Pathology Lecture 4 & 5 Upper GIT/Inflammatory Bowel Disease

LO1 Recognise the dysplasia to neoplasia pathway of malignancy, in particular those related to the
oesophagus
From Underwoods

Dysplasia = disordered growth

Dysplastic changes form a mild severe spectrum; dysplasia = progression to malignancy (carcinoma in situ)

NB: there is no stromal invasion by abnormal cells seen in severe dysplasia;

no vessels in epithelium = no metastases

Mitotic changes will also be seen:

Occurs in superficial cell layers where not normally found

no. of mitoses
Abnormal no. of mitoses e.g. tripolar

NB: dysplasia only occurs in the epithelium; carcinoma in situ = malignancy that hasnt crossed the basement
membrane

Barretts Oesophagus
Caused by GORD
Characterised by metaplastic change from flat squamous epithelium tall columnar epithelium with
goblet cells & tall mucin-secreting cells
Epithelial dysplasia (pre-cancer) detected in 0.2-2% of pt increased risk of oesophageal adenocarcinoma

LO2 Reflux oesophagitis

Acute oesophagitis

Cause Patient
HSV1 Immunocompromised --> chemotherapy, HIV, post-transplant
CMV
Candida Albicans Immunocompromised + diabetes + antibiotic therapy
Ingestion of corrosive Accidental, suicide
substances
Chronic oesophagitis
TB
Crohns disease
Reflux oesophagitis

Reflux oesophagitis
From Underwoods

Associated with GORD, but poor correlation between symptoms & oesophagitis
o Some patients have severe symptoms & little/no damage to oesophageal lining
o Others may be asymptomatic, but have obvious inflammation on endoscopy

Morphology

Exposure to refluxed acid cell injury accelerated desquamation erosion & inflammation

cell loss results in squamous hyperplasia with:

o Elongated sub-epithelial (lamina propria) papillae
o Thickened basal cell layer (basal zone hyperplasia)
o Less mature cells occupying most of the epithelial thickness

Epithelial injury accompanied by inflammatory response

o Polymorphs (eosinophils)
o Lymphocytes
o Granulation tissue

Endoscopy shows linear ulcers, erythema & oedema of mucosa

Complications (from TORG)

Ulceration (inc. acute inflammatory cells & fibrinous exudate)

o Healing achieved via epithelial regeneration & fibrosis
o Shrinking of fibrous tissue can produce narrowing (benign oesophageal stricture) in an area of
healed ulceration
o Bleeding

Possible progression to Barretts oesophagus oesophageal adenocarcinoma

Other pathologies of the oesophagus

Heterotopic tissue
Patches of gastric mucosa found in the oesophagus congenitally misplaced (heterotopic)
SE: Can lead to ulceration & stricturing due to local acid/pepsin secretion

Atresia
Failure of embryological canalisation (i.e. forming canals?)
Associate with fistula between proximal part of the oesophagus & trachea
SE: Inability to swallow & aspiration bronchopneumonia

Diverticula
Can be:
i. saccular dilatation (full thickness)
ii. herniation of mucosa/submucosa through a defect in the muscular wall
Diverticular in the oesophagus are caused by:
i. Traction (externa forces puling on the wall)
ii. Pulsion (forcible distension)
May be permanently distended with retained food dysphagia

Hiatus hernia
Protrusion of upper part of the stomach into the thorax via diaphragmatic orifice (intra-abdominal
pressure & loss of diaphragmatic muscular tone)
Most common mechanical disorder of the oesophagus, found in ~25% of people
Lower oesophageal sphincter becomes incompetent GORD

Achalasia
Loss of contractility of oesophagus & failure of lower oesophageal sphincter to relax
Presents with recurrent progressive dysphagia & vomiting of undigested food
Caused by neural degeneration loss of signalling b/w nerves & smooth muscle
o Chagas disease (trypanosoma cruzi)
o Varicella-zoster virus
o Measles
o HSV1
o MS
o Sjogrens syndrome
o Diabetes
o Alcoholism
 Oesophageal varices
Varices = localised dilatation of veins

Occurs when blood flow through the portal system is impaired (e.g. alcoholic liver disease cirrhosis)
portal venous pressure = blood diverted through collateral vessels (portal-caval anastomoses)
Results in congestion of distal oesophageal venous plexus
Varices protrude from the submucosa easily damaged by the passage of food
Leads to rupture & variceal haemorrhage shock/haematemesis (~30% pt)

Mallory Weiss tears/Boerhaave syndrome

Mallory-Weiss tear = rupture of oesophageal mucosa (bleeding may stop spontaneously)

Boerhaave syndrome = perforation of the whole thickness of oesophageal wall (requires immediate surgery)

Both result from repeated retching, forceful vomiting or trauma

Oesophageal tumours
Majority = squamous cell carcinoma/adenocarcinoma
Adenocarcinomas rise from areas of Barretts oesophagus (distal 1/3)
SCC is more common in men, with age, arise from areas of squamous dysplasia (middle 1/3)
o Risk factors:
Alcohol
Tobacco
Caustic oesophageal injury
Achalasia
Plummer-Vinson syndrome
Low fibre diet
African-American background

LO3 Pathology of chronic gastritis

From Underwoods

H. Pylori gastritis
Most common type - ~40% in developed countries, ~70% in developing countries
Gram ve curved rod binds to gastric surface epithelium
Bacterium protected from gastric acid via:
o Mucous
o Ability to neutralise H+ (urease & ammonia production)

2 types of H.Pylori gastritis

1. Antral predominant acid production leading to duodenal ulceration (10 15% pt)

2. Body predominant/pan-gastritis acid secretion with gastric ulceration

Histology

Diffuse infiltration of lamina propria with lymphocytes & plasma cells

Focal infiltration of epithelium in neck region with neutrophils (in active chronic infection)
H. Pylori can be seen in haematoxylin and eosinophil-stained tissue sections
Special stains: Giemsa/immunohistochemistry can be used for gastric epithelium-only
Consequences

Mucosal atrophy
Intestinal metaplasia
3-6 fold increase risk of developing gastric adenocarcinoma

NB: large lymphoid follicles may progress to MALT (mucosal-associated lymphoid tissue) lymphoma non-
Hodgkins lymphoma

Autoimmune gastritis
Characterised by diffuse mucosal damage to acid-producing mucosa within the body & fundus, resulting in
mucosal atrophy
Accounts for ~10% of chronic gastritis
1 2% of older patients with anaemia & chronic gastritis have AAb against parietal cell & intrinsic factor

[Serum gastrin] , pepsinogen

NB: Lack of intrinsic factor leads to vitamin B12 = pernicious anaemia

Has an inflammatory infiltrate consisting of lymphocytes, macrophages & plasma cells with lymphoid follicles

Histology

Loss of parietal cells (glandular atrophy)

o Loss of HCl secretion (hypochlorhydria)
Fibrosis of lamina propria
Chronic inflammation & intestinal metaplasia in the body mucosa

Antrum mucosa not usually inflamed, but shows hyperplasia of gastrin-producing cells

Effects of gastrin-producing cells:

o Response to hypochlorhydria to stimulate HCl production in parietal cells
o Also stimulates enterochromaffin-like cells secrete histamine

NB: Results in enterochromaffin-like cell hyperplasia & development of benign endocrine cell tumours
Acute gastritis
Diagnosed by presence of neutrophils in the mucosa
Causes include:

Drugs (NSAIDs, CCS, Fe2+) Alcohol (binge drinking)

Stress (e.g. shock, trauma, burns) Smoking
Trauma (e.g. NGT) Chemotherapy

Protective mechanisms

Foveolar cells secrete mucous forms protective layer on surface of epithelium

Surface cells secrete bicarbonate forms neutral pH layer b/w cells & mucous
Surface epithelial cells physical barrier with rapid turn-over (3 7 days)

Mechanisms of gastritis (from CCL-4)

1. Prostaglandins E2 & I2 stimulate protective mechanisms

NSAIDs inhibit cyclo-oxygenase-dependent synthesis of prostaglandins
o COX-1 & COX-2 inhibitors (ibuprofen, aspirin)
o Selective COX-1 inhibitor (celecoxib)

2. Effects on bicarbonate secretion & cell turn over

Caused by ischaemia, shock & age

3. Direct cellular injury

Can be due to alcohol, radiotherapy

From Underwoods

Exposure of mucosa to noxious agents results in loss of surface epithelial cells

bicarbonate secretion compromised physiological protective barrier
Mucosal response can be:
o Vasodilatation
o Oedema of lamina propria
o Erosion with fibrinous exudate & neutrophils (can result in severe haemorrhage)

Stress-related mucosal injury

Show sharply demarcated ulcer with normal adjacent mucosa; resolve after removal of stress/noxious stimulus
LO4 Identify the pathology of peptic ulcer disease

2 major factors:

H. Pylori (duodenal ulcers)

NSAIDs (gastric ulcers)

Other causes:

Gastric ischaemia (stress ulcers)

Zollinger-Ellison syndrome (gastric acid secretion caused by gastrin-secreting neuro-endocrine tumour)
KCl, bisphosphonates
Infections (CMV, HSV)
Crohns disease

H.Pylori

Possesses enzyme urease can convert endogenous urea to ammonia (aids survival in gastric lining)
Plays a role in the development of gastric adenocarcinoma and MALTomas

Pathophysiology

Imbalance between protective & offensive factors affecting the gastroduodenal mucosal lining.

Innate aggressive factor:

Gastric juice (HCl, pepsin, bile salts)

- Secretion DU (impaired secretion of somatostatin)
- Secretion normal/in GU

Defensive factors:

Mucous bicarbonate layer secreted by surface mucous cells

Integrity of tight junctions between adjacent epithelial cells
Restitution i.e. break in epithelial lining is filled by adjacent epithelial & mucosal stromal cells which migrate &
flatten to fill the gap
LO5 Discuss the concept of spread of tumours with particular reference to the stomach
From TORG

Direct tumour extension

Can occur proximally (oesophagus) or distally (duodenum)
Into continguous organs (pancreas, transverse colon, mesocolon, omentum)

Lymphatics
Occurs in scirrhous type gastric carcinomas (hard, slow growing malignant tumour)
Spreads through mucosal lymphatics of stomach & pylorus

Haematogenous
Spreads via the portal v. (esp. anaplastic gastric carcinoma) involves liver, lung, brain & bone

Transcoelomic
Involves:
o Diaphragm
o Parietal & visceral peritoneum
o Ovaries (Krukenberg tumour)
o Rectal shelf (palpable on PR exam)

LO6 Review the causes of gastric outlet obstruction

From TORG

Gastric outlet obstruction = clinical & pathophysiological consequence of any disease process that produces a
mechanical impediment to gastric emptying

May be acute, secondary to acute inflammation and oedema or chronic (secondary scarring & fibrosis)
Clinical symptoms:
o Nausea
o Vomiting

1. Mural
o Chronic peptic ulcer with stricture*
o Gastric malignancy large volume of tumour or cicatrizing effect (scar tissue)
Gastric carcinoma
GIST
Lymphoma
o Anastomotic/stomal ulcer following partial gastrectomy
o Pyloric stenosis

NB: in Zollinger-Ellison syndrome, resolution of gastric outlet obstruction will release highly acidic gastric contents
acute duodenal ulcer

2. Extramural (direct pressure/external restriction)

o Peritoneal adhesions compressing gastric outlet
o Pancreatic cyst
o Pancreatic carcinoma (most common cause of GO obstruction - >20%)
o Cholangiocarcinoma
o Malignant lymphoma

3. Intraluminal
o Rare
Neuroendocrine tumours (NET)
Tumours of the GIT which originate from diffuse neuroendocrine system (carcinoids)
2 main types:
1. Solid nests of regular cells with lightly stained nuclei neuroendocrine tumour
o Expresses neuroendocrine markers
2. Undifferentiated small/large tumours neuroendocrine carcinoma
o Basically identical to counterparts in the lung

Gastric
Frequent, composes up to 30% of all GI NET
2 types:
1. Multiple small polypoid tumours associated w. autoimmune chronic gastritis
o Considered benign

2. Solitary, large polyp no association

o Risk of metastasis

Duodenal
Gastrinoma = neuroendocrine tumour of the duodenum (previously carcinoids) which produce gastrin
(associated with Zollinger-Ellison syndrome)

LO7 Oesophageal & gastric cancer classification

Gastric cancer
From Underwoods

Gastric cancer = 4th most common cancer in the world

Account for 10% of all cancer deaths
Males = 2x risk

Aetiology

1 3% of gastric cancers = hereditary presence of CHD1 (E-cadherin) germline mutation

Majority caused by H.Pylori (early stages, predisposes to gastric cancer) + other pathogen
o EBV present in all cancerous cells; absent in normal/dysplastic gastric epithelia cells

Genetic changes in gastric cancer include:

o Loss of cell adhesion molecules (CDH1, CTNNB beta-catenin)
o Mutations/deletions of tumour suppressor genes (p53, KRAS, APC)
o Amplification of oncogenes (c-MYC, HER2)

Early = confined to mucosa (intramucosal) & submucosa invasion of lamina propria;

Late = invasion into muscularis propria or beyond

Morphology

NB: High-grade dysplasia & intramucosal cancer distinguished by presence of lamina propria invasion
As size increases:
o Elevated lesions polypoid fungating carcinoma;
o Depression excavated ulceration

NB: distinction b/w carcinoma & PUD must be made using multiple biopsies
Adenocarcinoma
Majority of gastric cancers are adenocarcinomas
o Graded according to their degree of differentiation

60 70% of gastric cancers are intestinal-type carcinomas i.e. have glandular or papillary structures
o Have expansile growth pattern with well-demarcated pushing border (cookie cutter ulcers)
30 40% are diffuse-type carcinoma