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- Barrett's oesophagus is the condition in which columnar epithelium replaces the squamous epithelium that normally lines the distal oesophagus.
- The condition develops when GORD damages the squamous oesophageal mucosa and the injury heals through a metaplastic process in which columnar cells replace squamous ones.
- The abnormal columnar epithelium that characterizes Barrett's oesophagus is an incomplete form of intestinal metaplasia (called specialized intestinal metaplasia) that predisposes patients to adenocarcinoma.
- Has been identified in 20% of patients undergoing investigative endoscopy for GORD symptoms.
Risk Factors
- Male: Female ratio of 1.5:1
- More common in Caucasians aged over 50
- Reflux of >5yrs duration
- Early onset reflux
- Nocturnal reflux symptoms
- Obesity, tobacco smoking and high-level alcohol intake.
Diagnosis
- Only around 5% of patients with adenocarcinoma of the oesophagus are diagnosed with Barrett’s prior to the diagnosis of oesophageal adenocarcinoma.
- Many patients with Barrett’s are asymptomatic
- The only effective screening method is upper GI endoscopy with biopsy
- A diagnosis requires evidence of intestinal metaplasia with histological evidence of goblet cells (specialised mucin-producing cells normally found only in the small and large intestinal mucosa) upon biopsy
Associated Risk of Adenocarcinoma
- Oesophageal adenocarcinoma has increased tenfold in the last few decades and is thought to primarily arise from Barrett’s Oesophagus – a faster rate of incidence increase than any other cancer.
- 0.4-0.5% of patients with Barrett’s will develop cancer each year.
- Barrett’s develops stepwise from metaplasia through various grades of dysplasia to adenocarcinoma.
Surveillance
- It is presently impossible to tell which patients will eventually progress from Barrett’s to adenocarcinoma. As a result regular screening of patients at risk is currently undertaken.
- The approximate costs for surveillance prior to cancer detection, according to one study, are £15,000 for men and £42,000 for women (the cost for women is higher per person due to the lower incidence of adenocarcinoma of the oesophagus).
Treatment
Pharmacological
- Primary intervention for treating Barrett’s is a PPI to suppress acid secretion in the stomach.
- In addition to making the acid reflux less harmful due to a higher pH, this also actively prevents reflux.
- Symptomatic relief is not necessarily indicative of controlled acid reflux.
- 24hr pH studies have shown periods of uncontrolled acid reflux, even in patients on high-dose PPIs
- High dose PPI therapy only very rarely leads to regression of Barrett’s metaplasia.
Surgical
- Nissen fundoplication is the favoured method, and can be done laparoscopically
- Should only be considered in those patients who are minimal surgical risk, or for whom PPI therapy is insufficient (including those who do not comply with medication)
- The surgery aims to restore the lower oesophageal sphincter function, thus reducing or abolishing reflux.
- Around 85% effective in the immediate post-operative period.
- Long-term follow-up has shown recurrence of symptoms in a few patients, due to breakdown of the surgical repair, or failure of the operation to control symptoms.
- Around 60% of patients continue on long-term anti-reflux medications
- Surgical Morbidity (8% of patients): Surgical mortality (<1%), Dysphagia, and Inability to belch and/or vomit
- Not proven to cause regression of Barrett’s, with only 17% of patients showing any histological regression postoperatively (with 74% showing no change, and 9% showing progression)
Endoscopic Therapy
Therapeutic endoscopy is a recent advancement in the treatment of Barrett’s oesophagus and superficial oesophageal adenocarcinoma. Techniques include Photodynamic Therapy (PDT), Endoscopic Mucosal Resection (EMR) and Thermal ablative methods. Currently, however, endoscopic therapies are not standard-of-care, and so should only be used in patients with dysplasia or adenocarcinoma who are not deemed to be surgical candidates.
Photodynamic Therapy (PDT)
- A photosensitiser precursor (aminolevulinic acid - ALA) is applied.
- A waiting period of a few hours is allowed to elapse, during which time
- ALA is taken up by cells
- ALA is converted by the cells to protoporphyrin IX (PPIX), a photosensitiser.
- The physician shines a bright red light (from an array of light-emitting diodes or a helium-neon laser) on the area to be treated. The light exposure lasts a few minutes to a few tens of minutes.
- PPIX absorbs light, exciting it to an excited singlet state;
- Intersystem crossing occurs, resulting in excited triplet PPIX;
- Energy is transferred from triplet PPIX to triplet oxygen, resulting in singlet (ground state) PPIX and excited singlet oxygen;
- Singlet oxygen reacts with biomolecules, fatally damaging dysplastic and neoplastic cells in the treatment area.
- Within a few days, the tissue will scab over and flakes away.
- Exposure to intense light is required for a further 30-90 days.
Risks include: severe skin phototoxicity, oesophageal strictures, chest pain, dysphagia and small pleural effusions – because of these relatively common side effects this therapy is not often recommended for patients who could undergo traditional surgical treatment. In addition, despite histological improvement, there is no reversal of genetic abnormalities, such as p53 mutations following PDT.
Endoscopic Mucosal Resection (EMR)
- An area of High-grade Dysplasia (HGD) or superficial adenocarcinoma is identified endoscopically.
- Saline & Adrenaline mix is injected into the submucosal layer below the affected area, detaching the lesion from the deeper mucosal layers.
- The raised area is then resected using a snare or Variceal Ligating Device
- The removed tissue is then sent for histological analysis to determine the depth of penetration, size and margins of the lesion.
Risks include: dysphagia, bleeding and perforation.
Recent data suggests that a combination of EMR followed by PDT can be safe and more effective than either therapy in isolation.
Thermal Ablative Therapy
- Usually utilises either an Argon Plasma Coagulator or Multipolar Electrocautery (MPEC) device to ablate the mucosa of the affected area
- Useful in treating non-dysplastic or LGD Barrett’s.
- Complications include squamous cell overgrowth (thus disguising the presence of dysplasia or adenocarcinoma)
Risks include: chest pain, dysphagia, perforation and high mortality.
Chemopreventative Therapy
- Studies show a decreased incidence of oesophageal adenocarcinoma in patients who take NSAIDs (COX inhibitors)
- Cyclooxygenase converts arachadonic acid into inflammatory mediators
- This is associated with a decrease in cell-cell cohesion and apoptosis
- And an increase in angiogenesis and proliferation
- COX-2 expression increases with the progression from Barrett’s through dysplasia to adenocarcinoma
- A selective COX-2 inhibitor can form the basis for chemopreventative agents for patients with Barrett’s metaplasia.
Oesophageal Cancer
- Oesophageal cancer is one of the least studied and deadliest cancers worldwide.
- It is the 6th leading cause of death from cancer worldwide, despite being relatively uncommon with around 14,000 new cases and 13,000 deaths in the USA in 2003.
- More than 90% of tumours are either squamous cell carcinomas (SSCa) or adenocarcinomas.
- Adenocarcinomas are most commonly found in the distal oesophagus, close to the gastro-oesophageal junction
- SSCa’s are more evenly distributed throughout the middle and lower oesophagus
- The upper (cervical) oesophagus is an uncommon site of neoplastic disease.
- The pathogenesis of oesophageal cancer is thought to be due to oxidative damage from factors such as tobacco smoke and acid reflux
- This causes inflammation, oesophagitis and increased cell turnover which is thought to initiate the carcinogenic process
Epidemiology
Squamous Cell Carcinoma
- Environmental:
- Alcohol use
- Cigarette smoking
- Betel nut chewing (common in India and parts of Asia)
- Caustic ingestion
- Oesophageal radiation exposure
- Diet high in saturated fats
- Diet low in vitamin C, folate, ß-carotene or vitamin E
- Demographic
- Residing in endemic region
- Male gender
- African-American race
- Low socio-economic status
- Associated Medical Conditions
- Head/Neck SSCa
- Plummer-Vinson syndrome
- Alchalasia
- Tylosis
- Celiac disease
- Human papilloma virus infection
Adenocarcinoma
- Environmental
- Cigarette smoking
- High fat diet
- Diet low in vitamin C, folate, ß-carotene or vitamin E
- Demographic
- High socio-economic status
- Caucasian race
- Male gender
- Associated Medical Conditions
- Barrett’s metaplasia
- Zollinger-Ellison syndrome
- Scleroderma
- Prior oesophageal dilations
Smoking cessation and moderation of alcohol intake are important steps in reducing the risk of SSCa of the oesophagus – the risk of developing cancer is substantially decreased within a decade of smoking cessation.
Adenocarcinoma risk on the other hand, is not significantly affected by cessation, even 30 years after quitting.
Substituting fresh fruit and vegetables for poorly preserved, high-salt foods may reduce the risk of all oesophageal cancers by as much as 50%.
Clinical Presentation
- A careful history and physical examination are required to determine the appropriate diagnostic test.
- A typical presentation will include: Dysphagia (74%), Odynophagia (pain on swallowing – 17%), Chest pain, Anorexia, Weight loss (57% - an independent indicator of poor prognosis if there is a loss of >10% of body mass), Aspiration pneumonia, Anaemia, and/or Haematemesis.
- The first step in diagnosis is the identification of an oesophageal lesion.
- Endoscopy is the favoured method of definitive diagnosis as it allows for direct visualisation of the lesion, evaluation of its extent and ability for biopsy.
- A CT scan of the chest, abdomen and pelvis should be obtained to detect any possible metastases
- Transoesophageal Ultrasound is currently the most accurate method of evaluating the extent of tissue invasion and identifying superficial lesions without the need for biopsy.
- It also allows the evaluation of regional lymphadenopathy.
Staging
Tis=carcinoma in situ; T1=tumour invades lamina propria or submucosa; T2=tumour invades muscularis propria; T3=tumour invades adventitia; T4=tumour invades adjacent structures.
N0=No regional lymph node metastases; N1=regional lymph node metastases.
M0=no distant metastases; M1a=distant metastases in celiac lymph nodes or cervical nodes; M1b=other distant metastases.
Management
The management of end-stage, advanced disease is via chemotherapy, to which 15-30% of patients respond, with tumour shrinkage of up to 50% when treated with flourouracil, and a taxane or irinotecan. This response can extend to over 50% of patients if cisplatin is added to the combination therapy. Irrespective of responsiveness to treatment, the effects rarely last beyond a couple of additional months, with survival beyond 1yr unlikely.
The management of more localised tumours is considerably more successful and can take a number of forms.
Surgery
- Most commonly achieved with use of either a right transthoracic or transhiatal approach
- Right transthoracic approach combines a laparotomy and right-sided thoracotomy
- Results in an oesophago-gastric anastomosis in either the chest or neck.
- The transhiatal approach uses a laparotomy with blunt dissection of the thoracic oesophagus
- The oesophago-gastric anastomosis is placed in the neck.
- Whilst the former technique allows for a better field view, the thoracotomy increases the risk of cardiopulmonary complications
- Patients undergoing surgery as the sole method of treatment had a median survival rate of between 13 and 19 months.
- 5yr survival is between 15% and 24%
Radiotherapy
- The primary advantage of radiotherapy is the avoidance of perioperative morbidity and mortality
- As a result it is a good alternative for patients for whom surgery is not a viable option.
- Not as effective a palliative method as surgery in providing reliable and prolonged relief of dysphagia and odynophagia.
- Associated with a higher probability of catastrophic local and regional complications (e.g. oesophageal fistulas)
Pre-operative Radio-/Chemo-therapies
- These are of little benefit over no preoperative therapy, with studies disagreeing over the effectiveness of chemotherapy.
- Radiotherapy alone offers no preoperative benefit.
Post-operative Treatment
- Postoperative chemotherapy/radiotherapy combination treatments are often offered to patients whose tumour cells extend into the surgical margin
- This has proven to be of some benefit
- This is of little benefit to patients who have no evidence of residual disease.
Non-surgical Combination Chemotherapy/Radiotherapy
- Combines radiotherapy with cisplatin and fluorouracil regimens
- Has led to long-term survival in approximately 25% of patients
- This outcome is comparable to that of surgical management
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