Esophageal and Gastric Cancer

Benign Tumours Malignant Tumour
  • Adenomas (gland cells;stomach)
  • Leiomyoma (muscle cells(
  • Schwannoma (neuro lining)
  • Granular Cell tumour
  • Squamous carcinoma (oesophagus)
  • Adenocarcinoma
  • Small cell carcinoma
  • Lymphoma
  • Endocrine Tumours
  • GI Stromal Tumours
  • Kaposis Sarcoma (immunosuppressed)

Esophageal Cancer

esophagus→ mainly squamous cells; no glands

  1. Squamous cell carcinoma (SCC)- commonest
  2. Adenocarcinoma – increased incidence ~SCC – up to 50% of all oeso carcinoma in US
  3. Small cell carcinoma- uncommon

Squamous Cell Carcinoma

  • Repeated inflammation of the epithelium

Risk Factors

Scenario
  • Nitrates and nitrosamines
  • Tobacco smoke
  • Alcohol
  • Vitamin deficiencies
  • Achalasia (LES stays closed)
  • Strictures (of esophagus)
  • HPV
 Low grade – high grade- invasive pathway:

  • Accumulation of unstable cells
  1. Pre- malignant
  2. Dysplasia- low grade and high grade
  3. Invasive carcinoma

(Adjacent to invasive SCC in 60-90% cases)
Location:

  • Upper(10-20%),
  • Middle (50-60%)*
  • Lower (30%) oesophagus

Clinical Presentation:

  • Obstruction / Dysphagia / weight loss
 Macroscopic type:

(luminal growth)

  • Ulcerating, Infiltrating, polypoid

Because infiltrative has slower presentation (less blockage), it has worse prognosis
Microscopic

Dysplastic squamous epithelium → Invades submucosa and deeper

(+/- keratinisation, intercellular bridges) Poorly differentiated sheets of cells (loss of identity)

(Carcinosarcoma)

  • Mixed cells type, Carcinoma (round) + Sarcoma (spindle shape)

 

Esophageal Adenocarcinoma

Adenocarcinoma: the cancer of Glandular Tissue

  • Exclusively @ lower esophagus (near the stomach – metaplasia)
  • Association with Barrett’s Esophagus (~99%)
    • GERD site: distal esophagus
    • 6-12% of patients with GE reflux – develop Barrett’s
    • 0.5 – 1% per year of patients with Barrett’s will develop Adenocarcinoma

Barrett’s Esophagus (Metaplasia)

  • Squamous cells (normal) → Columnar epithelium (replaced)
  • Caused by: chronic GE reflux
  • Identified by Goblet cells (glands – mucus) which should only be found in stomach

Risk Factors:

  1. Dysplasia present: (range)
    1. Low Grade: crowding (hyperplasia), basal nuclei
      1. 3 year surveillance
      2. p53 marker increased expression in most cases of dysplasia (stains)
  1. High Grade: stratified nuclei, pleomorphism (loss of features/function), mitoses to surface (goblet cells lose arrangement – no alignment)
    1. yearly follow up or surgery
    2. Assessment of neighbouring tissues (for tumour)

Macroscopic (adenocarcinoma):

  • Ulcer, mass, +/- extends across gastro-oesophageal junction

Microscopic

  • Invasive malignant glands

 

Prognosis of Carcinoma

  • Invasion through oeso wall → trachea, aorta,pericardium
  • Can cause Haemorrhage
  • 60% have lymph node metastases at presentation
  • Overall 5 year survival 30-40%- higher in those with early (less invasive) disease and node negative
  • Most adenocarcinomas have invaded mucosa propria at presentation
    • 10-20% 5 year survival

 

Gastric Cancer

As stomach is a place with many glands, the most common tumour of the stomach is:

  • Gastric Adenocarcinoma
    • 2nd most common cancer in the world
    • Increased advances in early detection in high incidence areas (monitoring)

Geographic Distribution:

  • High incidence (>40/100,000 M pop) : E Asia, Andes regions of S America, E Europe
  • Low incidence (<15/100,000 M pop): N America, N Europe, Most of Africa, SE Asia
  • 20-fold difference between the high to low incidence areas

Association:

  • Salt intake
  • Salt for fish / meat preservation (i.e. sausages)
  • Lack of fruits and vegetables in diet
Aetiology Diet (risk)
  • Diet
  • Bile reflux
  • H Pylori
  • Oxidative stress
  • Interference with antioxidant function
  • DNA damage (point mutations)

Role unclear:

  • Alcohol, nitrosamines, tobacco
 High risk:

  • Salt
  • Smoked/cured meat/fish
  • Pickled vegetables
  • Chilli peppers

Low risk:

  • Fruit/vege
    • Antioxidant effect

Key protective agents:

  • Ascorbic acid, carotenoids, folate

Helicobacter Pylori

  • Rod shaped organism
  • Lives in mucus over gastric epithelium
  • Most frequent cause of chronic gastritis (inflammation)
  • Associated with gastric adenocarcinoma and lymphoma

Causes:

Results
1. Chronic Gastritis Intestinal metaplasia
2. Decreased acid secretion Increased pH

– nitrosated products carcinogens
3. Decreased intra gastric ascorbic acid Loss of antioxidant AA

– increased oxidants
4. Increased oxidants DNA point mutations

 

Symptoms and Signs (gastric Adenocarcinoma)

  • Because the stomach is larger in volume, the tumour growth is generally larger before clinical presentation – often 80-90% in countries with lack of regular screening
  • Early – 50% will have non-specific dyspepsia
  • Late – persistent abdominal pain
    • Unrelieved by eating
    • Bleeding (ulceration) – hematemesis
    • Gastric outlet obstruction
    • Anorexia & weight loss (disseminated disease)

(as tumour can be found at any site, the dyspepsia [indigestion] depends on site, tumour can outgrow their blood vessel supply → necrosis → ulceration of gastric wall)

 

Diagnosis

  1. Endoscopy: visualisation of the site
    1. Early gastric cancer – slight changes in mucosa colour and architecture
    2. Advanced cancer- obvious lesion
  2. Biopsy of lesion
  3. Barium Meal: used as part of mass screening in some countries followed by endoscopy if abnormality detected

Early Gastric Cancer

Definition: Carcinoma confined to the mucosa or to mucosa and submucosa regardless of LN status

  • Better Prognosis: as it has not yet invaded much into gastric wall (wall integrity)
    • No metastasis
  • Aim of screening programmes is to detect EGC in high risk areas
  • Screening areas: 80% of cancers detected are EGC
  • Low Incidence areas- 80-90% of cancers are advanced at presentation
    • High surveillance population: Familiar (genetic) polyposis

 

AoE

Commonest site- distal stomach (antro-pyloric region)

  • Gravity collection of acid

Next commonest – body of stomach- greater or lesser curve

Macroscopic Microscopic
  • Elevated lesion (rim)
  • Polypoid
  • Ulcer
  • Diffuse infiltrative – linitis plastica (leather bottle stomach)
    • Metastatic before presentation
  • Intestinal type
  • Mucinous (extracellular mucin)
  • Papillary (irregular solid or cystic mass or nodule)
  • Signet ring (nucleus squeezed to one side)

Precursor lesions of Gastric adenocarcinoma

  • Gastritis (chronic H Pylori, autoimmune)
  • Intestinal Metaplasia (change in cell type)
  • Intraepithelial neoplasia (new abnormal growth)
  • Adenoma (glandular cancer)
  • Polyps

 

Precursor Lesions

  1. Gastritis

Gastric Carcinoma (precursor) Pathway

 

2. Intestinal Metaplasia (dysplasia)

  • Low grade dysplasia – mild crowding and some nuclear atypia (lack of)
  • High grade dysplasia – marked cell crowding (hyperplasia), stratification, nuclear pleomorphism (differing size of nucleus)

 

3.Gastric Neoplasia (definitions)

  • Intra-epithelial neoplasia = confined to surface epithelial (dysplasia, low and high grade) eg adenoma
  • Intramucosal carcinoma = invasion of lamina propria
  • Early Gastric Cancer = carcinoma confined to mucosa or into submucosa
  • Advanced Gastric cancer = invasion deeper than submucosa

4. Gastric Adenomas

  • 10% of all gastric polyps
  • Circumscribed benign lesions
  • Low and high grade dysplasia
    • < 2 cm: 2% risk of malignant transformation
    • > 2 cm: 40-50% malignant transformation

5. Gastric Polyps

Generally Benign, of the population of adenoma (10%) → only a few are malignant

  • Yet the increase in number of polyps can increase chances of cancer
    • Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated.

Molecular Genetics

Gastric Carcinoma
Majority of gastric cancer is sporadic

  • ~10% have an inherited familial component. Family clustering with a dominant inheritance pattern. (FAP)
  • Studies suggest a small increased risk of gastric cancer in first degree relatives
  • Hereditary diffuse gastric cancer (e-cadherin)
  • Gastric cancer as part of Hereditary nonpolyposis colon cancer HNPCC
  • Rarely gastric cancer in Peutz Jeghers syndrome
  • Blood group A associated with gastric cancer

Prognosis

Gastric Carcinoma
Early Gastric Cancer

Small mucosal lesions < 4cm with low incidence of vessel invasion

  • 10 year survival up to 90%

EGC with vessel invasion

  • 65% 5 year survival
 Advanced Gastric cancer

TNM staging system

  • prognostic information

LN positive :

  • 5 year survival 5-40%

Diffuse carcinoma poorer prognosis than

intestinal subtype

TNM Staging (prognosis)

Gastric / Esophageal Carcinoma
T: describes the size of the original (primary) tumour and whether it has invaded nearby tissue,
N: describes nearby (regional) lymph nodes that are involved,
M: describes distant metastasis (spread of cancer from one part of the body to another).
T= Primary tumour

  • Tis = ca in situ/intraepithelial
  • T1 =Invades lamina propria / submucosa
  • T2 = Invades into musc propria
  • T3 = Tumour invades through musc propria to peri-oeso or sub serosal fat
  • T4 = Tumour perforates serosa (stomach) or invades adjacent structures

Smaller number is better*

 N = Regional LN

N0 = no LN involved

N1 = mets in LN

N2/ N3 = number of positive LN

M= Distant metastases

Mx = cannot be assessed

M0 = no distant mets

M1 = distant mets

 

Advances in Treatment

Esophageal and Gastric Carcinoma
Neoadjuvant therapy

(Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery)

– Chemo and Radiotherapy

Chemo Drugs:

  • (both): Capcitabine, 5FU and Cisplatin
  • (gastric): MAGIC study

Metal stent to improve structural integrity (lumen)

Surgical excision:

  • distal oesophagus and prox gastrectomy;
  • Gastrectomy +/- distal gastrectomy

Post operative chemotherapy
Case:

Gastric / OG junction carcinoma and Herceptin (HER2 drug)

  • ToGA trail- phase 111 randomised multicentre trial
  • >3800 gastric ca
  • Trastuzumab (herceptin) associated with reduced death risk (26%) and survival benefit in advanced HER2 pos gastric cancer

 

Gastric Lymphoma

10% of all gastric cancers are lymphomas

Non Hodgkins Lymphoma – 2 main types:

  1. Low grade lymphomas arising from mucosal associated lymphoid tissue in bowel (MALT lymphomas)
  2. High Grade B cell NHL (majority)

Some of these will have evolved through progression of low grade lymphomas

Etiology Gastric Lymphoma
Low grade lymphomas:

Low grade & MALT lymphomas arising from Mucosa Associated Lymphoid Tissue in stomach wall;

  • Associated with H.pylori

(regress with H.pylori eradication)

Those not caused by H.pylori = > genetic instability

 High grade lymphoma

High grade Diffuse large B cell NHL

it develops from abnormal B lymphocytes (B cells)

  • Associated with immune deficiency (i.e. AIDs)
Gastric Lymphoma outcome (Prognosis) Microscopic
Low grade MALT lymphoma- regression on H

Pylori eradication:

  • 65-85% remission in these cases
  • Takes 1-18 months for remission
  • Up to 10% relapse in 24 months (study)
  • Best outcome where MALT NHL confined to mucosa/ upper submucosa

Poorer outcome for High-Grade and non H pylori:

  • Surgical resection of NHL prolongs survival
 High Grade- diffuse large B cell

  • Large cells infiltrate and destroy glandular epithelium and invade deeply
  • Prominent nucleoli and chromatin
  • May show plasma cell differentiation

Gastric Carcinoid Tumour

A carcinoid tumour is a rare cancer of the neuroendocrine system – the body system that produces hormones.

  • Usually non functioning
  • Single or multiple
  • >10% of all GI carcinoids
  • Female > Male 2.5:1
  • Groups of closely packed cells, round nuclei, granular cytoplasm

GIST

Gastrointestinal Stromal Tumour (GIST) of stomach

Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the GI tract. These tumors start in very early forms of special cells in the wall of the GI tract called the interstitial cells of Cajal (ICCs). ICCs are cells of the autonomic nervous system, the part of the nervous system that regulates body processes such as digesting food. ICCs are sometimes called the “pacemakers” of the GI tract because they signal the muscles in the GI tract to contract to move food and liquid along.

  • Tumour of mesenchyme (mesodermal embryonic tissue)
  • Account for > 2% of all malignant gastric tumours
  • Uncommon in oesophagus
  • Stomach is commonest GI site: 60-70% of GISTs occur in stomach

Macroscopic:

  • Nodular mass
  • Submucosal, intramural, subserosal, vary in size
  • Submucosal lesions may ulcerate

Microscopic:

  • Spindle cell neoplasm +/- plumper cells
  • Cells resemble smooth muscle but are negative with SM actin stain
  • Malignant behaviour determined by tumour size and counting of mitoses
  • Malignant tumours can metastasise
  • GISTs are positively staining with KIT (CD117)-typical

 

Golden Rule

Spindle cell Lesions – Esophagus and Stomach

Spindle cell lesion in oesophagus more likely to be a leiomyoma (muscle tumour) than GIST

Spindle cell lesion in stomach more likely to be a GIST than leiomyoma

Testing: Must to CD117 ,SMA, etc on all

Kaposis Sarcoma

a form of cancer involving multiple tumours of the lymph nodes or skin, occurring chiefly in people with depressed immune systems

  • Malignant tumour of blood vessels
  • Seen in gastric mucosa (and in small intestine) in immunosuppressed patients (HIV+)
  • Spindle cell lesion with slit-like vascular channels

Secondary Tumours

In the esophagus and stomach

  • Very uncommon
  • Direct spread: from carcinoma of pancreas, oesophagus and gallbladder to stomach
  • Distant metastases from breast carcinoma and melanoma
  • Macro: may show mass lesion or diffuse infiltration; +/- pigmentation (melanoma)
  • Micro: typical appearance of primary tumour
  • Poor prognosis – indicate late stage of tumour