Case 21.2 – Gastric Ulcers & Gastric Cancer

Differential Diagnosis:

• Peptic ulcer disease (gastric or duodenal ulcer): Most likely given NSAID use and melaena
  • Gastric ulcer: more concerning due to malignancy risk
  • Duodenal ulcer: pain classically relieved by eating (though not always)
• Gastric cancer: MUST be excluded in any patient >55 years with new-onset dyspepsia, especially with:
  • Weight loss
  • Upper GI bleeding
  • Anaemia
• Gastritis: NSAID-induced or H. pylori-related
• Gastro-oesophageal reflux disease (GORD): Though less likely with melaena
• Other causes of upper GI bleeding:
  • Oesophageal varices (no history of liver disease)
  • Mallory-Weiss tear (no history of vomiting)
  • Erosive oesophagitis

Most Concerning Diagnosis:

Gastric cancer is the most concerning diagnosis that MUST be excluded. Red flag features in this case include:

• Age >55 years with new-onset dyspepsia
• Unintentional weight loss
• Upper GI bleeding (melaena)
• Anaemia (suggested by pale conjunctivae and fatigue)

While NSAID use makes peptic ulcer disease very likely, it's crucial to differentiate a benign gastric ulcer from a malignant ulcer (which can account for 3-5% of gastric ulcers). All gastric ulcers should be biopsied and followed up to ensure healing, as malignancy can present as an ulcer.

Peptic Ulcer Disease Risk Factors:

• Helicobacter pylori infection: Present in ~90% of duodenal ulcers and 70-80% of gastric ulcers
• NSAIDs/Aspirin use: Disrupts mucosal protective mechanisms
  • Risk increases with dose and duration
  • Synergistic effect with H. pylori
  • COX-2 selective NSAIDs have lower but still significant risk
• Smoking: Impairs healing and increases recurrence
• Alcohol: High consumption increases risk
• Corticosteroid use: Especially when combined with NSAIDs
• Physiological stress: Critical illness, burns, head injury (stress ulceration)
• Zollinger-Ellison syndrome: Rare, gastrin-secreting tumour

Gastric Cancer Risk Factors:

• H. pylori infection: Most important modifiable risk factor
  • Causes chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → cancer
  • 6-fold increased risk
  • Designated as a Class I carcinogen by WHO
• Dietary factors:
  • High salt intake
  • Smoked/preserved foods
  • Low fruit and vegetable intake
  • Nitrates and nitrites in processed foods
• Smoking: 1.5-2 fold increased risk
• Pernicious anaemia/autoimmune gastritis: Increased risk of gastric cancer
• Previous gastric surgery: Increased risk after partial gastrectomy (especially >15 years post-op)
• Family history: 2-3 fold increased risk if first-degree relative affected
• Genetic syndromes:
  • Hereditary diffuse gastric cancer (CDH1 mutation)
  • Lynch syndrome
  • Familial adenomatous polyposis (FAP)
• Adenomatous polyps: Particularly if >2cm
• Chronic atrophic gastritis: Especially with intestinal metaplasia
• Ménétrier's disease: Rare, giant rugal folds
• Obesity: Particularly for gastric cardia cancer
• Lower socioeconomic status: Associated with higher H. pylori prevalence
• Geographical factors: Higher incidence in East Asia, Eastern Europe, South America

Key Differences:

• NSAIDs are a major cause of peptic ulcers but are NOT a risk factor for gastric cancer
• H. pylori is common to both but is the predominant risk factor for gastric cancer
• Dietary and genetic factors play a larger role in gastric cancer
• Previous gastric surgery and autoimmune gastritis are specific risk factors for gastric cancer

Role of H. pylori in Gastric Pathology:

H. pylori is a gram-negative spiral bacterium that colonizes the gastric mucosa and is implicated in several gastric conditions:

• Chronic gastritis: Present in almost all infected individuals
• Peptic ulcer disease:
  • ~90% of duodenal ulcers
  • 70-80% of gastric ulcers
• Gastric cancer:
  • Main environmental risk factor for non-cardia gastric adenocarcinoma
  • WHO Class I carcinogen
  • Chronic inflammation → atrophic gastritis → intestinal metaplasia → dysplasia → adenocarcinoma
• MALT lymphoma: Gastric mucosa-associated lymphoid tissue lymphoma
  • ~90% associated with H. pylori
  • May regress with H. pylori eradication in early stages

Pathophysiology:

• Produces urease (breaks down urea to ammonia, neutralizing gastric acid)
• Produces toxins (CagA, VacA) that damage gastric epithelium
• Triggers inflammatory response
• Disrupts acid secretion regulation

Diagnosis of H. pylori:

Non-invasive tests (no endoscopy required):

• Urea breath test (UBT):
  • Gold standard non-invasive test
  • Patient ingests ¹³C or ¹⁴C-labelled urea
  • H. pylori urease breaks down urea, releasing labelled CO₂ detected in breath
  • Sensitivity and specificity >95%
  • Cannot be used within 2 weeks of PPI use or 4 weeks of antibiotic use
• Stool antigen test:
  • Detects H. pylori antigen in stool
  • Good sensitivity and specificity (~90%)
  • Useful for initial diagnosis and confirming eradication
  • Also affected by recent PPI/antibiotic use
• Serology (antibody testing):
  • Detects IgG antibodies to H. pylori
  • Less accurate than UBT or stool antigen
  • Cannot distinguish active from past infection (antibodies persist after eradication)
  • NOT recommended for confirming eradication
  • Useful in population screening or when patient on PPIs/antibiotics

Invasive tests (require endoscopy):

• Rapid urease test (CLO test):
  • Gastric biopsy placed in medium containing urea and pH indicator
  • If H. pylori present, urease activity causes colour change
  • Results within hours
  • Quick and cheap
• Histology:
  • Direct visualization of H. pylori on stained biopsy specimens
  • Gold standard for diagnosis
  • Also provides information about gastritis, atrophy, metaplasia, dysplasia
  • Special stains (e.g., Giemsa, Warthin-Starry) improve detection
• Culture:
  • Rarely used (difficult and time-consuming)
  • Allows antibiotic sensitivity testing
  • May be useful in treatment failure

Treatment (Eradication Therapy):

First-line treatment options:

1. PAC Therapy (Preferred in areas of low clarithromycin resistance \<15%):

• PPI (standard dose, twice daily) +
• Amoxicillin 1g BD +
• Clarithromycin 500mg BD
• Duration: 7-14 days (14 days preferred for better eradication rates)

2. PBMT/Bismuth Quadruple Therapy (Preferred in areas of high clarithromycin resistance or penicillin allergy):

• PPI (standard dose, twice daily) +
• Bismuth subcitrate/subsalicylate +
• Metronidazole 400-500mg TDS +
• Tetracycline 500mg QDS
• Duration: 10-14 days

3. Concomitant Therapy:

• PPI (standard dose, twice daily) +
• Amoxicillin 1g BD +
• Clarithromycin 500mg BD +
• Metronidazole 400-500mg BD
• Duration: 10-14 days

Second-line treatment (if first-line fails):

• If PAC used first: use bismuth quadruple therapy
• If bismuth quadruple used first: use levofloxacin-based triple therapy or PAC
• Consider culture and sensitivity testing

Confirming Eradication:

• Essential to confirm eradication, especially in:
  • Peptic ulcer disease (particularly with complications)
  • Gastric cancer or pre-malignant lesions
  • MALT lymphoma
  • Persistent symptoms
• Test at least 4 weeks after completion of eradication therapy
• Use UBT or stool antigen test (NOT serology)
• PPIs should be stopped for at least 2 weeks before testing

Important considerations:

• Global antibiotic resistance is increasing, particularly to clarithromycin and metronidazole
• Eradication rates with standard triple therapy have fallen to 70-80% in many areas
• Patient adherence is crucial - counsel about importance of completing full course
• Side effects are common (diarrhoea, nausea, metallic taste)

Endoscopic Features Suggesting Benign Gastric Ulcer:

• Regular, round or oval shape
• Smooth, well-demarcated margins
• Ulcer base:
  • Clean appearance
  • White/yellow slough or granulation tissue
  • May see visible vessel if recent bleeding
• Surrounding mucosa:
  • Radiating folds converge towards the ulcer in a regular pattern
  • Mucosa appears normal or shows gastritis
• Flexibility: Normal peristalsis around the ulcer
• Common locations: Lesser curve of antrum or body

Endoscopic Features Suggesting Malignant Gastric Ulcer:

• Irregular shape: Asymmetric or irregular borders
• Raised, rolled, or heaped-up margins
• Ulcer base:
  • Necrotic appearance
  • Irregular or nodular base
  • May show areas of abnormal vascularity
• Surrounding mucosa:
  • Abnormal-appearing mucosa
  • Nodular or irregular mucosal pattern
  • Absence of normal converging folds or distorted folds
  • Friable mucosa that bleeds easily on contact
• Rigidity: Loss of normal gastric distensibility and peristalsis
• Large size: Ulcers >3cm more likely to be malignant
• Location: Greater curve ulcers more suspicious for malignancy

Critical Point:

BIOPSY IS MANDATORY for all gastric ulcers because:

• Endoscopic appearance alone cannot reliably distinguish benign from malignant ulcers
• 3-5% of gastric ulcers appearing benign endoscopically are malignant on histology
• Malignant ulcers may have an initially benign appearance

Biopsy Protocol:

• Multiple biopsies essential:
  • Minimum of 7-10 biopsies recommended
  • Take from all four quadrants of the ulcer margin
  • Include biopsies from the ulcer base
  • Separate biopsies from background mucosa for H. pylori testing
• Additional biopsies: Any suspicious-looking areas in the surrounding mucosa

Follow-up:

• All gastric ulcers require repeat endoscopy to document healing
  • Usually performed 6-8 weeks after initial diagnosis
  • Repeat biopsies if ulcer not completely healed
  • Non-healing ulcers are highly suspicious for malignancy
• Duodenal ulcers do NOT routinely require repeat endoscopy (very rarely malignant)

Systematic Assessment During Endoscopy:

• Careful examination of the entire gastric mucosa
• Document ulcer location, size, and appearance
• Use of enhanced imaging techniques:
  • Narrow-band imaging (NBI)
  • Chromoendoscopy
  • May help identify malignancy and guide biopsies
• Photography for documentation and comparison at follow-up

Gastric adenocarcinoma accounts for >90% of gastric malignancies. The two main classification systems are:

Lauren Classification (most commonly used):

1. Intestinal Type (~54% of cases):

• Characteristics:
  • Well-differentiated with gland-forming structures
  • Resembles intestinal epithelium
  • Often associated with pre-existing atrophic gastritis and intestinal metaplasia
  • Typically affects older patients (\>60 years)
  • More common in males
• Epidemiology:
  • Incidence declining in Western countries
  • More common in endemic areas (East Asia)
  • Strongly associated with H. pylori infection
  • Environmental factors play major role
• Growth pattern:
  • Tends to form distinct tumour masses
  • Ulcerating or polypoid appearance
  • Usually in distal stomach (antrum/body)
• Prognosis: Relatively better prognosis than diffuse type

2. Diffuse Type (~32% of cases):

• Characteristics:
  • Poorly differentiated
  • Individual cells or small groups infiltrate stomach wall
  • Cells often contain mucin (signet-ring cells characteristic)
  • No gland formation
  • Affects younger patients (can occur in 30s-40s)
  • More common in females
• Epidemiology:
  • Incidence relatively stable or slightly increasing
  • Less strongly associated with H. pylori
  • Genetic factors more important
  • Associated with hereditary diffuse gastric cancer syndrome (CDH1 mutation)
• Growth pattern:
  • Diffuse infiltration of gastric wall
  • May cause linitis plastica ("leather bottle stomach" - rigid, thickened stomach wall)
  • Can occur anywhere in stomach, proximal stomach more common
  • Often no obvious mass lesion
• Prognosis: Generally worse prognosis
  • Often diagnosed at more advanced stage
  • More likely to have peritoneal spread
  • Less responsive to chemotherapy

3. Mixed/Indeterminate Type (~14% of cases):

• Contains features of both intestinal and diffuse types
• Intermediate prognosis

WHO Classification (also used):

• Papillary adenocarcinoma
• Tubular adenocarcinoma
• Mucinous adenocarcinoma
• Signet-ring cell carcinoma
• Other variants

Other Gastric Malignancies (much less common):

• Gastric lymphoma (~4%):
  • MALT lymphoma (most common, associated with H. pylori)
  • Diffuse large B-cell lymphoma
  • Better prognosis than adenocarcinoma
  • Early stage MALT may respond to H. pylori eradication
• Gastrointestinal stromal tumours (GIST) (~1-3%):
  • Arise from interstitial cells of Cajal
  • Often submucosal
  • Treatment: surgical resection ± imatinib (targeted therapy)
• Carcinoid tumours/Neuroendocrine tumours:
  • Rare
  • Variable behaviour depending on type
• Other rare tumours: Leiomyosarcoma, squamous cell carcinoma, adenosquamous carcinoma

Prognostic Factors:

• Stage: Most important prognostic factor (TNM staging)
• Histological type: Diffuse worse than intestinal
• Grade of differentiation: Well-differentiated better than poorly differentiated
• Lymph node involvement: Number and location of positive nodes
• Molecular markers:
  • HER2 positivity (~15-20%): can be treated with trastuzumab, but still indicates aggressive disease
  • Microsatellite instability (MSI-high): better prognosis, may respond to immunotherapy
  • EBV-positive tumours: may have better prognosis
• Location: Proximal gastric cancers generally have worse prognosis
• Peritoneal involvement: Very poor prognosis

Immediate Management (In ED):

• Assess haemodynamic status:
  • Postural BP drop suggests hypovolaemia
  • IV access and fluid resuscitation if needed
• Investigations:
  • Full blood count: assess for anaemia, check haemoglobin level
  • Group and save/crossmatch if significant bleeding
  • Coagulation screen
  • Urea and electrolytes (raised urea with normal creatinine suggests upper GI bleeding)
  • Liver function tests
• Risk stratification:
  • Glasgow-Blatchford Score or Rockall Score to assess need for admission/intervention
• Decision on admission vs discharge:
  • If stable with minor bleeding: may be suitable for discharge with urgent outpatient follow-up
  • If ongoing bleeding, haemodynamic instability, or high-risk features: admit for observation

Medical Management:

1. H. pylori Eradication Therapy (essential):

• First-line: PAC therapy (or alternative as per local guidelines)
  • PPI (e.g., omeprazole 20mg or lansoprazole 30mg) BD +
  • Amoxicillin 1g BD +
  • Clarithromycin 500mg BD
  • For 14 days
• Alternative if penicillin allergy: bismuth quadruple therapy

2. Continued PPI Therapy After Eradication:

• Continue PPI for total of 8 weeks for gastric ulcer healing
  • Can switch to once daily after completing eradication therapy
  • Higher dose or longer duration may be needed for large ulcers

3. NSAID Management (critical):

• Stop NSAIDs immediately
• Discuss alternative pain management for osteoarthritis:
  • Paracetamol (first-line)
  • Topical NSAIDs (e.g., diclofenac gel)
  • Physical therapy, weight loss if applicable
  • Intra-articular injections if needed
  • Consider referral to orthopaedics if conservative management fails
• If NSAIDs absolutely necessary in future:
  • Use lowest effective dose for shortest duration
  • Use COX-2 selective NSAID (lower but not eliminated GI risk)
  • Co-prescribe PPI
  • Ensure H. pylori eradicated

4. Lifestyle Advice:

• Smoking cessation if applicable (impairs ulcer healing)
• Reduce alcohol consumption if excessive
• Stress management
• Dietary advice: avoid foods that trigger symptoms, no specific "ulcer diet" needed

5. Manage Anaemia:

• Oral iron supplementation once bleeding stopped
• Recheck FBC after treatment

Follow-up and Monitoring:

1. Test for H. pylori Eradication (essential):

• Perform at least 4 weeks after completing eradication therapy
• Use urea breath test or stool antigen test
• Must stop PPI for at least 2 weeks before testing
• If eradication fails: second-line therapy with different regimen

2. Repeat Endoscopy (mandatory for gastric ulcers):

• Repeat OGD in 6-8 weeks to document complete healing
• Repeat biopsies if:
  • Ulcer not completely healed
  • Any suspicious features
  • Any change in appearance
• Non-healing ulcer is highly suspicious for malignancy
• Continue PPI until healing confirmed

3. GP Follow-up:

• Review symptoms
• Check compliance with treatment
• Ensure NSAID cessation
• Arrange confirmation of eradication testing
• Monitor for recurrent bleeding or symptoms

Patient Education:

• Explain H. pylori and importance of completing full eradication course
• Warn about potential side effects of eradication therapy
• Emphasize importance of avoiding NSAIDs
• Explain need for repeat endoscopy
• Advise to seek urgent medical attention if:
  • Vomiting blood
  • Melaena (black stools)
  • Severe abdominal pain
  • Signs of shock (dizziness, palpitations, collapse)

Long-term Considerations:

• After confirmed healing and H. pylori eradication:
  • Can stop PPI if asymptomatic
  • Ulcer recurrence rate \<5% after successful H. pylori eradication (compared to ~60% without eradication)
• If PPI needed long-term:
  • Use lowest effective dose
  • Be aware of potential long-term risks (though generally small): C. difficile infection, pneumonia, fractures, hypomagnesaemia, B12 deficiency

Staging Investigations:

1. Endoscopic Assessment:

• Multiple biopsies for histological confirmation and typing
• HER2 testing on biopsy specimens (important for treatment decisions)
• Detailed assessment of tumour location, size, and extent
• Endoscopic ultrasound (EUS):
  • Best for T staging (depth of invasion)
  • Assessment of local lymph nodes
  • May allow FNA of suspicious nodes

2. Cross-sectional Imaging:

• CT chest, abdomen, and pelvis with IV and oral contrast:
  • Assessment of primary tumour
  • Locoregional lymph node involvement
  • Distant metastases (liver, lungs, peritoneum, distant nodes)
  • Ascites (suggests peritoneal disease)
• PET-CT:
  • May help detect occult metastases
  • Less sensitive for diffuse/signet ring cell tumours
  • Useful for assessing treatment response

3. Staging Laparoscopy:

• Recommended for potentially resectable gastric cancer
• Detects peritoneal disease not visible on CT (in ~25-30% of cases)
• Allows:
  • Direct visualization of peritoneal surfaces
  • Peritoneal washings for cytology
  • Biopsy of suspicious lesions
• Can prevent unnecessary laparotomy in patients with occult metastatic disease

4. Other Investigations:

• Full blood count (anaemia)
• Liver and renal function
• Tumour markers: CEA, CA19-9 (not diagnostic but may be useful for monitoring)
• Nutritional assessment
• Assessment of fitness for surgery/chemotherapy:
  • Cardiopulmonary exercise testing (CPET) if available
  • Pulmonary function tests
  • Cardiac evaluation if indicated

TNM Staging (simplified):

• T: Depth of invasion (T1: mucosa/submucosa → T4: invasion of adjacent structures)
• N: Regional lymph node involvement (N0 → N3)
• M: Distant metastases (M0: none, M1: present)

Treatment Approach (Multidisciplinary Team Decision):

Early Gastric Cancer (T1):

• Endoscopic resection: May be possible for selected cases
  • Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD)
  • Criteria: small (\<2cm), well-differentiated, no lymphovascular invasion, limited to mucosa
  • More commonly performed in Japan where screening programs detect early cancers
• Surgery alone: For T1b or if not suitable for endoscopic resection

Locally Advanced Resectable Disease (T2-4a, N0-3, M0):

Standard approach - Perioperative Chemotherapy:

• Neoadjuvant (pre-operative) chemotherapy:
  • Typically 3 cycles before surgery
  • Regimens: ECF (Epirubicin, Cisplatin, 5-FU), FLOT (5-FU, Leucovorin, Oxaliplatin, Docetaxel) - FLOT increasingly preferred
  • Aims to downstage tumour and treat micrometastases
• Surgery:
  • Performed after 3 cycles of chemotherapy
  • Type of surgery depends on location:
    • Distal gastrectomy (for antral tumours)
    • Total gastrectomy (for body/proximal tumours or diffuse type)
    • Proximal gastrectomy (occasionally for very proximal tumours)
  • D2 lymphadenectomy (extended lymph node dissection) is standard in specialized centres
  • Minimally invasive surgery increasingly used
• Adjuvant (post-operative) chemotherapy:
  • 3 more cycles after surgery (same regimen)
  • Complete the perioperative treatment course

Alternative approach - Surgery followed by Adjuvant Chemoradiotherapy:

• Used in some centres, particularly in the USA
• Based on different trial evidence

Locally Advanced Unresectable Disease (T4b):

• Chemotherapy ± radiotherapy
• May become resectable after treatment (downstaging)
• Primarily palliative intent

Metastatic Disease (M1):

Palliative chemotherapy (for fit patients):

• First-line regimens:
  • ECF, FLOT, or other platinum-based combinations
  • If HER2-positive: Add trastuzumab (targeted therapy) - improves survival
• Median survival with chemotherapy ~11 months vs ~4 months without
• Second-line chemotherapy if disease progression and patient still fit
• Immunotherapy: Pembrolizumab for MSI-high or PD-L1 positive tumours

Best supportive care:

• For patients unfit for chemotherapy
• Symptom control
• Nutritional support
• Palliative care input

Palliative Interventions:

• Gastric outlet obstruction: stenting or palliative bypass surgery
• Bleeding: endoscopic therapy, radiotherapy, or surgery if needed
• Pain management
• Nutritional support:
  • Dietary modification
  • Enteral feeding (jejunostomy)
  • Parenteral nutrition if appropriate

Prognosis:

• Overall 5-year survival for gastric cancer ~20-30% in Western countries
• Stage-specific survival:
  • Stage IA: ~90%
  • Stage IB-IIA: 60-80%
  • Stage IIB-III: 20-50%
  • Stage IV: \<5%
• Prognosis better in specialist high-volume centres
• Japan has better outcomes due to earlier detection through screening programs

Supportive Care Throughout:

• Dietitian involvement (gastrectomy has major nutritional consequences)
• Clinical nurse specialist
• Psychological support
• Social work support
• Early palliative care involvement for symptom management