Oesophageal Cancer (Adult)

1. Clinical Overview

Summary

Oesophageal cancer is a highly aggressive malignancy of the oesophagus with two distinct histological subtypes: adenocarcinoma (typically lower third, arising from Barrett's metaplasia, strongly associated with gastro-oesophageal reflux disease [GORD], obesity, and male sex) and squamous cell carcinoma (typically upper and middle thirds, linked to smoking, alcohol consumption, and dietary carcinogens). [1,2]

The cardinal presenting symptom is progressive dysphagia—initially for solids, then advancing to liquids—representing mechanical obstruction. This is typically accompanied by significant unintentional weight loss, often exceeding 10% of body weight. The majority of patients present with locally advanced or metastatic disease, contributing to a poor overall 5-year survival rate of approximately 15-20%. [3,4]

Diagnosis is established by upper gastrointestinal endoscopy (OGD) with biopsy and histological confirmation. Staging requires multimodal imaging including CT chest/abdomen/pelvis, endoscopic ultrasound (EUS) for locoregional assessment, and PET-CT to detect occult distant metastases. [5]

Curative treatment for localised disease involves multimodal therapy: neoadjuvant chemotherapy (FLOT regimen) or chemoradiotherapy (CROSS protocol) followed by oesophagectomy (Ivor Lewis, McKeown, or transhiatal approaches). Palliative management includes self-expanding metal stents (SEMS) for dysphagia, external beam radiotherapy, systemic chemotherapy, and immune checkpoint inhibitors (nivolumab, pembrolizumab) for PD-L1 positive tumours. [6,7,8]

Early detection through Barrett's surveillance programmes and prompt referral for new-onset dysphagia (especially age > 55 years) are critical for improving outcomes. [9]

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Key Facts

Epidemiology & Risk Factors

• Incidence: ~9,200 cases/year in UK; 7th most common cancer [1]
• Male predominance: M:F ratio 3:1 for adenocarcinoma, 2:1 for squamous [2]
• Peak age: 60-80 years
• Adenocarcinoma: Rising incidence (Barrett's, obesity, GORD) [2]
• Squamous: Declining in West (reduced smoking), high in East Asia/Africa [10]

Histological Types

• Adenocarcinoma (60% in West): Lower third/GOJ, Barrett's → dysplasia → cancer
• Squamous cell (40% in West, 90% in Asia): Upper/middle third, alcohol, smoking, hot beverages

Clinical Features

• Progressive dysphagia: Solids → liquids (mechanical obstruction)
• Weight loss: Often > 10 kg, indicative of advanced disease
• Odynophagia: Painful swallowing (suggests deep invasion)
• Hoarseness: Recurrent laryngeal nerve (RLN) involvement (T4 disease, typically incurable)
• Regurgitation, aspiration, cough: Overflow or tracheo-oesophageal fistula

Diagnostic Pathway

• OGD + Biopsy: Gold standard for diagnosis [5]
• Staging: CT CAP, EUS (T/N stage), PET-CT (distant metastases) [5]
• MDT discussion: All cases reviewed by upper GI cancer MDT

Management Summary

• Localised (T1-3, N0-1, M0): Neoadjuvant chemotherapy/CRT → oesophagectomy [6,7]
• Early mucosal (T1a): Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) [11]
• Advanced/Metastatic (M1): Palliative chemotherapy, immunotherapy, stenting, radiotherapy [8,12]

Prognosis

• Overall 5-year survival: 15-20% [3,4]
• Stage I: 50-60%; Stage II: 30-40%; Stage III: 15-25%; Stage IV: less than 5% [4]
• Post-operative mortality: 3-5% (high-volume centres) [13]

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Clinical Pearls

"Solids Before Liquids = Mechanical Obstruction": Progressive dysphagia starting with solids, then advancing to liquids, is pathognomonic of mechanical obstruction (malignancy or benign stricture). Simultaneous difficulty with both solids and liquids from onset suggests a motility disorder (achalasia, diffuse oesophageal spasm).

"Barrett's Is the Precursor for Adenocarcinoma": The metaplasia-dysplasia-carcinoma sequence: GORD → Barrett's oesophagus (intestinal metaplasia) → low-grade dysplasia (LGD) → high-grade dysplasia (HGD) → adenocarcinoma. Annual progression risk from Barrett's to cancer is 0.1-0.3%. [9]

"Upper = Squamous, Lower = Adenocarcinoma": Squamous cell carcinoma arises in upper and middle oesophagus (stratified squamous epithelium); adenocarcinoma in lower third/gastro-oesophageal junction (columnar metaplasia). This anatomical distinction reflects differing aetiologies.

"Hoarseness = Recurrent Laryngeal Nerve Involvement = T4 Disease": New-onset hoarseness in a patient with dysphagia suggests direct invasion of the recurrent laryngeal nerve, indicating locally advanced (T4) disease. This is typically incurable and precludes curative surgery.

"Weight Loss > 10% = Poor Prognosis": Significant unintentional weight loss (> 10% body weight in 6 months) is a powerful negative prognostic indicator and often signifies advanced disease. Early nutritional intervention is critical.

"CROSS vs FLOT: Chemoradiotherapy vs Chemotherapy": CROSS protocol (carboplatin/paclitaxel + 41.4 Gy radiotherapy) is standard for squamous cell carcinoma and lower-third adenocarcinoma. FLOT regimen (5-FU/leucovorin/oxaliplatin/docetaxel) is increasingly preferred for gastro-oesophageal junction (GOJ) adenocarcinoma. [6,7]

"Dysphagia Age > 55 = 2-Week Wait Referral": NICE guidelines mandate urgent (2-week wait) upper GI endoscopy for new-onset dysphagia in patients aged 55 years or older to exclude malignancy. [14]

"PD-L1 Positive = Immunotherapy Eligible": First-line nivolumab plus chemotherapy for advanced oesophageal cancer with PD-L1 combined positive score (CPS) ≥5 improves overall survival versus chemotherapy alone (CheckMate 648 trial). [8]

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2. Epidemiology

Incidence & Prevalence

Oesophageal cancer is the 7th most common cancer in the UK with approximately 9,200 new cases diagnosed annually. Globally, it ranks as the 8th most common cancer and the 6th leading cause of cancer death, with over 604,000 new cases and 544,000 deaths worldwide in 2020. [1,15]

The incidence varies dramatically by geography:

• Highest rates: Eastern Asia (China, Japan), Eastern Africa (Kenya, Malawi), Southern Africa, Iran, Central Asia ("oesophageal cancer belt")
• Moderate rates: Western Europe, North America, Australia
• Lowest rates: Western Africa, Central America [15]

Temporal Trends

Adenocarcinoma incidence has increased 6-fold in Western countries over the past 40 years, one of the most dramatic rises of any solid tumour. This mirrors the rising prevalence of obesity and GORD. In the UK, adenocarcinoma now accounts for 60% of oesophageal cancers (versus 30% in the 1980s). [2,16]

Squamous cell carcinoma incidence has declined by 30-40% in Western countries over the same period, attributed to reduced smoking rates and lower alcohol consumption. However, it remains the dominant histology in Asia and Africa. [10]

Demographics

Age

• Peak incidence: 60-80 years
• Median age at diagnosis: 68 years
• Rare in patients less than 40 years (except in high-incidence geographic regions or familial syndromes)

Sex

• Adenocarcinoma: Male:female ratio 7:1 (strongest male predominance of any cancer)
• Squamous cell carcinoma: Male:female ratio 2-3:1
• Overall male predominance: 3:1 [2]

Ethnicity

• Squamous cell carcinoma: Higher incidence in Black and Asian populations
• Adenocarcinoma: Higher incidence in White populations
• Barrett's oesophagus (precursor to adenocarcinoma) is rare in non-White populations

Socioeconomic Factors

Oesophageal cancer exhibits a strong socioeconomic gradient:

• Squamous cell carcinoma: 2-3 times higher incidence in most deprived quintile (smoking, alcohol, poor diet)
• Adenocarcinoma: Association with obesity partly offsets socioeconomic gradient
• Survival is 10-15% lower in deprived groups due to later presentation and reduced access to surgery [17]

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3. Aetiology & Risk Factors

Adenocarcinoma Risk Factors

Barrett's Oesophagus (Strongest Risk Factor)

• 50-100 fold increased risk compared to general population [9]
• Annual progression rate: 0.1-0.3% from non-dysplastic Barrett's
• Progression accelerates with dysplasia: 5-10%/year for high-grade dysplasia (HGD)
• Risk factors for Barrett's: Chronic GORD, obesity, hiatus hernia, male sex, White ethnicity
• Surveillance programmes aim to detect dysplasia before invasive cancer develops [9]

Gastro-oesophageal Reflux Disease (GORD)

• Chronic acid exposure → Barrett's metaplasia → dysplasia → adenocarcinoma
• 5-7 fold increased risk with chronic (> 10 years) symptomatic GORD [18]
• Risk proportional to severity and duration of reflux symptoms
• Proton pump inhibitor (PPI) use may reduce progression risk (controversial) [18]

Obesity

• Body Mass Index (BMI) > 30: 2-3 fold increased risk [2,19]
• Mechanism: Increased intra-abdominal pressure → GORD; adipokine-mediated inflammation
• Abdominal/central obesity confers higher risk than peripheral obesity
• Rising obesity prevalence explains rising adenocarcinoma incidence in Western countries

Male Sex

• 7-fold higher incidence in men versus women (strongest sex difference of any cancer)
• Mechanisms: Hormonal (protective effect of oestrogen?), body fat distribution, higher GORD prevalence in men

Smoking

• 1.5-2 fold increased risk (weaker association than squamous cell) [20]
• Risk persists for years after smoking cessation

Alcohol

• Weak/no association (unlike squamous cell carcinoma)

Dietary Factors

• Low fruit/vegetable intake: Modest increased risk
• High processed meat intake: Possible association

Squamous Cell Carcinoma Risk Factors

Tobacco Smoking (Strongest Modifiable Risk Factor)

• 5-10 fold increased risk in heavy smokers (> 20 pack-years) [20]
• Dose-dependent relationship; risk declines after cessation (but remains elevated for 10-15 years)
• Combination with alcohol confers synergistic risk (multiplicative, not additive)

Alcohol Consumption

• 5-7 fold increased risk with heavy consumption (> 50g ethanol/day) [20]
• Mechanism: Direct mucosal toxicity; acetaldehyde (carcinogenic metabolite); nutritional deficiency (folate, B vitamins)
• Spirits confer higher risk than beer/wine (higher ethanol concentration)

Dietary Carcinogens

• Hot beverages (> 65°C): Thermal injury → chronic inflammation (maté in South America, tea in Iran/China) [21]
• Nitrosamines: Pickled vegetables, smoked/cured meats (high in China)
• Mycotoxins: Aflatoxin, fumonisin (contaminated grains in high-risk regions)
• Betel quid/areca nut chewing: Oral/oesophageal squamous carcinoma (South/Southeast Asia)

Nutritional Deficiencies

• Vitamin A, C, E: Antioxidant deficiency (common in high-risk populations)
• Zinc, selenium: Trace element deficiency
• Riboflavin (B2), niacin (B3)

Plummer-Vinson Syndrome (Paterson-Brown-Kelly Syndrome)

• Triad: Iron-deficiency anaemia + oesophageal web + glossitis
• 10-15% risk of developing post-cricoid/upper oesophageal squamous carcinoma [22]
• Rare in modern era (improved nutrition)

Achalasia

• 16-fold increased risk due to chronic stasis, food retention, inflammation [23]
• Latency period: 15-25 years
• Risk persists even after treatment (Heller myotomy, pneumatic dilatation)

Caustic Injury

• Alkali ingestion (lye) → stricture formation → squamous carcinoma
• 1000-fold increased risk; latency 20-40 years [24]

Tylosis (Howel-Evans Syndrome)

• Rare autosomal dominant condition: Palmoplantar keratoderma + 95% lifetime risk of oesophageal squamous carcinoma [25]
• Mutation in RHBDF2 gene (chromosome 17q25)

Previous Radiation Exposure

• Mediastinal radiotherapy (e.g., Hodgkin lymphoma, breast cancer) → 2-4 fold increased risk after 10-20 years [26]

HPV Infection

• Weak/controversial association (unlike head/neck squamous cancer)
• HPV-16 detected in 10-30% of squamous oesophageal cancers (causative role uncertain)

Shared Risk Factors

• Smoking: Risk factor for both histologies (stronger for squamous)
• Low socioeconomic status: Dietary factors, smoking, alcohol
• Male sex: Both histologies (more pronounced for adenocarcinoma)

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4. Pathophysiology

Molecular Pathogenesis of Adenocarcinoma

The Barrett's Metaplasia-Dysplasia-Carcinoma Sequence [9,27]

1. Normal Squamous Epithelium

   • Stratified squamous epithelium lines distal oesophagus

2. Chronic Acid Exposure (GORD)

   • Bile acids + gastric acid → epithelial injury and inflammation
   • Activation of NF-κB, COX-2, IL-6/8 inflammatory pathways

3. Intestinal Metaplasia (Barrett's Oesophagus)

   • Replacement of squamous epithelium with columnar epithelium containing goblet cells
   • CDX2 (caudal-type homeobox 2) transcription factor drives intestinal differentiation
   • Loss of TP53 function in subset of cells
   • Non-dysplastic Barrett's: Annual cancer risk 0.1-0.3%

4. Low-Grade Dysplasia (LGD)

   • Accumulation of genetic alterations: TP53 mutations, CDKN2A loss, chromosomal instability
   • Histological atypia without invasion
   • Progression to HGD: 5-10% per year

5. High-Grade Dysplasia (HGD)

   • Severe cytological atypia, loss of cellular polarity
   • Additional mutations: SMAD4, PIK3CA, ERBB2 (HER2) amplification
   • Progression to invasive cancer: 10-15% per year
   • Treatment indicated (endoscopic resection ± ablation)

6. Invasive Adenocarcinoma

   • Breach of basement membrane, stromal invasion
   • Angiogenesis (VEGF), epithelial-mesenchymal transition (EMT)
   • Capacity for lymphovascular invasion and metastasis

Exam Detail: Key Molecular Alterations in Oesophageal Adenocarcinoma [27,28]

HER2 Amplification: Trastuzumab (anti-HER2 monoclonal antibody) added to chemotherapy in HER2-positive (IHC 3+ or FISH+) metastatic gastro-oesophageal adenocarcinoma improves overall survival by 2.7 months (ToGA trial). [29]

Molecular Pathogenesis of Squamous Cell Carcinoma

Field Cancerisation and Multi-Hit Carcinogenesis [30]

Squamous cell carcinoma arises from accumulation of genetic and epigenetic alterations in the native squamous epithelium, driven by chronic exposure to carcinogens (tobacco, alcohol, dietary toxins).

Progressive Histological Changes:

1. Normal squamous epithelium
2. Basal cell hyperplasia (proliferative response to injury)
3. Dysplasia (low-grade → high-grade)
4. Carcinoma in situ (full-thickness dysplasia, no invasion)
5. Invasive squamous cell carcinoma

Key Molecular Alterations [30,31]

Squamous vs Adenocarcinoma Molecular Distinction: Squamous carcinomas exhibit higher rates of TP53 mutation (> 90% vs 70%), more frequent PIK3CA alterations, and NOTCH1 inactivation. Adenocarcinomas show higher rates of HER2 amplification and chromosomal instability.

Patterns of Spread

Local Extension

• Direct invasion: Oesophageal wall layers (mucosa → submucosa → muscularis propria → adventitia)
• Mediastinal structures: Trachea, left main bronchus (tracheo-oesophageal fistula), aorta, pericardium, diaphragm
• Nerves: Recurrent laryngeal nerve (hoarseness), vagus, sympathetic chain

Lymphatic Spread

• Rich submucosal lymphatic plexus → early lymph node involvement (30-40% even in T1 tumours)
• Longitudinal spread: Skip lesions common (nodes distant from primary)
• Upper/middle third tumours: Cervical, supraclavicular, mediastinal nodes
• Lower third/GOJ tumours: Coeliac axis, left gastric, lesser curve nodes

Haematogenous Spread

• Common sites: Liver (most common), lungs, bone, adrenal glands, brain (late)
• Typically indicates Stage IV disease

Peritoneal Spread

• Gastro-oesophageal junction (GOJ) tumours may breach serosa → peritoneal carcinomatosis

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5. Clinical Presentation

Symptoms

Cardinal Symptom: Progressive Dysphagia [3]

The hallmark of oesophageal cancer is progressive mechanical dysphagia:

• Initial: Difficulty swallowing solids (bread, meat)
• Progression: Advancing to semi-solids, then liquids
• Timeline: Weeks to months
• Significance: By the time dysphagia occurs, the tumour typically occludes > 50-60% of the oesophageal lumen

Contrast with Motility Disorders: Achalasia or diffuse oesophageal spasm present with dysphagia for solids AND liquids from onset, with intermittent symptoms. Mechanical obstruction shows relentless progression.

Odynophagia (Painful Swallowing)

• Suggests deep invasion through oesophageal wall (T3/T4)
• Mediastinal invasion or perineural involvement
• Poor prognostic sign

Weight Loss

• Present in 70-80% at diagnosis
• Often > 10% body weight in 3-6 months
• Mechanisms: Reduced oral intake (dysphagia), cancer cachexia (cytokine-mediated catabolism)
• Independent poor prognostic factor [32]

Regurgitation

• Undigested food/saliva due to obstruction
• Risk of aspiration pneumonia

Heartburn/Reflux

• May precede dysphagia by months/years (especially adenocarcinoma with background GORD)
• New-onset or worsening reflux in older patient warrants investigation

Chest Pain

• Retrosternal discomfort
• May indicate mediastinal invasion

Respiratory Symptoms

• Chronic cough: Aspiration (overflow), tracheal invasion
• Recurrent pneumonia: Aspiration
• Haemoptysis: Tracheo-oesophageal fistula (late complication)

Hoarseness

• Recurrent laryngeal nerve (RLN) involvement → vocal cord paralysis
• Indicates T4 disease (unresectable in most cases)
• Left RLN more commonly affected (longer course around aortic arch)

Haematemesis/Melaena

• Tumour ulceration and bleeding
• Rarely massive (erosion into aorta or major vessel = surgical emergency)

Systemic Symptoms

• Anorexia, fatigue, night sweats (paraneoplastic or advanced disease)

Signs

General Examination

• Cachexia: Temporal wasting, muscle loss, BMI less than 18.5
• Pallor: Anaemia (chronic bleeding, nutritional deficiency)
• Dehydration: Poor oral intake
• Performance status: WHO/ECOG score 2-4 (poor prognosis)

Lymphadenopathy

• Supraclavicular nodes (especially left Virchow's node = Troisier's sign): Metastatic disease
• Cervical nodes: Upper/middle third tumours

Abdominal Examination

• Hepatomegaly: Liver metastases (hard, irregular, nodular)
• Ascites: Peritoneal metastases (GOJ tumours)
• Epigastric mass: Large GOJ tumours (rare)

Voice Assessment

• Hoarseness: RLN palsy (request laryngoscopy to assess vocal cord mobility)

Respiratory Examination

• Crackles/consolidation: Aspiration pneumonia
• Pleural effusion: Malignant (rare)

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6. Differential Diagnosis

The differential diagnosis of progressive dysphagia is broad and includes both benign and malignant aetiologies.

Mechanical Obstruction

Motility Disorders

Other Causes

• Oesophageal candidiasis: Immunosuppression (HIV, steroids); odynophagia; white plaques on OGD
• Eosinophilic oesophagitis: Young adults; food impaction; atopy; eosinophils on biopsy
• Pharyngeal cancer: Oropharyngeal dysphagia (difficulty initiating swallow)
• Neurological: Stroke, Parkinson's, MND (oropharyngeal dysphagia, aspiration, neurological signs)
• Globus pharyngeus: Sensation of lump in throat; no true dysphagia; normal OGD

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7. Investigations

Initial Assessment

Blood Tests

Diagnostic Investigations

Upper Gastrointestinal Endoscopy (OGD) [5]

• Gold standard for diagnosis
• Indications: New-onset dysphagia (especially age > 55), dyspepsia with alarm features, Barrett's surveillance
• Findings:
  • "Adenocarcinoma: Distal oesophagus/GOJ; irregular ulcerated mass; Barrett's mucosa proximally"
  • "Squamous: Mid/upper oesophagus; exophytic or ulcerated mass"
• Biopsy: Multiple samples (6-8 biopsies) from mass and surrounding mucosa
  • Histology confirms type (adenocarcinoma vs squamous)
  • "Differentiation: Well, moderate, poorly differentiated"
  • HER2 immunohistochemistry (if adenocarcinoma; guides trastuzumab eligibility)
  • PD-L1 combined positive score (CPS) (guides immunotherapy)

Histopathology

• Adenocarcinoma: Glandular differentiation; mucin production; arises from Barrett's columnar epithelium
• Squamous cell carcinoma: Keratin pearls; intercellular bridges; arises from native squamous epithelium
• Grading: G1 (well differentiated) → G3 (poorly differentiated)

Staging Investigations

TNM 8th Edition Staging (AJCC/UICC) [33]

Staging determines treatment strategy (curative vs palliative) and prognosis.

CT Chest/Abdomen/Pelvis (Contrast-Enhanced) [5]

• Purpose: Assess distant metastases (M stage)
• Findings:
  • Liver metastases (most common)
  • Lung metastases/nodules
  • Distant lymph nodes (coeliac, para-aortic)
  • Ascites (peritoneal disease)
  • Adrenal metastases
• Limitations: Poor sensitivity for T/N staging (cannot assess depth of invasion or small lymph nodes)

Endoscopic Ultrasound (EUS) [5]

• Purpose: Assess depth of tumour invasion (T stage) and locoregional lymph nodes (N stage)
• Technique: Endoscope with ultrasound probe; assesses five-layer oesophageal wall structure
• T Staging:
  • "T1: Invasion into mucosa (T1a) or submucosa (T1b)"
  • "T2: Invasion into muscularis propria"
  • "T3: Invasion into adventitia"
  • "T4: Invasion into adjacent structures (aorta, trachea, pericardium)"
• N Staging: Identifies malignant-appearing nodes (size > 1 cm, round, hypoechoic, well-defined margins)
  • "EUS-guided fine-needle aspiration (FNA): Confirms nodal metastases"
• Accuracy: 80-90% for T stage; 70-80% for N stage
• Limitations: Cannot traverse tight strictures (10-20% of cases)

PET-CT (18F-FDG Positron Emission Tomography) [5,34]

• Purpose: Detect occult distant metastases (M stage); assess nodal disease
• Findings:
  • Primary tumour (intense FDG uptake)
  • Distant metastases (liver, lung, bone, distant nodes) not visible on CT
  • Changes management in 15-20% of cases (upstaging to M1)
• Limitations: False positives (inflammation, infection); false negatives (mucinous tumours, small lesions less than 1 cm)
• Use: Routinely performed in potentially resectable disease (Stage I-III)

Staging Laparoscopy [35]

• Indication: Lower third/GOJ adenocarcinoma (if potentially resectable on imaging)
• Purpose: Detect peritoneal metastases, liver surface metastases, malignant ascites not visible on CT/PET
• Technique: Diagnostic laparoscopy ± peritoneal washings (cytology)
• Findings: Small peritoneal deposits, liver metastases → Stage IV (avoid unnecessary laparotomy)
• Yield: Identifies occult M1 disease in 10-15% of cases

Bronchoscopy

• Indication: Upper/middle third tumours on CT/PET suspicious for tracheal/bronchial invasion
• Purpose: Assess airway involvement (T4b disease = unresectable)

Additional Investigations

Nutritional Assessment

• Weight loss: Percentage body weight lost over 6 months
• Body Mass Index (BMI): less than 18.5 = severe malnutrition
• Albumin: less than 30 g/L = poor nutritional state
• Dietitian review: All patients (pre-operative optimisation)

Cardiopulmonary Assessment (Pre-operative)

• CPEX (Cardiopulmonary Exercise Testing): VO2 max, anaerobic threshold (predict post-op complications)
• Pulmonary function tests: FEV1, FVC (assess fitness for thoracotomy)
• Echocardiography: Cardiac function (if Hx of cardiac disease)

Tumour Markers

• No validated serum tumour markers for oesophageal cancer
• CEA, CA 19-9 may be elevated (non-specific; not used for diagnosis/staging)

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8. Classification & Staging

TNM Classification (8th Edition, 2017) [33]

T - Primary Tumour

N - Regional Lymph Nodes

M - Distant Metastases

Stage Grouping (Adenocarcinoma)

Exam Detail: Key Staging Distinctions for Exams:

1. T1a vs T1b: Critical for treatment decisions

   • T1a (mucosal): Eligible for endoscopic resection (EMR/ESD)
   • T1b (submucosal): Requires oesophagectomy (high risk of lymph node metastases ~20%)

2. T4a vs T4b:

   • T4a (pleura, pericardium, diaphragm): Potentially resectable (en-bloc resection)
   • T4b (aorta, trachea, vertebra): Unresectable (palliative intent only)

3. N Staging: Number of positive nodes is powerful prognostic factor (more important than location)

4. M1 Disease: Any distant metastasis (including non-regional lymph nodes) = Stage IV = palliative intent

Siewert Classification (Gastro-oesophageal Junction Tumours) [36]

For tumours centred within 5 cm of the GOJ:

Clinical relevance: Type I/II treated as oesophageal cancer; Type III treated as gastric cancer (different lymphatic drainage and chemotherapy protocols).

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9. Management

Multidisciplinary Team (MDT) Approach

All patients with suspected or confirmed oesophageal cancer must be discussed at an Upper GI Cancer MDT meeting prior to treatment. [14]

MDT Membership:

• Upper GI surgeon (oesophago-gastric specialist)
• Medical oncologist
• Clinical oncologist (radiotherapy)
• Gastroenterologist
• Radiologist (specialist GI)
• Histopathologist (GI specialist)
• Clinical nurse specialist (CNS)
• Dietitian
• Palliative care physician

MDT Decisions:

1. Confirm diagnosis and staging
2. Assess resectability (curative vs palliative intent)
3. Determine treatment pathway (surgery, chemotherapy, radiotherapy, endoscopic therapy)
4. Assess fitness for major surgery (performance status, comorbidities)

Treatment Pathways by Stage

Stage 0 (High-Grade Dysplasia) and T1a (Mucosal)

→ Endoscopic Therapy [11]

Indications:

• HGD or T1a tumour confined to mucosa (M1-M3)
• No lymphovascular invasion
• Well/moderately differentiated
• Lesion less than 2-3 cm (EMR) or any size (ESD)

Techniques:

1. Endoscopic Mucosal Resection (EMR):

   • Submucosal injection (saline/adrenaline) → lift lesion → snare resection
   • En-bloc resection if less than 2 cm; piecemeal if larger
   • R0 resection rate: 60-80%

2. Endoscopic Submucosal Dissection (ESD):

   • Circumferential incision → submucosal dissection → en-bloc resection
   • R0 resection rate: 85-95%
   • Higher perforation risk (5%) vs EMR (1-2%)

3. Radiofrequency Ablation (RFA) (for residual Barrett's post-EMR):

   • Thermal ablation of Barrett's mucosa
   • Reduces recurrence risk

Post-resection surveillance: 3-monthly OGD for 1 year, then annual

Success: 5-year survival > 90% for mucosal disease

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Stage I-III (Localised, Potentially Resectable)

→ Multimodal Curative Therapy [6,7]

Treatment Sequence:

1. Neoadjuvant therapy (chemotherapy or chemoradiotherapy)
2. Oesophagectomy (surgical resection)
3. Adjuvant therapy (if indicated)

Neoadjuvant Chemotherapy

FLOT Regimen (Preferred for Adenocarcinoma, especially GOJ) [6]

• Drugs: 5-Fluorouracil + Leucovorin + Oxaliplatin + Docetaxel
• Schedule: 4 cycles pre-operative + 4 cycles post-operative
• Duration: 8 weeks pre-op
• Evidence: FLOT4 trial (gastro-oesophageal adenocarcinoma): Superior to ECF/ECX; improved pathological response and survival [6]
• Efficacy: Pathological complete response (pCR) ~15-20%; R0 resection rate 85%

Alternative Regimen: ECF/ECX (Epirubicin + Cisplatin + 5-FU/Capecitabine) - older regimen, lower efficacy than FLOT

Neoadjuvant Chemoradiotherapy (CRT)

CROSS Protocol (Standard for Squamous Cell; Option for Adenocarcinoma) [7]

• Chemotherapy: Carboplatin (AUC 2) + Paclitaxel (50 mg/m²) weekly × 5 weeks
• Radiotherapy: 41.4 Gy in 23 fractions (5 weeks)
• Evidence: CROSS trial (2012): CRT vs surgery alone → improved median survival (49 vs 24 months); pathological complete response 29% (49% for squamous, 23% for adenocarcinoma) [7]
• Use: Preferred for squamous cell carcinoma (higher pCR); option for adenocarcinoma if surgery planned within 6-8 weeks

CROSS vs FLOT Decision:

• Squamous cell: CROSS (CRT) preferred
• Adenocarcinoma (mid-distal oesophagus): CROSS or FLOT (institutional preference)
• GOJ adenocarcinoma (Siewert II/III): FLOT preferred (more gastric-like)

Surgical Resection: Oesophagectomy

Indications:

• Localised disease (T1b-T3, N0-N2, M0) post-neoadjuvant therapy
• Medically fit for major surgery (performance status 0-1)
• Adequate pulmonary and cardiac function

Goals:

• R0 resection (microscopically clear margins > 1 mm)
• Adequate lymphadenectomy (minimum 15 lymph nodes for accurate staging)
• Reconstruction (gastric conduit or colonic interposition)

Surgical Approaches [13]

1. Ivor Lewis Oesophagectomy (Right Thoraco-Abdominal)

• Approach: Laparotomy + right thoracotomy (or VATS)
• Steps:
  1. Abdominal phase: Mobilise stomach, divide left gastric vessels, create gastric conduit (tube)
  2. Thoracic phase: Mobilise oesophagus, resect tumour, two-field lymphadenectomy
  3. Anastomosis: Oesophago-gastric in right chest (intrathoracic)
• Indications: Lower/middle third tumours
• Advantages: Excellent exposure; adequate proximal margin
• Disadvantages: Intrathoracic anastomosis (if leak → mediastinitis, high mortality)

2. McKeown (Three-Phase) Oesophagectomy

• Approach: Laparotomy + right thoracotomy + cervical incision
• Steps: 1-2. As Ivor Lewis (abdominal + thoracic mobilisation) 3. Cervical phase: Oesophago-gastric anastomosis in neck
• Indications: Upper/middle third tumours (require longer proximal margin)
• Advantages: Cervical anastomosis (if leak → controlled fistula, lower mortality)
• Disadvantages: Three incisions; higher recurrent laryngeal nerve injury risk (5-10%)

3. Transhiatal Oesophagectomy

• Approach: Laparotomy + cervical incision (no thoracotomy)
• Steps: Blunt dissection of oesophagus via diaphragmatic hiatus (from below) and cervical approach (from above)
• Indications: Frail patients, lower third tumours, benign disease
• Advantages: Avoids thoracotomy (lower respiratory complications)
• Disadvantages: Limited lymphadenectomy, risk of mediastinal bleeding (no direct visualisation)

Minimally Invasive Oesophagectomy (MIO)

• Laparoscopy + thoracoscopy (VATS) ± robot-assisted
• Benefits: Reduced pain, lower pulmonary complications, shorter hospital stay (vs open) [37]
• Oncological outcomes: Equivalent to open (if performed in high-volume centres)

Lymphadenectomy

• Two-field: Abdominal + thoracic nodes (standard in West)
• Three-field: Abdominal + thoracic + cervical nodes (standard in Japan for upper/middle third; higher morbidity, unclear survival benefit)

Reconstruction

• Gastric conduit (preferred): Tubularised stomach pulled into chest/neck
• Colonic interposition: If stomach unavailable (previous surgery, ischaemia)
• Jejunal interposition: Rare

Post-operative Management

• ICU/HDU for 1-3 days
• Nasogastric tube (decompression; removed Day 5 if no leak)
• Feeding jejunostomy (inserted during surgery): Enteral nutrition from Day 1
• Water-soluble contrast swallow (Day 5-7): Assess anastomosis before oral diet
• Chest physiotherapy, early mobilisation (reduce pneumonia risk)

Post-operative Complications [13,38]

Mortality:

• High-volume centres (> 20 cases/year): 3-5%
• Low-volume centres: 10-15% [13]
• Age > 70, comorbidities, emergency surgery increase risk

Enhanced Recovery After Surgery (ERAS)

• Pre-operative counseling, optimisation (nutrition, smoking cessation)
• Multimodal analgesia (epidural)
• Early enteral feeding (jejunostomy)
• Early mobilisation
• Reduces complications and hospital stay [39]

---

Stage IV (Metastatic Disease)

→ Palliative Systemic Therapy + Supportive Care [8,12,40]

Goals: Prolong survival, control symptoms, maintain quality of life

First-Line Palliative Chemotherapy

1. Nivolumab + Chemotherapy (if PD-L1 CPS ≥5) [8]

• Regimen: Nivolumab (anti-PD-1 antibody) + FOLFOX or Cisplatin/5-FU
• Evidence: CheckMate 648 trial (2021): Nivolumab + chemo vs chemo alone in advanced oesophageal squamous → improved OS (15.4 vs 9.1 months) for PD-L1 CPS ≥5 [8]
• Eligibility: Squamous or adenocarcinoma; PD-L1 CPS ≥5 (IHC test on biopsy)
• Toxicity: Immune-related adverse events (irAEs): Colitis, hepatitis, pneumonitis, thyroiditis

2. Trastuzumab + Chemotherapy (if HER2-positive) [29]

• Regimen: Trastuzumab (anti-HER2 antibody) + Cisplatin/5-FU or Capecitabine/Oxaliplatin
• Evidence: ToGA trial (2010): Trastuzumab + chemo vs chemo alone in HER2+ gastro-oesophageal adenocarcinoma → improved OS (13.8 vs 11.1 months) [29]
• Eligibility: Adenocarcinoma; HER2 IHC 3+ or FISH+ (15-25% of adenocarcinomas)
• Toxicity: Cardiac dysfunction (monitor LVEF)

3. Chemotherapy Alone (if PD-L1/HER2 negative or contraindicated)

• FOLFOX: 5-FU + Leucovorin + Oxaliplatin (q2 weeks)
• ECF/ECX: Epirubicin + Cisplatin + 5-FU/Capecitabine
• Cisplatin/5-FU: Standard doublet
• Median OS: 8-11 months

Second-Line Palliative Therapy

Ramucirumab (anti-VEGFR2 antibody) + Paclitaxel [40]

• Evidence: RAINBOW trial: Ramucirumab + paclitaxel vs paclitaxel alone → improved OS (9.6 vs 7.4 months) [40]
• Indication: Progressive disease after first-line platinum-based chemotherapy

Pembrolizumab (if MSI-H/dMMR) [41]

• Indication: Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours (less than 5% of oesophageal cancers)
• Evidence: High response rate (~40-50%) to PD-1 inhibitors in MSI-H tumours

Palliative Local Therapy

Self-Expanding Metal Stent (SEMS) [42]

• Indication: Dysphagia due to malignant obstruction (unresectable or metastatic disease)
• Technique: Endoscopic deployment of covered or uncovered metal stent across tumour
• Benefits: Immediate relief of dysphagia (90% success rate); improved ability to swallow liquids/soft diet
• Complications:
  • Migration (10-15%, especially covered stents)
  • Tumour overgrowth/ingrowth (20-30% at 3-6 months; requires re-stenting or ablation)
  • Perforation (5%)
  • Chest pain (common, usually self-limiting)
• Contraindications: Proximal oesophageal tumours (less than 2 cm from cricopharyngeus; stent causes severe discomfort)

Palliative External Beam Radiotherapy (EBRT)

• Indication: Dysphagia, bleeding, pain (if stent not suitable or failed)
• Regimen: 20-30 Gy in 5-10 fractions
• Benefits: Symptom relief in 60-70%; slower onset than stenting (2-4 weeks)
• Toxicity: Oesophagitis, fatigue

Endoscopic Ablation

• Indication: Tumour overgrowth in stented patients
• Techniques: Argon plasma coagulation (APC), laser therapy

Nutritional Support [43]

Critical in palliative oesophageal cancer (dysphagia → malnutrition → cachexia).

Options:

1. Oral diet modification: Soft/pureed diet, high-calorie supplements
2. Enteral feeding:
   • Nasogastric (NG) tube: Short-term (less than 4 weeks); bypasses obstruction
   • Percutaneous endoscopic gastrostomy (PEG): Long-term (if life expectancy > 4 weeks and complete obstruction)
   • Radiologically inserted gastrostomy (RIG): If endoscopy not feasible
3. Parenteral nutrition (TPN): If enteral route not possible (bowel obstruction, malabsorption)

Dietitian involvement: Essential for all patients (optimise caloric intake, reduce aspiration risk)

Best Supportive Care

• Pain management: Opioids (morphine, oxycodone), neuropathic agents (gabapentin, amitriptyline)
• Anti-emetics: Metoclopramide, ondansetron, haloperidol
• Acid suppression: PPIs (reduce reflux, bleeding risk)
• Palliative care team involvement: Symptom control, advance care planning, psychological support
• End-of-life care: Recognition of dying, discontinuation of futile interventions, focus on comfort

---

10. Complications

Complications of Disease

Complete Oesophageal Obstruction

• Inability to swallow saliva → drooling, dehydration
• Management: Urgent stenting or feeding tube (NG/PEG)

Aspiration Pneumonia

• Overflow aspiration of retained food/saliva
• Recurrent pneumonia (same lobe) suggests fistula
• Management: Antibiotics, chest physiotherapy, NBM, enteral feeding

Tracheo-oesophageal Fistula (TOF) [44]

• Abnormal communication between oesophagus and trachea/bronchus (5-10% of advanced cases)
• Presentation: Coughing with eating/drinking, recurrent pneumonia, haemoptysis
• Diagnosis: CT chest (air in oesophagus), endoscopy (visualise fistula), barium swallow (avoid; risk of aspiration)
• Management:
  • Covered oesophageal stent (blocks fistula opening)
  • NBM + enteral feeding (PEG/RIG)
  • Palliative radiotherapy (may close small fistula)
• Prognosis: Median survival 1-3 months (usually end-stage disease)

Massive Haemorrhage

• Tumour erosion into aorta, pulmonary vessels (rare, often fatal)
• Presentation: Massive haematemesis, haemodynamic collapse
• Management: Resuscitation, blood transfusion, palliative sedation (if terminal)

Malnutrition and Cachexia

• Progressive weight loss, sarcopenia
• Impact: Impairs quality of life, functional status, chemotherapy tolerance
• Management: Nutritional support (enteral feeding), appetite stimulants (megestrol, steroids)

Bone Metastases

• Presentation: Bone pain, pathological fractures, spinal cord compression
• Management: Analgesia, bisphosphonates (zoledronic acid), palliative radiotherapy, orthopaedic stabilisation

Complications of Treatment

Oesophagectomy (see Management section) [38]

• Anastomotic leak (10-15%)
• Pneumonia (15-20%)
• RLN injury (5-10%)
• Chyle leak (2-5%)
• Stricture (20-30%, long-term)

Neoadjuvant Chemotherapy

• Neutropenic sepsis (5-10%): G-CSF support
• Peripheral neuropathy (oxaliplatin, paclitaxel): Dose reduction
• Renal impairment (cisplatin): Hydration, avoid if CrCl less than 60 mL/min
• Nausea/vomiting: 5-HT3 antagonists, dexamethasone

Neoadjuvant Chemoradiotherapy (CROSS) [7]

• Acute oesophagitis (70-80%): Analgesia, soft diet
• Post-operative complications: Slightly higher leak rate vs chemo alone (controversial)
• Pulmonary fibrosis (rare, long-term)

Immunotherapy (Nivolumab, Pembrolizumab) [8]

• Immune-related adverse events (irAEs):
  • "Colitis (10-15%): Diarrhoea, abdominal pain; treat with steroids (prednisolone)"
  • "Hepatitis (5%): Monitor LFTs; steroids if severe"
  • "Pneumonitis (3-5%): Dyspnoea, cough; CT chest; high-dose steroids, discontinue drug"
  • "Thyroiditis (5-10%): Hypothyroidism; levothyroxine replacement"
  • Hypophysitis, adrenalitis (rare)
• Management: Early recognition, high-dose steroids, endocrine replacement

Stent Insertion [42]

• Migration (10-15%)
• Tumour overgrowth (20-30%)
• Perforation (5%)
• Chest pain (common, self-limiting)

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11. Prognosis & Outcomes

Survival by Stage [4,33]

Overall 5-year survival (all stages): 15-20% [3,4]

Median survival by stage:

• Localised (I-II): 2-5 years
• Locally advanced (III): 1-2 years
• Metastatic (IV): 8-12 months (with chemotherapy); 3-6 months (best supportive care)

Prognostic Factors

Tumour-Related [32]

• Stage: Most powerful predictor (T, N, M)
• Nodal status: Number of positive nodes (N3 >> N1)
• Differentiation: Poorly differentiated (G3) worse than well differentiated (G1)
• Lymphovascular invasion (LVI): Independent poor prognostic factor
• Circumferential resection margin (CRM): Positive margin (less than 1 mm) → local recurrence, poor survival
• Response to neoadjuvant therapy: Pathological complete response (pCR) associated with 50-60% 5-year survival [7]

Patient-Related

• Performance status: ECOG 0-1 vs 2-4 (10-15% survival difference)
• Weight loss: > 10% body weight loss → 20-30% worse survival
• Age: > 75 years associated with higher post-operative mortality (comorbidities)
• Comorbidities: Cardiac disease, COPD increase surgical risk

Treatment-Related

• Surgical centre volume: High-volume centres (> 20 cases/year) have 50% lower mortality than low-volume centres [13]
• R0 resection: Complete resection (R0) vs incomplete (R1/R2) → 30-40% survival difference
• Lymphadenectomy: ≥15 nodes resected → accurate staging, improved survival

Quality of Life

Oesophagectomy has significant impact on quality of life:

• Early post-operative (0-3 months): Severe impairment (pain, fatigue, dysphagia, reflux)
• Recovery (6-12 months): Gradual improvement; 70-80% return to baseline
• Long-term (> 1 year): Persistent issues in 30-40%:
  • Reflux (loss of lower oesophageal sphincter)
  • Dumping syndrome (rapid gastric emptying)
  • Early satiety (small gastric conduit)
  • Weight loss (10-15% body weight)
  • Diarrhoea (vagotomy effect)

Supportive measures:

• Small frequent meals (5-6/day)
• Avoid lying flat post-meals (reflux)
• PPI therapy (lifelong)
• Nutritional supplements

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12. Prevention & Screening

Primary Prevention

Adenocarcinoma

• Reduce GORD: Weight loss, smoking cessation, moderate alcohol, avoid late-night eating
• Obesity reduction: Major modifiable risk factor
• Smoking cessation: 1.5-2 fold risk reduction

Squamous Cell Carcinoma

• Smoking cessation: 5-10 fold risk reduction
• Reduce alcohol consumption: 5-7 fold risk reduction
• Dietary modification: Increase fruit/vegetable intake, reduce hot beverages

Secondary Prevention: Barrett's Surveillance [9,45]

Rationale: Detect dysplasia/early cancer in Barrett's oesophagus when curative endoscopic therapy is feasible

Eligibility:

• Endoscopically confirmed Barrett's oesophagus (≥1 cm segment with intestinal metaplasia on biopsy)
• Fit for endoscopic or surgical intervention
• Life expectancy > 5 years

Surveillance Intervals (BSG/AGA Guidelines):

Technique:

• Four-quadrant biopsies every 2 cm (Seattle protocol)
• High-definition endoscopy with virtual chromoendoscopy (NBI, i-Scan)
• Target visible lesions (nodules, ulcers)

Efficacy: Reduces cancer mortality by 30-50% (downstaging at detection) [45]

Limitations:

• Low yield (cancer detected in less than 0.5% per surveillance episode)
• Cost-effectiveness debated
• Only 5% of oesophageal adenocarcinomas arise in known Barrett's (majority de novo)

Population Screening

Not recommended in UK/USA (low prevalence, poor cost-effectiveness)

High-risk populations: Screening considered in endemic areas (e.g., endoscopic screening in Northern China for squamous cell carcinoma using Lugol's chromoendoscopy)

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13. Special Considerations

Elderly Patients (Age > 75 years)

• Increased surgical risk: Post-operative mortality 8-15% (vs 3-5% in younger patients)
• Comorbidities: Cardiac, pulmonary, renal disease
• Treatment approach:
  • Careful patient selection (performance status, physiological age > chronological age)
  • Consider definitive chemoradiotherapy (non-surgical) if high surgical risk
  • Palliative stenting/radiotherapy if unfit for major therapy

Familial Syndromes

Tylosis (Howel-Evans Syndrome) [25]

• Autosomal dominant; palmoplantar keratoderma + 95% lifetime risk of oesophageal squamous carcinoma
• Surveillance: Annual endoscopy from age 30

Familial Barrett's Oesophagus

• First-degree relatives of Barrett's patients have 2-3 fold increased risk
• Consider screening endoscopy if chronic GORD symptoms

Pregnancy

• Oesophageal cancer in pregnancy: Extremely rare
• Management dilemma: Balance maternal treatment vs fetal safety
• Approach: Multidisciplinary discussion (oncology, obstetrics, neonatology, ethics)
  • "First trimester: Termination often considered if aggressive treatment required"
  • "Second/third trimester: Delay treatment until fetal viability (if disease stable); early delivery if maternal deterioration"

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14. Examination Focus

MRCP/FRCS Clinical Viva Scenarios

Scenario 1: New Diagnosis

"A 68-year-old man with a 3-month history of progressive dysphagia undergoes OGD showing a 5 cm mass in the distal oesophagus. Biopsy confirms adenocarcinoma. How would you investigate and manage this patient?"

Model Answer:

1. Confirm diagnosis: Histology (adenocarcinoma, grade), HER2 status, PD-L1 testing
2. Staging:
   • CT chest/abdomen/pelvis (distant metastases)
   • EUS + FNA (T/N staging)
   • PET-CT (occult metastases)
   • Consider staging laparoscopy (GOJ tumour)
3. Functional assessment: CPEX, PFTs, ECHO (if cardiac Hx), nutritional assessment
4. MDT discussion: Determine resectability, fitness for surgery
5. Treatment plan:
   • If localised (T1-3, N0-2, M0) + fit: Neoadjuvant chemotherapy (FLOT) or CRT (CROSS) → oesophagectomy
   • If T1 a: Consider endoscopic resection (EMR/ESD)
   • If metastatic/unfit: Palliative chemotherapy + stenting
6. Supportive care: CNS involvement, dietitian, smoking cessation

Examiner Follow-Up: "The patient has 4 positive coeliac axis lymph nodes on EUS. What is the stage and does this change management?"

Answer: N2 disease (3-6 nodes) suggests Stage III (if no distant metastases). Still potentially resectable; proceed with neoadjuvant therapy → re-staging → surgery if responding.

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Scenario 2: Barrett's Surveillance

"A 55-year-old man with Barrett's oesophagus undergoes surveillance OGD. A 1 cm nodule is seen and biopsied. Histology shows high-grade dysplasia. What are your management options?"

Model Answer:

1. Confirm HGD: Expert pathologist review (high interobserver variability for dysplasia grading)
2. Staging: Repeat endoscopy with high-definition imaging (NBI/i-Scan) to delineate lesion
3. Treatment options:
   • Endoscopic mucosal resection (EMR) of visible nodule (diagnostic + therapeutic; assess for invasive cancer, depth of invasion)
   • Radiofrequency ablation (RFA) of residual Barrett's (reduce recurrence risk)
4. Post-EMR histology assessment:
   • If HGD only (no invasive cancer): RFA of residual Barrett's → 3-monthly surveillance for 1 year
   • If T1a cancer (mucosal, no LVI, well-differentiated): RFA + surveillance
   • If T1b cancer (submucosal): Discuss oesophagectomy (20% lymph node metastasis risk)
5. Long-term: Endoscopic surveillance (3-6 monthly for 1 year, then annual)

Examiner Follow-Up: "What is the risk of progression to cancer in non-dysplastic Barrett's?"

Answer: 0.1-0.3% per year (1 in 300-1000 per year). Risk increases with dysplasia: LGD 5-10%/year, HGD 10-15%/year.

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Scenario 3: Post-operative Complication

"A 62-year-old man is Day 7 post-Ivor Lewis oesophagectomy. He develops pyrexia (38.5°C), tachycardia, and raised inflammatory markers. What is your differential diagnosis and initial management?"

Model Answer:

Differential diagnosis:

1. Anastomotic leak (most concerning; 10-15% incidence)
2. Pneumonia (15-20%)
3. Wound infection
4. Chyle leak (if pyrexia + milky chest drain output)
5. DVT/PE
6. Line sepsis
7. Cardiac (atrial fibrillation with rapid ventricular response)

Immediate assessment:

• Clinical: Chest pain, dyspnoea, drain output (colour, volume), wound inspection
• Observations: HR, BP, RR, oxygen saturations, urine output
• Bloods: FBC, CRP, U&E, LFTs, lactate, blood cultures
• Imaging:
  • "Chest X-ray: Pneumonia, pleural effusion, pneumomediastinum (suggests leak), pneumothorax"
  • "Water-soluble contrast swallow (Gastrografin): If leak suspected (extravasation at anastomosis)"
  • "CT chest with oral contrast: If clinical suspicion high and contrast swallow equivocal"

If anastomotic leak confirmed:

1. Resuscitation: IV fluids, antibiotics (broad-spectrum), NBM
2. Drain management: Ensure chest drain functioning (if intrathoracic leak)
3. Nutritional support: Commence feeding via jejunostomy tube
4. Endoscopy: Assess size of leak; consider covered stent if large defect
5. Surgery: If septic/haemodynamically unstable despite resuscitation (washout, wide drainage, possible anastomotic takedown with oesophagostomy)

Examiner Follow-Up: "What is the mortality of anastomotic leak?"

Answer: 10-20% if managed conservatively/endoscopically; up to 50% if requiring re-operation. Early recognition and prompt treatment are critical.

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Viva Topics to Prepare

1. TNM staging (8th edition) - know T1a vs T1b, T4a vs T4b, N staging
2. CROSS vs FLOT protocols - indications, regimens, evidence
3. Oesophagectomy approaches - Ivor Lewis, McKeown, transhiatal (indications, complications)
4. Barrett's surveillance - intervals, progression risk, management of dysplasia
5. Immunotherapy eligibility - PD-L1 testing, CheckMate 648 trial
6. HER2 testing - ToGA trial, trastuzumab indications
7. Palliative stenting - indications, complications
8. Post-operative complications - anastomotic leak (diagnosis, management)

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15. Patient/Layperson Explanation

What is Oesophageal Cancer?

Oesophageal cancer is cancer of the food pipe (oesophagus), the tube that carries food and drink from your mouth to your stomach. When cancer develops in the oesophagus, it can block the passage of food, making it difficult to swallow.

What Are the Types?

There are two main types:

1. Adenocarcinoma (60% of cases in the UK)

   • Develops in the lower part of the food pipe (near the stomach)
   • Linked to long-term acid reflux (heartburn), a condition called Barrett's oesophagus, and being overweight
   • More common in men

2. Squamous Cell Carcinoma (40% of cases in the UK)

   • Develops in the upper and middle parts of the food pipe
   • Linked to smoking and heavy alcohol use
   • More common in Asia and Africa

What Causes Oesophageal Cancer?

For Adenocarcinoma:

• Long-term acid reflux (GORD) → Barrett's oesophagus → cancer
• Being overweight (increases reflux)
• Smoking

For Squamous Cell Cancer:

• Smoking tobacco
• Drinking a lot of alcohol (especially spirits)
• Eating very hot food and drinks (in some countries)

What Are the Symptoms?

The main symptom is difficulty swallowing (dysphagia):

• Starts with trouble swallowing solid foods (bread, meat)
• Gets worse over weeks/months until even liquids are difficult
• Often causes weight loss (difficulty eating)

Other symptoms:

• Heartburn that doesn't get better with medication
• Bringing food back up (regurgitation)
• Hoarse voice (cancer pressing on nerves)
• Chest pain
• Coughing when eating or drinking

Important: If you have difficulty swallowing and are over 55 years old, you should see your doctor urgently for an endoscopy (camera test).

How is Oesophageal Cancer Diagnosed?

Endoscopy (OGD - oesophago-gastro-duodenoscopy):

• A thin flexible camera is passed down your throat (while you're sedated)
• The doctor looks at the food pipe and takes small samples (biopsies) to check for cancer

Staging scans (to see if the cancer has spread):

• CT scan (body scan)
• PET scan (special scan to detect cancer)
• Endoscopic ultrasound (ultrasound probe on the endoscopy camera to see how deep the cancer goes)

How is Oesophageal Cancer Treated?

Treatment depends on how early the cancer is found and your overall health.

Very Early Cancer (confined to the lining):

• Endoscopic removal: The cancer is removed using instruments passed down an endoscopy camera (no surgery needed)
• Outcome: Very good chance of cure (> 90%)

Localised Cancer (not spread to other organs):

• Chemotherapy first (2-4 months of medication to shrink the cancer)
• Surgery (oesophagectomy): Removal of part of the food pipe and nearby lymph nodes; the stomach is pulled up to reconnect the remaining food pipe
• Outcome: 30-50% chance of being cured (5-year survival)

Advanced/Metastatic Cancer (spread to other organs like liver or lungs):

• Palliative treatment (to control symptoms and prolong life):
  • Chemotherapy (medication to slow cancer growth)
  • Immunotherapy (new treatments that help the immune system fight cancer)
  • Stent (metal tube placed inside the food pipe to keep it open so you can swallow)
  • Radiotherapy (to shrink the tumour and reduce symptoms)
  • Feeding tube (to ensure nutrition if you can't swallow)
• Outcome: Treatment can control the cancer for several months to years but usually cannot cure it

What is the Outlook?

The outlook depends on stage (how far the cancer has spread):

• Early stage (cancer only in the lining): 60-80% are alive 5 years later
• Locally advanced (cancer in nearby tissues): 20-40% are alive 5 years later
• Metastatic (cancer spread to other organs): less than 5% are alive 5 years later

Overall, about 15-20% of people with oesophageal cancer are alive 5 years after diagnosis. This is because most cancers are found late (when symptoms like difficulty swallowing occur).

Can Oesophageal Cancer Be Prevented?

Yes, some cases can be prevented:

• Stop smoking (biggest risk factor for squamous cancer)
• Reduce alcohol (especially heavy drinking)
• Maintain healthy weight (reduces reflux and Barrett's risk)
• Treat acid reflux (take medication as prescribed; see doctor if reflux doesn't improve)

Barrett's Oesophagus Surveillance:

• If you have Barrett's oesophagus (a pre-cancerous condition from long-term reflux), you may have regular endoscopies (every 3-5 years) to detect early changes before cancer develops

Living After Treatment

After surgery (oesophagectomy):

• Recovery takes 6-12 months
• You'll need to eat small frequent meals (5-6 times a day) instead of 3 large meals
• You may have reflux (take medication to control this)
• You may lose 10-15% of your body weight initially
• Most people can return to normal activities after recovery

After palliative treatment:

• Stents can help you swallow and maintain nutrition
• Ongoing support from cancer nurses, dietitians, and palliative care teams
• Focus on quality of life and symptom control

Where Can I Get Support?

• Clinical Nurse Specialist (CNS): Your hospital cancer team
• Macmillan Cancer Support: macmillan.org.uk / 0808 808 00 00
• Oesophageal Patients' Association (OPA): opa.org.uk (patient support group)
• Cancer Research UK: cancerresearchuk.org

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16. Key Evidence & Guidelines

Guidelines

1. NICE NG83: Oesophago-gastric Cancer: Assessment and Management in Adults (2018)

   • Comprehensive guideline covering diagnosis, staging, treatment (surgery, chemotherapy, radiotherapy), palliative care
   • Recommends 2-week wait referral for dysphagia age ≥55 years
   • https://www.nice.org.uk/guidance/ng83

2. ESMO Clinical Practice Guidelines: Oesophageal Cancer (2022)

   • European consensus on diagnosis, staging, multimodal therapy, follow-up
   • https://www.esmo.org/guidelines

3. NCCN Guidelines: Esophageal and Esophagogastric Junction Cancers (2024)

   • US guidelines; comprehensive treatment algorithms by stage
   • https://www.nccn.org/guidelines

4. British Society of Gastroenterology (BSG): Guidelines on the Diagnosis and Management of Barrett's Oesophagus (2014)

   • Surveillance intervals, dysplasia management, endoscopic therapy
   • https://www.bsg.org.uk/clinical-guidance

Landmark Trials & Key Evidence

Neoadjuvant Therapy

5. van Hagen P, et al. (CROSS Trial). Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074-2084.

   • RCT: Neoadjuvant CRT (carboplatin/paclitaxel + 41.4 Gy) vs surgery alone
   • Result: Improved median OS (49 vs 24 months); pCR 29% (49% squamous, 23% adenocarcinoma)
   • Impact: Established CROSS as standard for squamous and option for adenocarcinoma
   • PMID: 22646630 | DOI: 10.1056/NEJMoa1112088

6. Al-Batran SE, et al. (FLOT4-AIO Trial). Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948-1957.

   • RCT: FLOT vs ECF/ECX for gastro-oesophageal adenocarcinoma
   • Result: Improved median OS (50 vs 35 months); higher pCR rate (16% vs 6%)
   • Impact: FLOT now preferred for GOJ adenocarcinoma
   • PMID: 30982686 | DOI: 10.1016/S0140-6736(18)32557-1

Immunotherapy

7. Doki Y, et al. (CheckMate 648 Trial). Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449-462.

   • RCT: Nivolumab + chemo vs chemo alone in advanced oesophageal squamous
   • Result: Improved OS (15.4 vs 9.1 months for PD-L1 CPS ≥5); 13.2 vs 10.7 months overall
   • Impact: Nivolumab + chemo now first-line for PD-L1+ squamous
   • PMID: 35108470 | DOI: 10.1056/NEJMoa2111380

8. Bang YJ, et al. (ToGA Trial). Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697.

   • RCT: Trastuzumab + chemo vs chemo alone in HER2+ gastro-oesophageal adenocarcinoma
   • Result: Improved median OS (13.8 vs 11.1 months)
   • Impact: HER2 testing mandatory for metastatic adenocarcinoma; trastuzumab if HER2+
   • PMID: 20728210 | DOI: 10.1016/S0140-6736(10)61121-X

Palliative Therapy

9. Wilke H, et al. (RAINBOW Trial). Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235.
   • RCT: Ramucirumab (anti-VEGFR2) + paclitaxel vs paclitaxel alone (second-line)
   • Result: Improved median OS (9.6 vs 7.4 months)
   • Impact: Standard second-line therapy for metastatic disease
   • PMID: 25240821 | DOI: 10.1016/S1470-2045(14)70420-6

Surgical Outcomes

10. Biere SS, et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet. 2012;379(9829):1887-1892.
    • RCT: Minimally invasive (MIO) vs open oesophagectomy
    • Result: Lower pulmonary complications (9% vs 29%), shorter hospital stay; equivalent oncological outcomes
    • Impact: MIO now standard in high-volume centres
    • PMID: 22552194 | DOI: 10.1016/S0140-6736(12)60516-9

Barrett's Surveillance

11. Hvid-Jensen F, et al. Incidence of adenocarcinoma among patients with Barrett's esophagus. N Engl J Med. 2011;365(15):1375-1383.
    • Population-based cohort study (Denmark): 11,028 Barrett's patients
    • Result: Annual cancer incidence 0.12% (1 in 833 per year)
    • Impact: Confirmed low but significant cancer risk; supports surveillance programmes
    • PMID: 21995385 | DOI: 10.1056/NEJMoa1103042

Epidemiology

12. Arnold M, et al. Global burden of oesophageal and gastric cancer by histology and subsite in 2018. Gut. 2020;69(9):1564-1571.

    • Global cancer statistics: Incidence, mortality, temporal trends
    • Result: 572,000 new oesophageal cancers/year globally; adenocarcinoma rising in West, squamous declining
    • PMID: 32327482 | DOI: 10.1136/gutjnl-2020-321600

13. Cook MB, et al. Gastroesophageal reflux in relation to adenocarcinomas of the esophagus: a pooled analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Cancer Epidemiol Biomarkers Prev. 2014;23(2):304-313.

    • Pooled case-control study: GORD and adenocarcinoma risk
    • Result: 5-7 fold increased risk with chronic GORD
    • PMID: 24302677 | DOI: 10.1158/1055-9965.EPI-13-0829

14. Tramacere I, et al. A meta-analysis on alcohol drinking and esophageal and gastric cardia adenocarcinoma risk. Ann Oncol. 2012;23(2):287-297.

    • Meta-analysis: Alcohol and oesophageal squamous vs adenocarcinoma
    • Result: Strong dose-response for squamous (RR 5.1 for heavy drinking); weak/no association for adenocarcinoma
    • PMID: 21551004 | DOI: 10.1093/annonc/mdr136

15. Islami F, et al. High-temperature beverages and foods and esophageal cancer risk—A systematic review. Int J Cancer. 2009;125(3):491-524.

    • Systematic review: Hot beverages (> 65°C) and squamous cancer
    • Result: 2-4 fold increased risk with very hot tea/maté
    • PMID: 19415743 | DOI: 10.1002/ijc.24445

Pathophysiology

16. Dulak AM, et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013;45(5):478-486.

    • Genomic profiling of oesophageal adenocarcinoma
    • Result: TP53 (72%), CDKN2A (47%), SMAD4 (24%), ERBB2 (15%)
    • PMID: 23525077 | DOI: 10.1038/ng.2591

17. Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541(7636):169-175.

    • Comprehensive molecular classification: Adenocarcinoma vs squamous
    • Result: Squamous similar to head/neck SCC; adenocarcinoma similar to chromosomal instability gastric cancer
    • PMID: 28052061 | DOI: 10.1038/nature20805

Complications

18. Low DE, et al. International Consensus on Standardization of Data Collection for Complications Associated With Esophagectomy: Esophagectomy Complications Consensus Group (ECCG). Ann Surg. 2015;262(2):286-294.

    • International consensus: Standardized definitions of post-oesophagectomy complications
    • Result: Leak 10-15%, pneumonia 15-20%, RLN injury 5-10%, mortality 3-5% (high-volume centres)
    • PMID: 25607756 | DOI: 10.1097/SLA.0000000000001098

19. Markar SR, et al. Volume-outcome relationship in surgery for esophageal malignancy: systematic review and meta-analysis 2000-2011. J Gastrointest Surg. 2012;16(5):1055-1063.

    • Meta-analysis: Hospital volume and oesophagectomy mortality
    • Result: High-volume centres (> 20 cases/year) have 50% lower mortality (3-5% vs 10-15%)
    • PMID: 22089950 | DOI: 10.1007/s11605-011-1731-3

20. Straatman J, et al. Minimally Invasive Versus Open Esophageal Resection: Three-year Follow-up of the Previously Reported Randomized Controlled Trial: the TIME Trial. Ann Surg. 2017;266(2):232-236.

    • RCT long-term follow-up: MIO vs open oesophagectomy
    • Result: Equivalent 3-year OS (56% vs 54%); MIO maintains lower pulmonary complications
    • PMID: 28525411 | DOI: 10.1097/SLA.0000000000002171

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17. Summary: High-Yield Points for Exams

Epidemiology

• 7th most common cancer in UK; M:F = 3:1 (adenocarcinoma 7:1)
• Adenocarcinoma (60% in West): Rising incidence (obesity, GORD, Barrett's)
• Squamous (90% in Asia): Declining in West (reduced smoking)

Risk Factors

• Adenocarcinoma: Barrett's (strongest), GORD, obesity, male sex
• Squamous: Smoking (5-10 fold), alcohol (5-7 fold), hot beverages, achalasia, Plummer-Vinson, tylosis

Pathophysiology

• Adenocarcinoma: GORD → Barrett's → LGD → HGD → cancer (TP53, CDKN2A, HER2)
• Squamous: Tobacco/alcohol → dysplasia → cancer (TP53, PIK3CA, NOTCH1)

Clinical Presentation

• Progressive dysphagia (solids → liquids) + weight loss (> 10%)
• Red flags: Hoarseness (RLN = T4), Virchow's node (metastatic)

Investigations

• Diagnosis: OGD + biopsy (histology, HER2, PD-L1)
• Staging: CT CAP (M), EUS (T/N), PET-CT (occult M), staging laparoscopy (GOJ)

Staging

• T1a vs T1b: Mucosal vs submucosal (determines EMR vs surgery)
• T4a vs T4b: Resectable vs unresectable
• Overall 5-year survival: 15-20%

Management

• T1a: EMR/ESD + RFA
• Localised (I-III): Neoadjuvant therapy (FLOT/CROSS) → oesophagectomy (Ivor Lewis/McKeown)
• Metastatic (IV): Palliative chemo ± immunotherapy (nivolumab if PD-L1+), ± trastuzumab (if HER2+), stenting, radiotherapy

Key Trials

• CROSS: Neoadjuvant CRT → improved OS (49 vs 24 months); pCR 29%
• FLOT4: FLOT > ECF for GOJ adenocarcinoma
• CheckMate 648: Nivolumab + chemo for PD-L1+ squamous
• ToGA: Trastuzumab + chemo for HER2+ adenocarcinoma

Complications

• Post-op: Leak (10-15%), pneumonia (15-20%), RLN injury (5-10%), stricture (20-30%)
• Disease: TOF, aspiration, massive bleed, cachexia

Prognosis

• Stage I: 60-80%; Stage IV: less than 5%
• Prognostic factors: Stage (most important), nodal burden, performance status, weight loss, surgical centre volume

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Document generated: 2026-01-07 Evidence Level: High Citations: 20 Target Examinations: MRCP, MRCS, FRCS (Upper GI), Gastroenterology, Oncology