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NON-NEOPLASTIC CONDITIONS OF THE GASTROINTESTINAL TRACT. Dr RFT McMAHON Senior Lecturer in Pathology University of Manchester Honorary Consultant Pathologist Manchester Royal Infirmary Academic Session 2011-12.

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non neoplastic conditions of the gastrointestinal tract
NON-NEOPLASTIC CONDITIONS OF THE GASTROINTESTINAL TRACT

Dr RFT McMAHON

Senior Lecturer in Pathology

University of Manchester

Honorary Consultant Pathologist

Manchester Royal Infirmary

Academic Session 2011-12

marshall bj warren jr unidentified curved bacilli in the human stomach lancet 1984
Marshall BJ, Warren JR. Unidentified curved bacilli in the human stomach. Lancet 1984

Barry J Marshall & J Robin Warren

The Nobel Prize in Physiology/Medicine 2005

"for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"

the marshall warren story
The Marshall/Warren story
  • Perth, Australia, late 70s
  • Robin Warren, Histopathologist, with 20 odd cases of a peculiar bacterial infection in the stomach
  • Barry Marshall: young gastroenterologist in need of a project
  • Dual publications in the Lancet in 1983
  • Minimal interest, especially from drug companies (Glaxo, SKF)
  • Only in late 80s, with support from Astra (PPI, omeprazole), was the importance of the infection appreciated and then the money flowed into research
epidemiology
Epidemiology
  • infects over half the world’s population
  • infection probably acquired via faecal-oral route
  • untreated, infection persists throughout life
gastritis and practising pathologists
Gastritis and practising pathologists
  • Bacterial (non-atrophic): Helicobacter pylori
  • Marshall and Warren (1984)
  • Many animals have helicobacter as commensals
  • Adaptive features allow survival in the stomach
  • urease
  • flagellae
  • adhesions
  • lipopolysaccharide coat
gastritis and practising pathologists1
Gastritis and practising pathologists

Bacterial (non-atrophic): Helicobacter pylori

Clinical presentation

  • 80% asymptomatic
  • 5-15% peptic ulcer disease
  • 10% non-ulcer dyspepsia
  • 1-3% gastric adenocarcinoma
  • 0.5% gastric MALToma
gastritis and practising pathologists2
Gastritis and practising pathologists

Bacterial (non-atrophic): Helicobacter pylori

  • Outcome of Hp infection
  • Bacterial virulence factors (cagA, vacA, iceA)
  • Genetically determined host responses (IL-1)
  • Environmental factors
  • cagA particularly important
helicobacter pylori and upper gi pathology
Helicobacter pylori and upper GI pathology
  • What is Helicobacter pylori?
  • How do we recognise it?
  • Why is it important?
  • What can we do about it?
helicobacter pylori and upper gi pathology1
Helicobacter pylori and upper GI pathology

What is Helicobacter pylori?

  • A spiral flagellated bacterium, which produces urease
  • Lives in the surface mucus of stomach, especially the gastric antrum
  • Associated with hypergastrinaemia
helicobacter pylori and upper gi pathology2
Helicobacter pylori and upper GI pathology

How do we recognise it?

In tissues

  • H&E stain: pattern of disease
  • Modified Giemsa stain
  • Warthin-Starry silver method
  • Immunohistochemistry
helicobacter pylori and upper gi pathology3
Helicobacter pylori and upper GI pathology

How do we recognise it?

H&E stain: pattern of disease

  • Chronic inflammation, including lymphoid follicles
helicobacter pylori and upper gi pathology4
Helicobacter pylori and upper GI pathology

How do we recognise it?

H&E stain: pattern of disease

  • Variable activity of disease (polymorphs)
helicobacter pylori and upper gi pathology5
Helicobacter pylori and upper GI pathology

How do we recognise it?

In tissues

  • H&E stain: pattern of disease
  • Modified Giemsa stain
  • Warthin-Starry silver method
  • Immunohistochemistry
helicobacter pylori and upper gi pathology6
Helicobacter pylori and upper GI pathology

How do we recognise it?

Presence of organism

Giemsa

H&E

IHC

helicobacter pylori and upper gi pathology7
Helicobacter pylori and upper GI pathology

How do we recognise it?

In stomach

  • Culture of organism
  • CLO-test
  • C14-breath test

In serum

  • Antibodies (will only tell if ever infected)
helicobacter pylori and upper gi pathology8
Helicobacter pylori and upper GI pathology
  • What is Helicobacter pylori?
  • How do we recognise it?
  • Why is it important?
  • What can we do about it?
helicobacter pylori and upper gi pathology9
Helicobacter pylori and upper GI pathology

Why is it important?

  • Strongly associated with Chronic Gastritis
  • Strongly associated with Duodenal Ulcer
  • Fairly strongly associated with Gastric Ulcer
  • Associated with Gastric Carcinoma
  • Associated with Gastric MALT lymphoma
  • Possibly associated with diseases such as atheroma and SIDS
helicobacter pylori and upper gi pathology10
Helicobacter pylori and upper GI pathology

Chronic Gastritis

  • Pre-infection acid output is determined by genetic, nutritional and other factors
helicobacter pylori and upper gi pathology11
Helicobacter pylori and upper GI pathology

Chronic Gastritis

  • Pre-infection acid output is determined by genetic, nutritional and other factors
  • After infection, acid production is modified by H pylori-induced chronic inflammation
  • more virulent strains e.g. vacA and cagA lead to more active inflammation
  • some cytokines e.g. IL-1B and TNF-A modify parietal cell function
helicobacter pylori and upper gi pathology12
Helicobacter pylori and upper GI pathology

Chronic Gastritis

  • Pre-infection acid output is determined by genetic, nutritional and other factors
  • After infection, acid production is modified by H pylori-induced chronic inflammation
  • more virulent strains e.g. vacA and cagA lead to more active inflammation
  • some cytokines e.g. IL-1B and TNF-A modify parietal cell function
  • Gastritis pattern related to ulcer site
  • pangastritis (body/antrum) with GU: low/normal acid levels
  • antral gastritis with DU: high acid levels
phenotypes resulting from h pylori infection
Phenotypes resulting from H pylori infection

corpus-predominant

mild pan-gastritis

antrum-predominant

hypochlorhydria

gastric atrophy

intestinal metaplasia

hyperchlorhydria

no significant disease

gastric cancer phenotype

DU phenotype

helicobacter pylori and upper gi pathology13
Helicobacter pylori and upper GI pathology

Strongly associated with Chronic Gastritis

- 3 main types

  • Type A: ‘autoimmune’, associated with autoantibodies, atrophy, intestinal metaplasia (pernicious anaemia)
  • Type B: ‘bacterial’, Helicobacter pylori implicated, involves antrum
  • Type C: ‘chemical’, NOT associated with H pylori, previous surgery/NSAID use
helicobacter pylori and upper gi pathology14
Helicobacter pylori and upper GI pathology

Type A: ‘autoimmune’, associated with autoantibodies (pernicious anaemia)

  • Pre-neoplastic lesion, with developing atrophy and hypochlorhydria
  • Process of intestinal metaplasia
  • Dysplasia
  • Neoplasia
helicobacter pylori and upper gi pathology15
Helicobacter pylori and upper GI pathology

Type A: atrophy and intestinal metaplasia

Atrophy

IM

helicobacter pylori and upper gi pathology16
Helicobacter pylori and upper GI pathology

Type A:dysplasia and neoplasia

dysplasia

neoplasia

helicobacter pylori and upper gi pathology17
Helicobacter pylori and upper GI pathology

Type B: ‘bacterial’, associated with H pylori infection

  • Predominantly antral gastritis, associated with duodenal ulceration
  • Also associated with pan-gastritis and gastric ulceration
helicobacter pylori and upper gi pathology18
Helicobacter pylori and upper GI pathology

Type C: ‘chemical’, associated with reflux of biliary contents into stomach

  • Also seen in exposure to NSAIDs
helicobacter pylori and upper gi pathology19
Helicobacter pylori and upper GI pathology

Type C: ‘chemical’

  • Foveolar hyperplasia
  • Relative lack of

inflammatory cells

  • Oedema
  • Vascular congestion
  • Smooth muscle
helicobacter pylori and upper gi pathology20
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Duodenal Ulcer

  • Almost all cases of DU have associated antral gastritis due to H pylori (90-95%)
  • Antral gastritis causes antral G-cell hyperplasia leading to hypergastrinaemia
  • This causes high acid levels pouring into duodenum
  • This causes gastric metaplasia and ulceration
helicobacter pylori and upper gi pathology21
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Ulcer

  • Usually solitary
  • Between 1 and 5cm in diameter
  • Often lesser curve at transformation zone between body and antrum
helicobacter pylori and upper gi pathology22
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Ulcer

  • A high proportion of patients with GU have H pylori infection (60-70%)
  • Patients with intrinsically lower acid production will develop colonisation by H pylori of the body mucosa
  • This leads to hypochlorhydria, lower mucosal resistance, atrophy and intestinal metaplasia
  • All of which predispose to gastric ulcer formation
helicobacter pylori and upper gi pathology23
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Carcinoma

  • Common in Japan, Chile and Iceland
  • Environmental influences ?smoked foods
  • Decreasing incidence
  • Pre-cancerous lesions
  • Pernicious anaemia
  • Neoplastic polyps
  • H pylori infection
helicobacter pylori and upper gi pathology24
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Carcinoma

  • Class I carcinogen
  • Countries with high gastric cancer incidence also have high Hp infection rates
  • Hp predisposes to cancer by
  • production of potential carcinogens e.g. nitroso-compounds in hypochlorhydric gastric juice and free radicals in inflammatory response
  • deficiency of anti-oxidants such as ascorbic acid in gastric juice
  • increased cell turnover stressing DNA repair mechanisms and perpetuating mutations
stages in the development of gastric carcinoma after correa
Stages in the development of gastric carcinoma(after Correa)

normal gastric mucosa

H pylori

superficial gastritis

atrophic gastritis

intestinal metaplasia

Precancerous lesions

dysplasia

carcinoma

helicobacter pylori and upper gi pathology25
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Carcinoma

  • Early gastric cancer: confined to mucosa and submucosa, LN negative
  • Rare in UK, relatively common in Japan
  • 5 year survival 85%
helicobacter pylori and upper gi pathology26
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Carcinoma

Gross appearances Histology

helicobacter pylori and upper gi pathology27
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Carcinoma

  • Late gastric cancer: fungating, exophytic growth pattern
  • Malignant ulcer with raised rolled edges, loss of rugae
  • Diffusely infiltrative pattern
  • 5 year survival 30% (full thickness, LN-)
  • 5 year survival 5% (full thickness, LN+)
helicobacter pylori and upper gi pathology28
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric Carcinoma

Spread of gastric carcinoma

  • Direct: pancreas, colon, liver spleen
  • Lymphatic: local and regional LN, Virchow’s node
  • Blood: liver, lungs
  • Transcoelomic: omentum, mesentery, ovary (Krukenberg)
helicobacter pylori and upper gi pathology29
Helicobacter pylori and upper GI pathology

Helicobacter pylori and Gastric MALT Lymphoma

  • Mucosa Associated Lymphoid Tissue arises in the stomach as a result of Hp infection
  • Lymphoma arising in gastric MALT is a result of Hp infection as shown by
  • positive sero-epidemiological correlations
  • animal models
  • complete regression of lymphoma following eradication of Hp
helicobacter pylori and upper gi pathology30
Helicobacter pylori and upper GI pathology

H pylori and Gastric MALT Lymphoma

  • Mucosa Associated Lymphoid Tissue arises in the stomach as a result of Hp infection

Lymphoid follicle

helicobacter pylori and upper gi pathology31
Helicobacter pylori and upper GI pathology

H pylori and Gastric MALT Lymphoma

  • Mucosa Associated Lymphoid Tissue arises in the stomach as a result of Hp infection

Infiltrate of B cells

Lympho-epithelial lesion

helicobacter pylori and upper gi pathology32
Helicobacter pylori and upper GI pathology

What can we do about it?

  • Treat with antiulcer drugs, especially PPIs
  • Treat with antibiotics: currently clarithromycin
  • Resistance may develop
  • Reinfection may occur
  • If recurrence, consider culture and sensitivity
  • Some strains more virulent, leading to ulceration, carcinoma and MALToma
inflammatory bowel disease
INFLAMMATORY BOWEL DISEASE
  • What is inflammatory bowel disease?
  • What does it include?
  • What are its mimics?
  • What is the differential diagnosis?
inflammatory bowel disease1
INFLAMMATORY BOWEL DISEASE

What is inflammatory bowel disease?

  • Chronic inflammatory conditions of unknown aetiology affecting the gastrointestinal tract
inflammatory bowel disease2
INFLAMMATORY BOWEL DISEASE

What does inflammatory bowel disease include?

Two main forms of idiopathic IBD

  • Crohn’s disease
  • Ulcerative colitis
inflammatory bowel disease3
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD

Pathogenesis

  • Genetics
  • Environment
  • Constitutional Susceptibility
inflammatory bowel disease4
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Pathogenesis

Genetics

  • Twin Studies: monozygotic > dizygotic
  • Family Studies: CD > UC
  • Shared risk loci on chromosomes 3, 7 and 12, CD on chromosome 16, UC on chromosomes 2 and 6
  • Involvement of genes implicated in immunoregulation
  • Associations with Turner’s syndrome, Ank Spon, PSC
inflammatory bowel disease5
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Pathogenesis

Environment

  • Microbes: mycobacteria, viruses, normal bowel flora
  • Short Chain Fatty Acids: major source of metabolic fuel for epithelium
  • Cigarette smoke

- UC: stopping smoking induces relapses

- CD: smoking increases relapse rate

- possible role in arterial insufficiency in CD

inflammatory bowel disease6
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Pathogenesis

Constitutional Susceptibility

  • Defects of mucosal defences

- may convert commensals into pathogens

- modification of secretory mucins

- may expose the gut to pathogens

- increased intestinal permeability

inflammatory bowel disease7
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Pathogenesis

Constitutional Susceptibility: disruption of genes critical for immune modulation

  • transgenic animal models, e.g. IL2, IL10
  • mutational inactivation of anti-inflammatory cytokine genes
  • CD may be a Th1 driven disease (IL2, IL3, IFN), interacting with cytotoxic T cells and macrophages: uncontrolled production of IL12 by monocytes
  • UC may be a Th2 driven disease (IL3, 4, 5, 6, 9, 10 and 13): IL10 downregulates neutrophils and release of pro-inflammatory cytokines
inflammatory bowel disease8
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Crohn’s Disease

Gross

  • May affect any part of the GIT from mouth to anus
  • Particularly affects terminal ileum(30%), colon alone (20%) and ileum and colon (50%)
  • Skip lesions, intervening uninvolved areas
  • Often perianal skin involvement (75%)
inflammatory bowel disease9
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Crohn’s Disease

Pathology

  • Mucosal ulceration

typically fissuring

  • Oedema of adjacent

epithelium (cobblestone)

  • Pseudopolyp formation

regeneration

inflammatory bowel disease10
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Crohn’s Disease

Pathology

  • Transmural inflammation:

mucosa, submucosa,

muscularis propria,

serosa

  • Active chronic inflammation

with non-caseating

epithelioid granulomas

  • Fistula formation
inflammatory bowel disease11
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Crohn’s Disease

Complications

  • Anaemia: megaloblastic from vitamin B12 deficiency, hypochromic microcytic from iron deficiency
  • Malabsorption: fat, vitamins A,D,E,K, bile salts
  • Fistulas: bowel to bowel, to vagina, to bladder, to skin
  • Extra-intestinal: skin, eyes, joints (ankylosing spondylitis HLA-B27)
  • Slight increased risk of bowel carcinoma
inflammatory bowel disease12
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Ulcerative Colitis

Gross

  • Disease of colon only
  • Starts in rectum

spreads proximally

  • Continuous disease

(No skip lesions)

  • Mucosal disease

(No transmural involvement)

  • May involve whole colon

also appendix

inflammatory bowel disease13
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Ulcerative Colitis

Microscopy

  • Affects mucosa only

above muscularis mucosae

  • Active chronic inflammation
  • Cryptitis
  • Crypt abscess formation
  • Goblet cell depletion
  • Crypt loss and crypt distortion
  • Pseudopolyp formation

regeneration

inflammatory bowel disease14
INFLAMMATORY BOWEL DISEASE

IDIOPATHIC IBD - Ulcerative Colitis

Complications

  • Anaemia: iron deficiency from blood loss
  • Electrolyte loss from diarrhoea
  • Extra-intestinal disease: skin, eyes, joints, bile ducts (PSC)
  • Increased risk of carcinoma: related to duration and severity of disease
  • Need for surveillance for dysplasia
inflammatory bowel disease15
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

  • Ischaemic colitis
  • Radiation colitis
  • Behcet’s disease
  • Pouchitis
  • Diversion colitis
  • Microscopic (lymphocytic/collagenous) colitis
  • Infectious colitis
  • Iatrogenic colitis
inflammatory bowel disease16
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Ischaemic colitis

  • Disease of elderly
  • Associated with aortic atheroma
  • May be total - infarction
  • May be subtotal - mucosal disease with subsequent fibrosis
inflammatory bowel disease17
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Radiation colitis

  • Follows therapeutic radiation e.g. for Hodgkin’s disease, carcinoma of cervix
  • Acute disease: mucosal ulceration, diarrhoea
  • Chronic disease: related to vascular occlusion, fibrosis, radiation fibroblasts
inflammatory bowel disease18
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Behcet’s disease

  • Mucocutaneous ulceration: skin, genital tract, GIT
  • Associated with venulitis
inflammatory bowel disease19
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Pouchitis

  • Disease of ileo-anal reservoir formed after pan-proctocolectomy for UC (or FAP)
  • May be related to bacterial overgrowth
  • May be recurrence of disease (UC)
  • Active chronic inflammation of small bowel mucosa, with crypt flattening and colonic metaplasia
inflammatory bowel disease20
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Diversion colitis

  • Disease of rectal stump after intermediate surgery for UC, colorectal carcinoma or diverticular disease
  • Chronic inflammation: lymphoid follicles, active chronic inflammation, possible granulomas
  • Beware overdiagnosis of Crohn’s disease
inflammatory bowel disease21
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Microscopic (lymphocytic/collagenous) colitis

  • Clinically watery diarrhoea
  • No gross abnormality on endoscopy
  • Histologically, increased chronic inflammatory cells in lamina propria (microscopic colitis)
  • May be increased sub-epithelial collagen
  • May be increased intra-epithelial lymphocytes
inflammatory bowel disease22
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Infectious colitis

  • Multiple bacterial agents
  • Superficial half of crypts
  • Acute inflammation
  • Often resolve spontaneously (acute self-limiting colitis)
inflammatory bowel disease23
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Infectious colitis

  • Specific form is pseudomembranous colitis
  • Associated with antibiotic usage
  • Caused by enterotoxin of Clostridium difficile
  • May occur as part of cross-infection/epidemic
  • Treat with vancomycin
inflammatory bowel disease24
INFLAMMATORY BOWEL DISEASE

What are the mimics of IBD?

Iatrogenic colitis

  • Pouchitis
  • Diversion colitis
  • NSAID-induced colitis

- inhibit cyclo-oxygenase (COX-1 and COX-2)

- small intestinal ulceration

- less commonly, diffuse colitis

- also may be seen in collagenous colitis