.

9

What is oesophageal carcinoma?

Oesophageal carcinoma is a malignant tumour originating in the oesophageal mucosa or wall.

The two predominant histological subtypes are:

a)

adenocarcinoma (Figure 4A);

b)

squamous cell carcinoma (SCC) (Figure 4B).

Less common malignant oesophageal tumours include melanoma, leiomyosarcoma and small cell carcinoma.

10

What is the epidemiology of oesophageal carcinoma?

Oesophageal carcinoma has a rising incidence, with over 450,000 patients diagnosed every year worldwide.

It represents the seventh leading cause of cancer-related mortality.

Oesophageal carcinoma is more common in men (male: female ratio 2-4:1) and in patients with an advancing age (peak 60-70 years of age).

In the UK, the incidence is 12.6 (men) and 5.9 (women) per 100,000 population.

Despite advances in treatment, oesophageal carcinoma is still associated with a very poor prognosis, with 5-year survival rates of 15-20% and median survival of 18 months, due to the high propensity for metastases and late diagnosis.

SCC is the most common form in Asia and Africa, with adenocarcinoma being the predominant form in northern Europe, USA and Australia.

11

What are the pathological features of oesophageal carcinoma?

Macroscopically, it appears as a protruding, ulcerated or infiltrating oesophageal mass.

It can be located throughout the oesophagus – upper third (15%), middle third (60%) and lower third (25%).

The endoscopic appearances of early tumours include a mosaic or hypervascular pattern. Some, however, remain occult.

Tumour infiltration and spread depends on the site of the primary tumour and the lymphatic drainage of the oesophagus.

Approximately 75% of tumours at presentation extend through the submucosa and deep muscle layers into adventitial tissue.

Submucosal tumours show a 10-fold increase in lymph metastasis as compared to intramucosal tumours.

About 40% of upper third tumours spread to the abdominal nodes and 40% of lower third tumours spread to the cervical nodes.

SCC can be classified as well-, moderate- or poorly-differentiated, depending on the degree of keratinisation, keratin whirl formation and cytological atypia.

Two variants of SCC include verrucous carcinoma and carcinosarcoma.

Ca p53 gene abnormalities are associated with up to 50% of SCC.

Increased expression of the human epidermal growth factor receptor 2 (HER2-neu) is seen in patients with oesophageal adenocarcinoma (15-30%) and SCC (5-13%). Its expression correlates with the presence of lymph node metastasis and tumour invasion.

12

What are the predisposing risk factors for the development of oesophageal carcinoma?

Squamous cell carcinoma:

a)

achalasia;

b)

tobacco and alcohol (independently and synergistically);

c)

caustic injury (acid or alkali mucosal injury or thermal injury);

d)

Plummer-Vinson or Paterson-Brown-Kelly syndrome (post-cricoid dysphagia, iron deficiency anaemia and oesophageal mucosal webs) – 16% of these patients may develop oesophageal SCC;

e)

tylosis – which is a rare autosomal dominant condition with abnormal keratinisation of palms and soles, and is caused by the tylosis oesophageal cancer (TOC) gene mapped to chromosome 17q25;

f)

dietary deficiency of vegetables, fruit and dairy products – especially with a low intake of vitamins A and C, and riboflavin;

g)

low social status, poor oral hygiene and malnutrition;

h)

Zenker’s diverticulum – where the tumour usually develops at the apex of the diverticulum. The patients usually present at an advanced stage, with reported incidences of 0.3-0.8%.

Adenocarcinoma:

a)

Barrett’s oesophagus;

b)

GORD;

c)

obesity;

d)

tobacco.

Although Helicobacter pylori infection is associated with gastric carcinoma, there is no evidence linking it with oesophageal carcinoma.

13

What are the clinical features of oesophageal carcinoma?

Patients that are detected through a Barrett’s oesophagus surveillance programme are often asymptomatic.

Progressive dysphagia, however, is the commonest presenting symptom of oesophageal carcinoma and is classified as:

a)

Grade 1 – able to swallow most foods;

b)

Grade 2 – able to swallow soft food only;

c)

Grade 3 – able to swallow liquids only;

d)

Grade 4 – unable to swallow (no oral intake).

Other less common symptoms include:

a)

odynophagia (painful swallowing);

b)

epigastric discomfort;

c)

weight loss;

d)

hoarse voice;

e)

supraclavicular mass;

f)

respiratory symptoms of cough after swallowing or recurrent chest infections, which may indicate aspiration pneumonia or a tracheo-oesophageal fistula.

Some patients may also present with evidence of hepatic, pulmonary or bone metastases.

Patients with SCC typically present with dysphagia, weight loss and a history of tobacco and alcohol use.

Patients with adenocarcinoma are predominantly middle-aged male Caucasians, and typically present with a history of dyspepsia and chronic antacid use (representing underlying GORD), and recent onset of dysphagia.

14

Which tests are used to investigate a patient with oesophageal carcinoma?

Blood tests – which may show evidence of anaemia, hypoalbuminaemia, hepatic dysfunction or hypercalcaemia.

Chest radiograph (CXR) – which may show evidence of a soft tissue mass, mediastinal air-fluid level, aspiration pneumonia or pulmonary metastases.

Barium swallow (BaS) – which is often used as the first line of investigation in symptomatic patients with dysphagia and may demonstrate the level of any obstruction.

Oesophagogastroduodenoscopy (OGD) – which can clearly delineate the location and extent of the tumour, and allows for biopsies to be taken.

Computed tomography (CT) scan of the thorax and abdomen – which can assess for local spread and the presence of metastatic disease.

Endoscopic ultrasound (EUS) – which can assess the depth of the primary tumour and regional lymph node involvement, and allows for EUS-guided fine needle aspiration (FNA).

PET scan – which can assess for the presence of distant metastatic disease.

Bronchoscopy – which is recommended in patients with middle and upper oesophageal tumours to exclude invasion of the trachea or bronchi.

Minimally invasive staging – which can be used to identify the presence of peritoneal and hepatic spread with laparoscopy or malignant pleural effusion and pleural spread with thoracoscopy.

Molecular staging – which uses analysis of gene expression to help identify the presence of micro-metastases.

15

What are the barium swallow features of oesophageal carcinoma?

Barium swallow can be used to provide information on the:

a)

diagnostic features of the lesion;

b)

location of the lesion to aid surgical planning;

c)

detection of any underlying tracheo-oesophageal fistula;

d)

diagnosis of coexisting pathology, including hiatus hernia or diverticulum.

Characteristic features of oesophageal carcinoma on barium swallow include:

a)

‘apple-core’ strictures with mucosal irregularity (Figure 5A);

b)

polypoid tumours (Figure 5B).

16

What are the oesophagogastroduodenoscopy features of oesophageal carcinoma?

Oesophagogastroduodenoscopy (OGD) is important in the management of oesophageal tumours and is used for:

a)

diagnosis – presence of carcinoma, size and extent of the lesion, location (Figure 6) and obtaining biopsies;

b)

staging – with EUS and EUS-FNA;

c)

treatment – with endoscopic mucosal resection (EMR), ablation, stenting and dilation;

d)

surveillance – for Barrett’s oesophagus or following treatment.

Characteristic features of oesophageal carcinoma on OGD include (Figure 7):

a)

nodular irregularities;

b)

ulceration;

c)

polypoid lesions.

17

What are the endoscopic ultrasound features of oesophageal carcinoma?

Endoscopic ultrasound (EUS) uses a small ultrasound probe attached to the tip of the endoscope, which is passed inside the oesophagus to scan its lumen, wall and surrounding structures (Figure 8).

It is the primary imaging modality for assessing the tumour (T) stage on the TNM system, giving information on the location and depth of the primary tumour, with an overall accuracy of up to 89% (Figure 9).

Regional lymph node (N) stage can also be determined, with an overall accuracy of 70-81% (Figure 10). Accuracy increases to 92% with EUS-guided fine needle aspiration (FNA).

18

What are the computed tomography features of oesophageal carcinoma?

Computed tomography (CT) scanning is important in the diagnostic and staging process of oesophageal carcinoma:

a)

tumour (T) stage – although CT is able to visualise abnormal wall thickening >5mm, it is not very sensitive at distinguishing the depth of invasion through the different histological layers of the oesophageal wall (Figure 11);

b)

invasion of the oesophageal tumour into adjacent structures (T4 disease), which is demonstrated by contiguity and loss of the normal peri-oesophageal fat planes (Figure 12);