Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Objectives

• Describe the common clinical presentations of common gastrointestinal diseases

• Understand the pathophysiology behind selected common non-neoplastic conditions affecting the
gastrointestinal tract (GIT)
• Describe the pathogenesis and pathology of tumours of the stomach and gastrointestinal tract,
including selected associated cancer syndromes

Outline

I. Anatomy, Physiology and Congenital Conditions of the GIT

a. Normal Anatomy and Function
b. Manifestations of GI diseases
c. Congenital anomalies: Meckel diverticulum, pyloric stenosis, Hirschsprung disease etc.
II. Oesophagus
a. Obstruction: Mechanical vs Functional
b. Causes of Bleeding: Lacerations / perforation and Varices
c. Oesophagitis: Reflux oesophagitis (GERD), Eosinophilic oesophagitis (EoE) etc.
d. Barrett oesophagus
e. Tumours: Adenocarcinoma, Squamous cell carcinoma
III. Stomach
a. Gastropathy, Acute gastritis and Chronic gastritis: Helicobacter pylori, Autoimmune etc.
b. Peptic ulcer disease (PUD)
c. Other causes of gastric bleeding: Stress-related and non-stress related
d. Miscellaneous non-neoplastic conditions: Gastritis cystica, hypertrophic gastropathies
e. Dysplasia
f. Polyps: Inflammatory/hyperplastic, fundic gland polyps, adenomas
g. Tumours: Adenocarcinoma, lymphoma, neuroendocrine tumour (NET), gastrointestinal
stromal tumour (GIST)
IV. Small intestine and colon
a. Intestinal obstruction (IO): Hernia, adhesions, volvulus, intussusception
b. Ischaemic bowel disease
c. Angiodysplasia
d. Malabsorption and Diarrhoea: Cystic fibrosis, celiac disease etc.
e. Infectious enterocolitis
f. Irritable bowel syndrome (IBS)
g. Inflammatory bowel disease (IBD): Crohn disease and Ulcerative colitis
h. Other forms of colitis: Diversion colitis, microscopic colitis (lymphocytic, collagenous), Graft
vs host disease
i. Diverticular disease
j. Polyps: Non-neoplastic vs neoplastic
k. Colorectal cancer: Polyposis vs non-polyposis syndromes, and colorectal adenocarcinoma

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

V. Anal canal
a. Haemorrhoids
b. Tumours
VI. Vermiform appendix
a. Acute appendicitis
b. Tumours
VII. Peritoneal cavity
a. Peritonitis
b. Tumours

References

Kumar V, Abbas A, Aster J. Robbins & Cotran Pathologic Basis of Disease. 9th ed.
WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International
Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol1).

Image credits
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore
Pathopic© Accessible at: https://alf3.urz.unibas.ch/pathopic/e/copyright.htm

Note: Pathweb Study Notes are based on the key topics covered in the lectures in the Yong Loo Lin
School of Medicine, as well as additional topics covered in major texts. For more comprehensive
discussion on specific pathology topics, readers are advised to refer to the recommended texts in your
respective courses.

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

I. ANATOMY, PHYSIOLOGY AND CONGENITAL CONDITIONS OF THE GIT

Normal anatomy and function

• Hollow tube extending from oral cavity to anus, with regional variations in structure and function
• Important functions: Motility, secretion, digestion, absorption and excretion

Manifestations of GI diseases

GI diseases may be

(i) Limited to GIT e.g. peptic ulcer

(ii) Manifestation of systemic disorder e.g. CMV infection
(iii) Presents as a systemic disorder but resulting from GI problem e.g. Iron deficiency anaemia
from bleeding PUD, vitamin deficiencies due to malabsorption

Cardinal signs and symptoms: Abdominal / chest pain, altered ingestion of food (nausea, vomiting,
dysphagia, anorexia), altered bowel movements (diarrhoea or constipation), GI bleeding

Complications: Acute – dehydration, sepsis, bleeding, perforation. Chronic: Malabsorption (malnutrition,

deficiency states), obstruction

Congenital anomalies

• Depends on the nature and timing of the insult during gestation

• Presence of congenital GI anomalies should prompt evaluation of other organs as many organs
develop simultaneously during embryogenesis

Atresia, fistulae and duplications

• May occur in any part of the GIT

• Agenesis = absence; atresia = incomplete development (often resulting in a thin non-canalised cord);
stenosis = developmental or acquired luminal narrowing due to thickening of the wall. Causes
complete / partial mechanical obstruction requiring surgical repair
o Oesophageal atresia: may be associated with a fistula connecting the oesophagus to the
tracheobronchial tree (tracheo-oesophageal fistula); fistula may also be present without
atresia. Results in aspiration, pneumonia, fluid and electrolyte imbalances
o Intestinal atresia: frequently duodenal, or imperforate anus (most common)

Diaphragmatic hernia, omphalocele and gastroschisis

• Diaphragmatic hernia = when incomplete formation of the diaphragm allows herniation of the
abdominal viscera into the thoracic cavity. If severe, may result in pulmonary hypoplasia
o Hiatus hernia = Due to separation of diaphragmatic crura and widening of space between
muscular crura and esophageal wall. Can be congenital or acquired. Associated with reflux
oesophagitis and may be a cause of lower oesophageal sphincter incompetence; may be
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complicated by ulceration, bleeding, perforation, strangulation (paraoesophageal hernia),

increased risk of oesophageal and gastric adenocarcinoma
• Omphalocele = incomplete closure of abdominal musculature, with herniation of the abdominal
viscera into a ventral membranous sac. Due to failure of midgut to return to abdomen during midgut
rotation. 40% of infants have other associated birth defects (especially heart and renal anomalies)
• Gastroschisis = similar to omphalocele except it involves all layers of the abdominal wall from
peritoneum to skin and therefore has no covering sac. Due to defective ingrowth of mesoderm,
impaired midline fusion or inappropriate apoptosis. 10-15% may have associated intestinal atresia,
but associated anomalies are otherwise rare.

Ectopia

• Ectopia = normally formed tissues in an abnormal site (‘developmental rests’). Common in GIT e.g.
ectopic gastric mucosa in upper oesophagus (‘inlet patch’) or small bowel/colon, ectopic pancreatic
tissue in oesophagus / stomach. Can cause inflammation and scarring with occult bleeding and/or
pain

Meckel diverticulum

• True diverticulum = blind outpouching of the GIT that communicates with the lumen and includes all
three layers of the bowel wall
• Acquired diverticulum = lacks or has an attenuated muscularis propria e.g. in sigmoid colon
• Meckel diverticulum is the most common true diverticulum as a result of failed involution of the
vitelline duct (connects lumen of developing gut on the antimesenteric side to yolk sac). Often
contains ectopic gastric tissue which may result in occult bleeding
• ‘Rule of ‘2’s’ = occurs in 2% of population, within 2 feet (60 cm) of ileocaecal valve, 2 inches (5 cm)
long, twice as common in males and most often symptomatic by age 2 (although only 4% are ever
symptomatic)

Pyloric stenosis

• Congenital vs acquired (e.g. antral gastritis / peptic ulcers at pylorus, carcinomas of distal stomach
or pancreas)
• Congenital hypertrophic pyloric stenosis is 3-5x more common in males and has strong but
multifactorial pattern of inheritance and genetic basis
• Hyperplasia of the pyloric muscularis propria +/- oedema and inflammation results in gastric outlet
obstruction, usually presenting between 3-6th wks of life as projectile non-bilious vomiting after
feeding. Surgical splitting of the muscularis (myotomy) is curative

Hirschsprung disease (congenital aganglionic megacolon)

• 1 in 5000 live births; 10% of all cases occur in Down syndrome

• Absence of neural crest derived ganglion cells (both Meissner submucosal and Auerbach myenteric
plexus) in the distal colon due to (1) premature arrest of normal migration of neural crest cells from

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caecum to rectum, or (2) premature death of ganglion cells. This results in absent peristalsis and
functional obstruction, with dilatation of the proximal unaffected bowel segment
• Presents with failure to pass meconium in the immediate postnatal period, followed by constipation,
abdominal distension and bilious vomiting, which may be complicated by enterocolitis, fluid and
electrolyte imbalances, perforation and peritonitis. Treatment: surgical resection

II. OESOPHAGUS

• Extends from epiglottis in pharynx to gastro-oesophageal junction

• Clinical presentations: Dysphagia, haemetemesis, odynophagia (painful swallowing), heartburn
• Non-neoplastic conditions: congenital anomalies, obstruction, lacerations/perforation, varices,
oesophagitis, Barrett oesophagus
• Tumours: most commonly adenocarcinoma and squamous cell carcinoma

Obstruction

Structural (mechanical) vs functional (dysmotility i.e. disruption of the coordinated waves of peristaltic
contractions following swallowing)

• Mechanical obstruction: stenosis / strictures due to inflammation and scarring (GERD, radiation,
caustic injury), mucosal webs or rings, cancer
• Functional: Achalasia = triad of (1) incomplete lower oesophageal sphincter (LES) relaxation, (2)
increased LES tone and (3) aperistalsis of the oesophagus.
o Primary achalasia = due to distal oesophageal inhibitory neuronal (ganglion cell)
degeneration. Cause is unknown
o Secondary achalasia = e.g. Chagas disease where Trypanosoma cruzi infection causes
destruction of the myenteric plexus, failure of peristalsis and oesophageal dilatation;
diabetic autonomic neuropathy etc.

Lacerations / perforation

• One of the causes of haemetemesis

• Mallory-Weiss tears = superficial longitudinal tears near the GEJ, most often associated with severe
retching due to acute alcohol intoxication. Thought to be due to failure of the reflex oesophageal
musculature relaxation preceding the antiperistaltic contractile wave, causing stretching and tearing
of the oesophagus by the refluxed gastric contents. Does not usually require surgical intervention
• Boerhaave syndrome = transmural tearing and rupture of the distal oesophagus, also usually
associated with vomiting, causing severe mediastinitis. Requires urgent surgical intervention.

Varices

• Tortuous dilated veins primarily within submucosa and lamina propria of distal oesophagus and
proximal stomach

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

• Consequence of portal hypertension, which causes the development of porto-

systemic collateral channels. Present in nearly 50% of cirrhotic patients, with
variceal rupture and bleeding in 25-40% (manifesting as haematemesis +/-
melena) which is an emergency treated medically or endoscopically. However,
30% or more of patients with variceal haemorrhage still die from hypovolemic
shock, hepatic coma etc., and those that survive may have recurrent bleeds
with mortality risk. Surveillance with prophylactic treatment with beta-
blockers to reduce portal blood flow and endoscopic variceal ligation helps
mitigate the risk.

Oesophagitis

• Reflux oesophagitis (gastro-oesophageal reflux disease or GERD): Most frequent cause of

oesophagitis. Reflux of gastric juices +/- duodenal bile results in oesophageal mucosal injury
o Pathogenesis: (1) Transient LES relaxation: mediated by vagal pathways and triggered by
gastric distension, stress, swallowing-induced (2) Abrupt increase in intra-abdominal
pressure: causes forceful opening of a relatively hypotensive LES e.g. coughing, straining.
Stratified squamous epithelium of the oesophagus is resistant to abrasion from foods but
sensitive to acid, triggering an inflammatory response.
o Risk factors: alcohol, smoking, obesity, CNS depressants, pregnancy, hiatal hernia, delayed
gastric emptying and increased gastric volume
o Clinical features: Most common in individuals above 40, but can occur in infants and
children. Usually presents with heartburn, dysphagia, sore throat and acid regurgitation.
May be complicated by ulceration, haemetemesis, melena, strictures, Barrett oesophagus.
Proton-pump inhibitors (PPI) to reduce gastric acidity provides symptomatic relief
o Endoscopy: Erythema +/- erosions, ulceration
o Histology: basal zone hyperplasia, elongation of the lamina propria papillae, intraepithelial
eosinophils and neutrophils
• Eosinophilic oesophagitis: most common cause of GERD-like symptoms in children living in
developed countries. Strongly associated with atopy - food allergy, allergic rhinitis, asthma or
modest peripheral eosinophilia. Histology = large numbers of intraepithelial eosinophils. Treatment
= dietary restriction to food allergens and topical / systemic corticosteroids. A subset may respond
to PPIs.
• Chemical: irritants e.g. alcohol, corrosive acids/alkalis, pill-induced, chemotherapy
• Radiation: vascular injury resulting in mucosal damage
• Infections (immunocompetent vs immunocompromised): Herpes simplex virus (HSV) [punched-out
ulcers, epithelial viral nuclear inclusions], cytomegalovirus (CMV) [shallower ulcers, stromal nuclear
and cytoplasmic inclusions], fungal e.g. Candidiasis [adherent gray-white pseudomembranes, fungal
hyphae]
• Graft-vs-host disease: basal epithelial cell apoptosis without significant acute inflammation
• Involvement by skin diseases e.g. bullous pemphigoid

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Barrett oesophagus (BE)

• Complication of chronic GERD characterized by columnar / intestinal metaplasia within the

oesophageal squamous mucosa.
• Clinical features: Rising incidence, ~10% of individuals with symptomatic GERD. White males, 40-
60yo. Risk factor for dysplasia (preinvasive change) and oesophageal adenocarcinoma. Presence of
dysplasia a/w prolonged symptoms, longer segment length, increased patient age and Caucasian
race. Management is controversial, but most currently do periodic endoscopy with biopsy for
dysplasia surveillance. Intramucosal or submucosal invasive carcinoma requires treatment.
• Diagnosis requires endoscopy and histology:
• Endoscopy: tongues / patches of red velvety mucosa extending upward from the GEJ, alternating
with the pale smooth squamous oesophageal mucosa and interfacing distally with the light brown
columnar gastric mucosa. Long segment = 3cm or more, short segment = less than 3 cm
• Histology: columnar / intestinal metaplasia (requirement of goblet cells depends on UK/US
guidelines). Dysplasia is characterized by architectural and cytologic atypia, and can be low or high
grade.

Adenocarcinoma

• Most oesophageal adenocarcinomas arise from Barrett oesophagus → usu. distal 1/3 of
oesophagus, may involve the gastric cardia
• Risk factors: GERD, smoking, radiation, reduced rates of H.pylori infection (because H.pylori causes
gastric atrophy which reduces acid secretion and reflux and therefore Barrett oesophagus)
• Pathogenesis: Progression from BE to adenocarcinoma occurs over an extended period through the
stepwise acquisition of genetic and epigenetic changes. Early stages: chromosomal abnormalities,
TP53 mutation, downregulation of CDKN2A (p16/INK4a). Later progression: amplification of EGFR,
ERBB2, MET, cyclin D1 and cyclin E
• Clinical features: Caucasian males. Rapid increase in incidence since 1970s. Patients usually present
with pain or dysphagia, progressive weight loss, haemetemesis, chest pain or vomiting. Tumour
usually has already spread to submucosal lymphatic vessels by the time patients are symptomatic
and therefore has poor prognosis due to advanced stage at presentation. Prognosis is much better
(5yr survival of 80%) in tumours limited to mucosa or submucosa.
• Gross: flat/raised patches, ulceration, diffuse infiltration
• Histology: adjacent BE. Gland formation +/- mucin, often intestinal-type or less commonly signet-
ring cell morphology.

Squamous cell carcinoma

• 50% in middle third of oesophagus

• Risk factors: Alcohol and tobacco use, poverty, caustic oesophageal injury, achalasia, frequent
consumption of very hot beverages, diets deficient in fruits or vegetables, nutritional deficiencies,
mutagenic compounds e.g. nitrosamines and polycylic hydrocarbons, HPV infection in high risk areas

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

• Pathogenesis: Molecular pathogenesis incompletely defined, but recurrent abnormalities include

SOX2 amplification, cyclin D1 overexpression and loss of function mutations in tumour suppressors
TP53, e-cadherin and NOTCH1
• Clinical features: M:F = 4:1, older than 45 years old, African-Americans. Usually insidious onset,
presenting with dysphagia, odynophagia or obstruction (with subconscious adjustment of diet from
solid to liquid foods), prominent weight loss due to impaired nutrition and effects of tumour itself.
Complications: Tumour ulceration causing haemorrhage, iron deficiency anemia and sepsis; local
invasion into surrounding structures e.g. trachea-oesophageal fistula resulting in aspiration of food
and pneumonia; aorta-oesophageal fistula causing exsanguination. Prognosis: Poor, especially with
advanced tumours and LN metastases (which are common - LN drainage = upper 1/3: cervical LN,
middle 1/3: mediastinal, paratracheal and tracheobronchial LN, lower 1/3: gastric and celiac LN)
• Gross: Small grey-white plaque-like thickenings, growing into tumour masses that may be polypoid /
exophytic, protruding and obstructing the lumen. Also may be ulcerative or diffusely infiltrative
lesions, causing thickening, rigidity and luminal narrowing. Rich lymphatic network promotes
circumferential and longitudinal spread; tumour nodules may present several cm away from the
principal mass
• Histology: Begins as in-situ lesion (squamous dysplasia → carcinoma in-situ). Most SqCC are well to
moderately differentiated.

III. STOMACH

• 4 major anatomic regions: Cardia, fundus, body, antrum.

o Cardia and antrum: mucin-secreting foveolar cells that form small glands. Antral glands also
contain endocrine G cells that release gastrin to stimulate luminal acid secretion by parietal
cells in the body and fundus
o Body and fundus: acid-secreting parietal cells (also secretes intrinsic factor) and digestive
enzymes-secreting chief cells (oxyntic mucosa)
• Normal gastric lumen is extremely acidic (pH close to 1), which contributes to digestion but has
potential to damage mucosa
• Clinical presentations: asymptomatic, epigastric pain, nausea, vomiting, haematemesis, melena

Gastropathy and acute gastritis

• Gastritis = mucosal inflammation. Acute gastritis = neutrophils present

• Gastropathy = gastric dysfunction or injury with rare or absent inflammatory cells. Causes: NSAIDs,
alcohol, bile, stress-induced, portal hypertension.
o Hypertrophic gastropathy: specific group of diseases including Menetrier disease and
Zollinger-Ellison syndrome
• Causes: Chemical e.g. alcohol, bile reflux (post-gastrectomy), corrosives, chemotherapy; radiation
therapy; NSAIDs; corticosteroids. Contributory factors: Smoking, elderly age (?due to reduced mucin
and bicarbonate secretion), high altitudes (decreased oxygen)

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

• Pathogenesis: Disruption of the normal protective mechanisms in the stomach –

(i) Mucus barrier: mucin secretion by surface foveolar cells forms a thin layer of mucus and
phospholipids that prevents large food particles from directly touching the epithelium
(ii) Bicarbonate secretion: the mucus layer has a neutral pH as a result of bicarbonate ion
secretion by surface epithelial cells
(iii) Epithelial barrier: the gastric epithelial cells beneath the mucus layer has intercellular tight
junctions, forming a physical barrier that limits back-diffusion of acid and leakage of other
luminal materials, including pepsin, into the lamina propria. The epithelial layer is
maintained by complete replacement of the surface foveolar cells every 3 to 7 days
(iv) Rich mucosal blood flow: delivers bicarbonate, oxygen and nutrients to epithelial cells while
washing away acid that has back-diffused into the lamina propria. In acid-secreting parts of
the stomach, a capillary ‘alkaline tide’ is generated as parietal cells secrete hydrochloride
acid into the gastric lumen and bicarbonate into the vessels
NSAIDs: inhibit cyclooxygenase (COX)-dependent synthesis of prostaglandins E2 and I2, which
stimulate nearly all of the above defense mechanisms while reducing acid secretion. Both COX1 and
2 isoenzymes contribute to mucosal protection, so even selective COX2 inhibitors e.g. celecoxib can
result in gastropathy or gastritis
Uremic patients and urease-secreting H.pylori: inhibition of gastric bicarbonate transporters by
ammonium ions
Chemicals/alcohol/chemoradiotherapy: Direct mucosal damage to both epithelial and stromal cells.
Chemotherapy agents that inhibit DNA synthesis or the mitotic apparatus also cause generalized
mucosal damage by insufficient epithelial renewal
• Clinical presentation: depends on etiology e.g. NSAID-induced gastropathy may be asymptomatic,
or persistent epigastric pain that responds to antacids or PPIs, while pain associated with bile reflux
is refractory to such therapies and may be accompanied by occasional bilious vomiting
• Histology: foveolar hyperplasia, lamina propria oedema and vascular congestion. Neutrophils seen
in acute gastritis (vs ‘gastropathy’). Acute erosive haemorrhagic gastritis = erosions (superficial
mucosal defect due to loss of epithelium) in more severe mucosal damage +/- haemorrhage.
Extensive erosions may progress to ulcers

Chronic gastritis

• Chronic mucosal inflammation that can lead to mucosal atrophy and intestinal metaplasia (IM)
• Causes: Most common - Helicobacter pylori infection (longstanding can result in atrophic, usually
multifocal, gastritis). Others - autoimmune gastritis (most common cause of diffuse atrophic
gastritis), radiation injury, chronic bile reflux, mechanical injury, involvement by systemic diseases
e.g. Crohn disease, amyloidosis, graft vs host disease
• Clinical presentation: Symptoms usually less severe but more persistent compared to acute
gastritis. Nausea, abdominal pain, +/- vomiting. Haematemesis is uncommon.
• Complications: Peptic ulcer disease, mucosal atrophy which is associated with intestinal
metaplasia (IM) and a risk factor to gastric adenocarcinoma (greatest in autoimmune gastritis,
possibly because achlorhydia of gastric mucosal atrophy permits overgrowth of bacteria that

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

produce carcinogenic nitrosamines. IM in chronic H.pylori gastritis may regress after clearance of
the organisms)

Helicobacter pylori gastritis

• Spiral-shaped or curved bacilli that causes predominantly antral gastritis with normal or increased
(local) gastrin production
• Pathogenesis: Pattern of H.pylori gastritis is a result of interplay between gastroduodenal mucosal
defenses, host inflammatory responses and bacterial virulence factors. There is an inverse
relationship between risk of duodenal ulcer and gastric adenocarcinoma depending on the pattern:
1. Antral-limited: Greater risk of duodenal peptic ulcer due to the increased acid production
(due to stimulation of gastrin release by cytokines released or specific products of H.pylori)
2. Pangastritis: Body and fundus progressively involved, resulting in multifocal atrophic
gastritis associated with reduced parietal cell mass and acid secretion, IM and increased risk
of gastric adenocarcinoma
Virulence of H.pylori is linked to several factors:
• Flagella: allows the bacteria to be motile in viscous mucus
• Urease: generates ammonia from endogenous urea and thereby elevates local gastric pH
and enhances bacterial survival
• Adhesins: enhance bacterial adherence to surface foveolar cells
• Toxins: cytotoxin-associated gene A (CagA) and the associated 20 gene pathogenicity islands
that are present in 50% of H.pylori isolates overall but 90% in populations with elevated
gastric cancer risk and therefore may be involved in disease progression, partly because
CagA expressing strains can effectively colonize the gastric body and cause multifocal
atrophic gastritis
Host factors:
• Genetic polymorphisms that lead to increased expression of proinflammatory cytokines
tumour necrosis factor (TNF) and interleukin IL-1b or decreased expression of the anti-
inflammatory cytokine IL-10 are associated with development of pangastritis, atrophy and
gastric cancer.
• Iron deficiency may also be risk factor of H.pylori associated gastric cancer
• Clinical features: Fecal-oral transmission → higher rates in areas of poverty, household crowding.
Infection typically acquired in childhood and persists for life without treatment. Mostly
asymptomatic; symptoms usually only in chronic infection. Complications: Peptic ulcer, gastric
adenocarcinoma, gastric lymphoma. Treatment: combination of antibiotics (triple therapy) and
proton pump inhibitor. Relapses can occur after incomplete eradication or reinfection, which is
common in regions with high endemic colonization rates
• Endoscopy: erythematous mucosa +/- coarse nodular appearance
• Histology: H.pylori organisms within the superficial mucus overlying the epithelial cells in the
surface and neck regions (has tropism for gastric epithelia, not found in areas of IM or duodenal
epithelium). Can be demonstrated with special stains

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

1. Antral-limited (usually): +/- cardia → antral biopsies performed for evaluation of H.pylori.
Mucosa shows mixed inflammatory infiltrate: neutrophils (activity), plasma cells,
lymphocytes (+/- lymphoid aggregates) and macrophages
2. Pangastritis (if long standing): In addition to inflammation, body and fundus show patchy
mucosal atrophy (loss of chief and parietal cells → looks like antral mucosa) (vs. diffuse
atrophy in autoimmune gastritis), typically associated with IM and increased risk of gastric
adenocarcinoma
• Other diagnostic tests: (Non-invasive) Serologic test for H.pylori antibodies, fecal bacterial
detection, urea breath test (based on conversion of urea into ammonia and CO2 by bacterial
urease). (Invasive) Gastric biopsy specimens can also be analyzed by rapid urease test, bacterial
culture or PCR detection of bacterial DNA

Autoimmune (AI) gastritis (less than 10% of chronic gastritis)

• Body-predominant gastritis characterized by antibodies to parietal cells and intrinsic factor (IF) (can
be detected in serum and gastric secretions), resulting in defective gastric acid secretion
(achlorhydria), endocrine cell hyperplasia (hypergastrinemia), decreased ileal vitamin B12
absorption (leading to deficiency and pernicious anaemia) and reduced serum pepsinogen I
secretion (from chief cells)
• Pathogenesis: Autoimmune destruction of parietal cells (which secretes gastric acid and IF) causes:
o Absence of acid production (achlorhydria), stimulating increased gastrin secretion
(hypergastrinemia), hyperplasia of the antral gastrin-producing G cells and hyperplasia of
enterochromaffin-like cells in the gastric body (neuroendocrine cell hyperplasia, which can
progress to form small multicentric low grade neuroendocrine tumours). Achlorhydria also
decreased iron absorption (iron deficiency anaemia)
o Lack of intrinsic factor, disabling ileal vitamin B12 absorption, leading to vitamin B12
deficiency and slow-onset megaloblastic anaemia (pernicious anaemia)
Chief cell destruction also occurs (through general gastric gland destruction during the autoimmune
attack on the parietal cells), resulting in reduced serum pepsinogen I concentration
Note: H.pylori chronic gastritis doesn’t have achlorhydria or pernicious anaemia despite gastric
atrophy because it is usually patchy / multifocal with residual patches of parietal and chief cells vs
diffuse atrophy of AI gastritis
The principal agent of injury is actually CD4+ T cells directed against parietal cell components,
including the H+, K+-ATPase proton pump. Autoantibodies against parietal cell components
(including the proton pump) and intrinsic factor are present in 80% of patients with AI gastritis but
are NOT thought to be pathogenic - neither secreted IF nor the luminally oriented proton pump are
accessible to the circulating antibodies, and passive transfer of the antibodies does not produce
gastritis in experimental animals. Hence they are important mainly for diagnosis only
• Clinical features: slow onset disease with variable progression to gastric atrophy over 2-3 decades –
median age at diagnosis is 60, and anaemia is only seen in a few patients. Patients may present with
symptoms of anaemia or vitamin B12 deficiency (atrophic glossitis, malabsorptive diarrhoea,
peripheral neuropathy with numbness or paraesthesias, cerebral dysfunction e.g. memory loss,

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

personality changes, subacute combined degeneration of the spinal cord). Slightly more F>M; a/w
other autoimmune diseases e.g. Hashimoto thyroiditis, but little evidence of linkage to specific HLA
alleles so far. Treatment: Prevention/treatment of vitamin B12 and iron deficiencies (prevention is
important because unlike anaemia, neurologic changes are not reversed by vitamin B12 therapy)
• Histology: diffuse mucosal atrophy of the oxyntic glands (chief and parietal cells) within body and
fundus +/- intestinal metaplasia, with no/minimal damage to antrum and cardia. Mainly chronic
inflammation (lymphocytes, macrophages, plasma cells with lymphoid aggregates) +/- neutrophils,
deep in the lamina propria and centered on the gastric glands. Also varying degrees of
neuroendocrine cell hyperplasia +/- neuroendocrine tumours

H.pylori associated gastritis Autoimmune gastritis

Location Antrum Body
Inflammation Neutrophils, subepithelial plasma cells Lymphocytes, macrophages, plasma cells +/-
neutrophils
Acid production Increased to slightly decreased Decreased
Gastrin Normal to decreased Increased
Complications Peptic ulcer, adenocarcinoma, MALT Atrophy, pernicious and iron deficiency anaemia,
lymphoma adenocarcinoma, neuroendocrine tumours

Eosinophilic gastritis

• Tissue damage associated with dense infiltrates of eosinophils in the mucosa and muscularis, usually
antral or pyloric region. May be caused by allergic reactions e.g. cow’s milk allergy, in association
with some immune disorders e.g. systemic sclerosis, parasitic infections and H.pylori infection
• May affect other GI sites, a/w peripheral eosinophilia and raised serum IgE levels

Lymphocytic gastritis

• Idiopathic but 40% associated with celiac disease, suggesting an immune-mediated pathogenesis.
Typically affects entire stomach
• F>M, presents with non-specific abdominal symptoms
• Endoscopy: thickened gastric folds covered by small nodules with central aphthous ulceration on
endoscopy (varioliform gastritis). Histology: Marked increase in intraepithelial T lymphocytes

Granulomatous gastritis

• Descriptive term for any gastritis that contains granulomas / aggregates of epithelioid macrophages.
E.g. Idiopathic, gastric involvement by Crohn disease, sarcoidosis, infections

Peptic ulcer disease (PUD)

• Chronic mucosal ulceration affecting the duodenum or stomach, usually due to H.pylori infection
o Antrum/proximal duodenum (most common location): usually due to chronic H.pylori
induced antral gastritis, which is associated with increased acid secretion and decreased
duodenal bicarbonate secretion

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o Body/fundus: usually due to some H.pylori gastritis or AI gastritis, resulting in mucosal

atrophy and lesser acid secretion. Therefore protects from antral/duodenal ulcers
o Oesophagus (rare): due to GERD or acid secretion by ectopic gastric mucosa (can occur
occur in duodenum or Meckel diverticulum)
• Pathogenesis: Imbalance between mucosal defenses and damaging factors of chronic gastritis (PUD
therefore generally develops on a background of chronic gastritis). Likely host and bacterial factors
determine why some people develop only chronic gastritis and others get PUD
• Clinical features: Most due to H.pylori infection, NSAIDs (potentiated by steroids) or cigarette
smoking (synergizes with H.pylori for gastric PUD). Rare causes e.g. Zollinger-Ellison syndrome
Presentation: Epigastric burning or aching pain (can be chronic/recurring, occurring 1-3hrs after
meals, worse at night and relieved by alkali or food). With penetrating ulcers, pain may be referred
to the back, left upper quadrant or chest, mimicking cardiac chest pain. Nausea/vomiting,
bloating/belching, weight loss. May also be symptomatic from complications e.g. iron deficiency
anaemia, haemorrhage or perforation.
Complications: Bleeding (most frequent - 15-20% of patients; may be life threatening or first
presentation); Perforation (5%; accounts for 2/3 of ulcer deaths – surgical emergency!); Obstruction
(2%; mostly in chronic ulcers, secondary to oedema or scarring usually in pyloric channel ulcers +/-
duodenal ulcers). Malignant transformation occurs rarely, if ever.
Treatment: H.pylori eradication, neutralization of gastric acid (primarily with proton pump inhibitors
(PPI)), and withdrawal of offending agents e.g. NSAIDs. Surgery for treatment of bleeding or
perforated ulcers (previously, antrectomy and vagotomy to prevent the acid-stimulatory effects
mediated by the vagus nerve, but now not necessary with medical treatment)
• Gross: Solitary (>80%), round to oval, sharply punched-out defect with
a smooth clean ulcer base as a result of peptic digestion of exudate.
The mucosal margin may overhang the base slightly, but is usually level
with surrounding mucosa vs. heaped up margins characteristic of
cancers. (Note: Size and location do not differentiate between benign
and malignant ulcers)
• Histology: thin surface layer of fibrinopurulent exudate, underlying
suppurative necrosis, granulation tissue with mononuclear leukocytes, and a fibrocollagenous scar
forming the ulcer base. Vessel walls are thickened and possibly thrombosed within the scarred area
– bleeding from these damaged vessels from the ulcer base may cause life-threatening
haemorrhage.

Stress-related mucosal disease

• Occurs in patients with severe physiologic stress, usually during the 1st 3 days (acute)
o Stress ulcers: shock, sepsis, severe trauma, post-myocardial infarction
o Curling ulcers: severe burns or trauma. Proximal duodenum
o Cushing ulcers: intracranial disease. Duodenum and oesophagus. High incidence of
perforation

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Healing with complete re-epithelisation occurs within days to several weeks after correction of the
underlying condition
• Pathogenesis: Local ischaemia from systemic hypotension or stress-induced splanchnic
vasoconstriction, upregulation of inducible nitric oxide synthase and increased release of
vasoconstrictor endothelin-1. Other contributing factors: systemic acidosis, gastric acid
hypersecretion from vagal nuclei stimulation in intracranial injuries
• Gross: shallow erosions to deeper ulcers anywhere in stomach, usually multiple, rounded and less
than 1 cm in size. Ulcer base frequently stained brown to black by acid digestion of extravasated
blood
• Histology: erosion/ulcer sharply demarcated with adjacent normal mucosa. No scarring or blood
vessel thickening seen in peptic ulcers (which arise in the setting of chronic injury).

Non-stress related causes of gastric bleeding

• Dieulafoy lesion: submucosal artery that does not branch properly within the wall of the stomach,
resulting in a mucosal artery 10x the size of mucosal capillaries. Usually lesser curvature near the
GEJ. Erosion of the overlying mucosal epithelium can cause self-limited but copious gastric bleeding.
Bleeding often associated with NSAID use and can be recurrent
• Gastric antral vascular lesion (GAVE): Mostly idiopathic but can also be associated with cirrhosis
and systemic sclerosis. Endoscopy - longitudinal stripes of oedematous erythematous mucosa
created by ectatic mucosal vessels alternates with less severely injured, paler mucosa (‘watermelon
stomach’). Histology - antrum shows reactive gastropathy with dilated capillaries containing fibrin
thrombi

Other miscellaneous non-neoplastic conditions

Gastritis cystica: Exuberant reactive epithelial proliferation associated with entrapment of epithelial-
lined cysts within the submucosa (gastritis cystica polyposa) or deeper layers of the gastric wall (gastritis
cystica profunda). Mimics invasive adenocarcinoma

Hypertrophic gastropathies: Characterized by giant ‘cerebriform’ enlargement of the rugal folds due to
epithelial hyperplasia without inflammation, linked to excessive growth factor release

• Menetrier disease: rare disorder caused by excessive secretion of TGFa characterized by diffuse
foveolar hyperplasia of the gastric body and fundus, and hypoproteinaemia due to protein-losing
enteropathy. A/w weight loss, diarrhoea. Risk of gastric adenocarcinoma increased in adults.
Treatment is supportive
• Zollinger-Ellison syndrome: Caused by gastrin-secreting tumours (‘gastrinomas’) commonly found in
small intestine or pancreas. Can be sporadic (75%) or syndromic (MEN1). Gastrinomas cause parietal
cell hyperplasia and acid hypersecretion → often present with peptic ulcers. Histology: Marked
thickening of oxyntic mucosa due to marked increase in parietal cells, hyperplasia of mucous neck
cells, mucin hyperproduction and proliferation of endocrine cells within the oxyntic mucosa

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

(neuroendocrine cell hyperplasia → tumour). Treatment: blockade of acid hypersecretion usu. with
PPIs, and treatment of the gastrinoma.

Dysplasia

• Preinvasive in-situ lesion with architectural and cytologic atypia

• Often arises in background of chronic gastritis, which exposes the epithelium to inflammation-
related free radical damage and proliferative stimuli that lead to the accumulation of genetic
alterations over time that result in carcinoma

Polyps

Develop due to epithelial or stromal cell hyperplasia, inflammation, ectopia or neoplasia.

• Inflammatory and hyperplastic polyps: 75% of all gastric polyps. Reactive lesions, usually in a/w
chronic gastritis which initiates the injury that leads to reactive hyperplasia and polyp growth. Risk
of dysplasia correlates with polyp size
• Fundic gland polyps: sporadic or in patients with familial adenomatous polyposis (FAP). Increasing
incidence with use of PPI therapy, which inhibits acid production, thereby increasing gastrin
secretion which stimulates oxyntic gland growth. Sporadic polyps have no cancer risk, while FAP-
associated polyps may develop dysplasia and cancer
• Gastric adenoma: 10% of all gastric polyps. Frequency increases with age; prevalence varies and
parallels incidence of gastric adenocarcinoma. M:F = 3:1. Incidence also increased in FAP patients.
Similar to dysplasia, it occurs on a background of chronic gastritis with atrophy and intestinal
metaplasia. Significant risk of adenocarcinoma (up to 30% of adenomas; related to size of lesion) →
requires more aggressive therapy than colonic adenomas

Gastric adenocarcinoma

- More than 90% of all gastric cancers. Malignant epithelial neoplasm with glandular differentiation -
Two main (Lauren) histologic subtypes: Intestinal-type and diffuse-type
o Intestinal-type: Predominates in high-risk areas (e.g. Japan, East Europe). Precursor lesions
include flat dysplasia and adenoma. M:F = 2:1
o Diffuse-type: Incidence is relatively uniform across countries, with no clearly identified
precursor lesions. M=F.
- Risk factors: Lower socioeconomic status, multifocal mucosal atrophy, intestinal metaplasia. PUD is
not a risk factor (although patients with partial gastrectomies for PUD have a slightly higher risk of
developing cancer in the residual gastric stump, possibly due to hypochlorhydria, bile reflux and
chronic gastritis)
- Pathogenesis: Majority are sporadic; familial gastric cancers tend to be diffuse-type.
o Diffuse-type: Loss of expression of cell adhesion protein E-cadherin is a key step. This may
occur via loss of function mutations in the tumour suppressor gene CDH1 which encodes E-
cadherin (germline loss is strongly associated in familial gastric cancer, but loss of function is
also seen in ~50% of sporadic diffuse-type tumours). Other mechanisms of decreased E-

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

cadherin expression in sporadic tumours include hypermethylation and silencing of the

CDH1 promoter. CDH1 mutations are also common in sporadic and familial breast lobular
carcinoma. Individuals with BRCA2 mutations are also at increased risk of developing diffuse
gastric cancer
o Intestinal-type: Strongly associated with mutations that result in increased signaling via the
Wnt pathway, including loss-of-function mutations in the adenomatous polyposis coli (APC)
tumour suppressor gene and gain-of-function mutations in the gene encoding b-catenin.
FAP patients (who carry germline APC mutations) thus have increased risk of intestinal-type
gastric cancer. Loss of function mutations or silencing of a number of other tumour
suppressor genes including those involved in TGF-b signaling, regulation of apoptosis (BAX)
and cell cycle control (CDKN2A)
o TP53 mutations are also found in the majority of sporadic gastric cancers of both diffuse
and intestinal types
o Chronic inflammation promotes gastric neoplasia: Genetic variants of proinflammatory and
immune response genes, including those that encode IL-1b, TNF, IL-10, IL-8 and Toll-like
receptor 4 (TLR4), are associated with elevated risk of gastric cancer when accompanied by
H.pylori infection. Environmental factors also affect risk
- Clinical features: Overall incidence falling due to decrease in intestinal-type gastric carcinoma,
paralleling the decrease in H.pylori prevalence and decreased consumption of dietary carcinogens
(found in preserved foods), although cancer of the gastric cardia is increasing (whose profile is
similar to distal oesophageal adenocarcinomas). Early symptoms are usually non-specific (e.g.
dyspepsia, nausea, dysphagia). Tumours are therefore often diagnosed at late stage with weight
loss, anorexia and haemorrhage. Treatment: Surgical resection (preferred); if not, chemotherapy,
radiotherapy and palliative care. Prognosis: depends on depth of tumour invasion (e.g. into adjacent
organs), extent of nodal and distant metastases. Favourite sites of metastases: supraclavicular LN
(Virchow node), periumbilical LN (Sister Mary Joseph nodule), ovary (Krukenberg tumour), pouch of
Douglas (Blumer shelf). Also suggested that diffuse histologic type may have worse prognosis than
intestinal type. 5 yr survival rate can exceed 90% in early gastric cancer (i.e. tumour with no deeper
than submucosal invasion irrespective of LN mets), but is overall low because of advanced stage at
presentation → screening is important
- Gross: mostly antrum (lesser curve > greater curve)
o Intestinal-type: usually bulky exophytic masses or ulcers/excavated
o Diffuse-type: usually flat/depressed, widely infiltrative, inducing
stromal desmoplasia that thickens and stiffens the gastric wall and
causes rugal flattening, imparting a leather bottle appearance (‘linitis
plastica’), rather than forming a discrete tumour mass
- Histology:
o Intestinal-type: glandular structures with apical and luminal mucin
o Diffuse / poorly cohesive-type: discohesive cells that infiltrate singly or in small clusters and
do not form glands; may have ‘signet-ring cell’ appearance (i.e. large intracytoplasmic mucin
vacuole that pushes the nucleus to the periphery

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Lymphoma

• Extranodal lymphomas arise commonly in the GI tract, especially the stomach. ~5% of all gastric
malignancies are primary lymphomas, most commonly extranodal marginal zone B-cell lymphoma
of mucosa-associated lymphoid tissue (MALT lymphoma). MALT lymphoma can transform into
more aggressive tumours that are histologically identical to diffuse large B-cell lymphoma (DLBCL),
often in association with additional genetic changes
• Pathogenesis: MALToma usually arises at sites of chronic inflammation - H.pylori infection is the
most common inducer of MALT lymphoma in the stomach, possibly via NF-KB dysregulation. NF-KB
is a transcription factor that promotes B-cell growth and survival. The 3 chromosomal translocations
associated with gastric MALT lymphoma t(11;18), t(1;14) and t(14;18) also result in constitutive
activation of NF-KB
• Clinical presentation: dyspepsia, epigastric pain +/- haematemesis, melena and constitutional
symptoms. Treatment: H.pylori eradication (results in durable remission with low rates of
recurrence in most patients). Radiation/chemotherapy may be required with failure of H.pylori
eradication e.g. tumours with translocations (due to constitutive activation of NF-KB), tumours
invading to the muscularis propria or beyond, lymph node involvement, or transformation to DLBCL
• Histology: dense lymphoid infiltrate in the lamina propria, which infiltrates gastric glands to form
lymphoepithelial lesions. Expresses B cell marker CD20, negative for CD5 and CD10.

Well-differentiated Neuroendocrine Tumours (NET)

• Previously known as carcinoid or ‘carcinoma-like’ tumours as they have a more indolent clinical
course than GI carcinomas; more than 40% of GI NET occur in the small intestine
• Risk factors / associations: Neuroendocrine cell hyperplasia, autoimmune chronic atrophic gastritis,
MEN1 and Zollinger-Ellison syndrome. PPI therapy may be associated with NE cell hyperplasia but
the risk of progression to a NET is extremely low
• Clinical presentation: Asymptomatic or symptomatic depending on the hormones produced e.g.
gastrin-secreting tumours may cause Zollinger-Ellison syndrome, while ileal tumours may cause
carcinoid syndrome (cutaneous flushing, sweating, bronchospasm, diarrhoea etc. due to released
substances including serotonin) especially in the presence of metastatic liver disease (whereby the
bioactive products are directly released into the systemic circulation without the ‘first-pass effect’)
or with a large enough tumour burden. The clinical course of NET is quite variable; even low grade
NET can metastasize. Most important prognostic factor is location (midgut most aggressive and
often multiple > hindgut/foregut).
• Gross: Intramural or submucosal masses that create small polypoid yellow-tan lesions. Often firm
(due to desmoplastic reaction) → can cause kinking and small bowel obstruction
• Histology: Islands, trabeculae, strands, glands or sheets of uniform cells with round to oval nucleus,
‘salt and pepper’ chromatin and scant pink cytoplasm. Positive with immunohistochemical stains for
neuroendocrine granule markers e.g. Synaptophysin and Chromogranin A

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Gastrointestinal stromal tumour (GIST)

• Most common mesenchymal tumour of the abdomen arising from interstitial cells of Cajal of the
muscularis propria; more than 50% occur in the stomach
• Pathogenesis: ~75-80% have oncogenic gain-of-function mutations in the tyrosine kinase receptor
(TKR) KIT, while ~8% have activating mutations in a closely related TKR, platelet-derived growth
factor receptor α (PDGFRA). KIT and PDGFRA gene mutations are mutually exclusive since they act
within the same signal transduction pathway to promote tumour cell proliferation and survival. Both
sporadic and germline mutations result in constitutively active KIT or PDGFRA TKR. Mutation of KIT
or PDGFRA is an early event in sporadic GISTs and alone are insufficient for tumorigenesis.
GISTs without KIT or PDGFRA mutations have mutations in other genes that function in these
pathways (NF1, BRAF, HRAS, NRAS). Patients may also have germline loss of function mutations in
genes encoding components of the mitochondrial succinate dehydrogenase complex (SDHA/B/C/D),
which confer an increased risk for GIST and paraganglioma (Carney-Stratakis syndrome)
• Clinical features: Usually in adults ~60 yo, uncommonly in children (some of which are related to
Carney triad, a nonhereditary syndrome seen primarily in young females that includes gastric GIST,
paraganglioma and pulmonary chondroma, or Neurofibromatosis (NF) type 1). Patients can be
asymptomatic or symptomatic related to mass effect or mucosal ulceration causing blood
loss/anemia. Treatment: if resectable → complete surgical resection. If not resectable, those with
KIT or PDGRFA mutations often respond to tyrosine kinase inhibitor imatinib. Development of
imatinib-resistance can occur due to secondary KIT or PDGFRA mutations. Prognosis: correlates with
tumour size, mitotic index and location. Metastasis usually to liver or as multiple peritoneal nodules
• Gross: usually solitary, well-circumscribed fleshy mass covered by ulcerated or intact mucosa; may
also bulge out towards serosa. Cut surface has a whorled appearance
• Histology: Spindle cell or epithelioid type or mixed. Immunohistochemical expression of KIT/CD117
(detectable even for those without the mutation) or DOG1

IV. SMALL INTESTINE AND COLON

• Main functions: Nutrient and water transport → dysfunction causes malabsorption and diarrhoea
• Immune system interfaces with a diverse array of antigens present in food and gut microbes →
infectious and inflammatory disorders
• Colon is also a frequent site of gastrointestinal tumours

Intestinal obstruction

• Can occur at any level, but frequently small intestine because of its relatively narrow lumen
• Causes: Hernias (most frequent cause worldwide), intestinal adhesions, intussusception, volvulus,
and more rarely, tumours, infarction and other causes of strictures e.g. Crohn disease
• Clinical presentation: abdominal pain and distension, vomiting and constipation. May be
complicated by bowel perforation → surgical emergency

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Hernia sac: protrusion of a serosa-lined pouch of peritoneum through any weakness or defect in the
abdominal wall e.g. inguinal/femoral canal, umbilicus or surgical scar site (‘external herniation’). The
pouch may contain viscera that may become entrapped, causing obstruction. Pressure at neck of the
pouch may further impair venous drainage of the entrapped viscus, resulting in stasis and oedema,
increasing the bulk of the herniated loop, leading to permanent entrapment (incarceration), arterial and
venous compromise (strangulation) and infarction

Adhesions: fibrous bridges that can develop between bowel segments, abdominal wall or other sites.
Usually acquired (e.g. due to previous surgery, infection or other causes of peritoneal inflammation e.g.
endometriosis) but can rarely be congenital. Adhesions can cause bowel kinking or form closed loops
through which other viscera may slide and become entrapped (‘internal herniation’)

Volvulus: twisting of a loop of bowel about its mesenteric point of attachment, resulting in both luminal
and vascular compromise (i.e. obstruction and infarction). Most often occurs in large redundant loops of
the sigmoid colon, followed by caecum, small bowel, stomach or transverse colon

Intussusception: when a segment of intestine, constricted by a wave of peristalsis, telescopes into the
immediately distal segment. Once trapped, the invaginated segment is further propelled by peristalsis
and pulls the mesentery along. May progress to intestinal obstruction as well as compression of
mesenteric vessels (infarction). Most common cause of IO in children <2yo, where it is usually
idiopathic with no underlying anatomical cause and can be resolved by enemas. In older children and
adults, it may be due to reactive hyperplasia of Peyer’s patches which acts as the leading edge of the
intussusception, or an intraluminal mass or tumour requiring surgery

Ischaemic bowel disease

• Majority of GI tract supplied by celiac, superior mesenteric and inferior mesenteric arteries (SMA
and IMA), with collateral supplies from the proximal celiac and distal pudendal and iliac circulations.
Disease extent depends on (1) severity of vascular compromise, (2) the time frame during which it
develops (acute compromise vs chronic progressive hypoperfusion) and (3) vessels affected
• Particularly vulnerable regions of the GIT:
o Intestinal segments at the end of their respective arterial supplies (‘watershed zones’) i.e.
splenic flexure (where the SMA and IMA circulations terminate), and rectosigmoid colon
(where the IMA, pudendal and iliac arterial circulations end). Even generalized hypotension
/ hypoxemia can cause localized injury at these areas (‘focal colitis’)
o Surface epithelium (relative to the crypts) as intestinal capillaries run alongside the glands
from crypt to surface before making a hairpin turn to empty into the post-capillary venules.
This vascular supply protects the epithelial stem cells located within the crypts
• Risk factors: (systemic) coexisting cardiac or vascular disease, therapeutic vasoconstrictors, some
illicit drugs e.g. cocaine, (localized) CMV infection causing endothelial damage and small vessel
occlusion, strangulated hernia. Specific causes include:
o Acute arterial obstruction: severe atherosclerosis, aortic aneurysm, hypercoagulable states,
oral contraceptive use, embolization of cardiac vegetations or aortic atheromas

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

o Intestinal hypoperfusion: cardiac failure, shock, dehydration, vasoconstrictive drugs,

systemic vasculitides e.g. polyarteritis nodosa
o Mesenteric venous thrombosis: inherited or acquired hypercoagulable states, invasive
neoplasms, cirrhosis, trauma or abdominal masses that compress the portal drainage
• Pathogenesis: 2 phases - (1) initial hypoxic injury at the onset of vascular compromise (2)
reperfusion injury, initiated by restoration of the blood supply. Greatest damage occurs during
reperfusion, and if severe may even trigger multiorgan failure. Underlying mechanisms of
reperfusion injury may include leakage of gut lumen bacterial products e.g. lipopolysaccharide into
the systemic circulation, free radical production, neutrophil infiltration and release of additional
inflammatory mediators
• Clinical features: Elderly patients, slightly more women. Acute ischaemia typically presents with
sudden onset of cramping, left lower abdominal pain, a desire to defecate, and bloody diarrhoea.
Surgical emergency if there is paralytic ileus or other features of infarction e.g. guarding and
rebound tenderness → can be complicated by gram-negative bacteraemia (endotoxic shock) or
perforation. Chronic ischaemia may mimic inflammatory bowel disease, with episodes of bloody
diarrhoea interspersed with periods of healing
• Gross: lesions are most often segmental and patchy. Major vessel occlusions tends to cause
transmural infarction, while hypoperfusion / partial occlusion cause mucosal / mural infarction only.
Mucosa haemorrhagic and may be ulcerated, while the bowel wall is thickened by oedema
o Acute arterial obstruction: transmural infarction with sharp demarcation between normal
and ischaemic bowel, which appears intensely congested, dusky to purple-red initially. Later,
blood-tinged mucus or frank blood accumulates in the lumen, and the wall becomes
edematous, thickened and rubbery. Within 1-4 days, coagulative necrosis of the muscularis
propria occurs and perforation may occur. Also serositis, with fibrinopurulent exudates
o Mesenteric venous thrombosis: less abrupt transition from affected to normal bowel as
arterial blood continues to flow for a time. However, impaired venous drainage eventually
prevents oxygenated arterial blood from entering the capillaries, resulting in arterial
compromise and similar appearance
• Histology: atrophy or sloughing of surface epithelium, with normal or hyperproliferative crypts.
Bacterial superinfection and enterotoxin release may also induce pseudomembrane formation
(resembling Clostridium difficile-associated pseudomembranous colitis).
Acute ischaemia: Inflammation initially absent, but neutrophils are recruited within hours of
reperfusion. Chronic ischaemia: Accompanied by fibrous scarring / hyalinization of the lamina
propria, and (rarely) stricture formation

Radiation enterocolitis: radiation-induced vascular injury may produce changes that are similar to
ischaemic disease, although it usually also causes epithelial damage

Necrotizing enterocolitis (NEC): acute disorder of small and large intestines that can result in transmural
necrosis, possibly partly due to ischaemic injury. Most common acquired GI emergency of neonates

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Angiodysplasia

• Lesion characterized by malformed submucosal and mucosal blood vessels, most often in the
caecum or right colon, and usually presents after 50yo. Low incidence but accounts for 20% of
major episodes of lower intestinal bleeding; may be chronic and intermittent or acute and massive
• Pathogenesis: attributed to mechanical and congenital factors. Normal distension and contraction
may intermittently occlude the submucosal veins that penetrate through the muscularis propria and
lead to focal dilatation and tortuosity of overlying submucosal and mucosal vessels.
• Histology: ectatic nests of tortuous veins, venules and capillaries, which may be separated from the
intestinal lumen by only the vascular wall and a layer of attenuated epithelial cells → can be easily
traumatized resulting in significant bleeding

Malabsorption and diarrhoea

Malabsorption: defective absorption of fat, fat- and water-soluble vitamins, proteins, carbohydrates,
electrolytes, minerals, and water, presenting most commonly as chronic diarrhoea

• Causes: pancreatic insufficiency, celiac disease, Crohn disease, intestinal graft-vs-host disease
• Pathogenesis: malabsorption results from disturbance in at least one of the 4 phases of nutrient
absorption: (1) intraluminal digestion: proteins, carbohydrates and fats are broken down into forms
suitable for absorption (2) terminal digestion: hydrolysis of carbohydrates and peptides by
disaccharidases and peptidases in the brush border of the small intestinal mucosa (3) transepithelial
transport: nutrients, fluid and electrolytes are transported across and processed within the small
intestinal epithelium (4) lymphatic transport of absorbed lipids. A defect in more than 1 process
usually contributes although one process may predominate.
• Clinical symptoms: Steatorrhoea (hallmark - excessive fecal fat and bulky frothy greasy yellow or
clay-coloured stools), weight loss, flatus, anorexia, abdominal distension/pain, muscle wasting,
symptoms of vitamin deficiency e.g. anaemia (B12 deficiency), bleeding (vitamin K deficiency) etc.

Diarrhoea: increase in stool mass, frequency or fluidity, typically greater than 200g per day. Dysentery:
painful, bloody, small-volume diarrhoea

• Secretory: isotonic stool; persists during fasting

• Osmotic: due to excessive osmotic forces exerted by unabsorbed luminal solutes e.g. with lactase
deficiency. Diarrhoea fluid is more concentrated than plasma (hypertonic); abates with fasting
• Malabsorptive: generalized failure of nutrient absorption, a/w steatorrhoea; relieved by fasting
• Exudative: due to inflammatory disease, characterized by purulent bloody stools; continues during
fasting

Cystic fibrosis

• Defect in chloride (+/- bicarbonate ion) secretion due to the absence of the epithelial cystic fibrosis
transmembrane conductance regulator (CFTR), resulting in defective luminal hydration and
thickened secretions. Pancreatic intraductal concretions can form, causing duct obstruction, low

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grade chronic autodigestion of the pancreas and eventual exocrine pancreatic insufficiency →
malabsorptive diarrhoea. Treatment = oral enzyme supplementation

Celiac disease (aka celiac sprue, gluten-sensitive enteropathy)

• Immune-mediated enteropathy triggered by ingestion of gluten-containing foods e.g. wheat, rye,

barley, in genetically predisposed individuals
• Pathogenesis: triggered by ingestion of gluten (the major storage protein of wheat etc.), of which
the alcohol-soluble fraction gliadin contains most of the disease-producing components. Some
gliadin peptides may induce intestinal epithelial cells to express IL-15, triggering activation and
proliferation of CD8+ intraepithelial lymphocytes which damage the epithelial cells. This may
enhance passage of other gliadin peptides into the lamina propria, interact with HLA-DQ2 or HLA-
DQ8 on antigen-presenting cells and stimulate CD4+ T cells to produce cytokines that contribute to
tissue damage. Malabsorption probably results from this loss of mucosal and brush-border surface
area. Increased rates of epithelial turnover, reflected in increased crypt mitotic activity, may also
limit the ability of absorptive enterocytes to fully differentiate and express proteins necessary for
terminal digestion and transepithelial transport. Host factors determines whether disease
develops, in particular the HLA locus (almost all patients carry the class II HLA-DQ2 or HLA-DQ8
allele). Other genetic factors may include polymorphisms of genes involved in immune regulation
and epithelial function, which may also contribute to associations between celiac disease and other
immune diseases e.g. T1DM, thyroiditis, Sjogrens syndrome
• Clinical features: Bimodal distribution
o Adults (30-60 yo), F>M: present with chronic diarrhoea, bloating, chronic fatigue, anaemia
(due to iron and vitamin malabsorption). May have atypical or asymptomatic presentation
(‘silent’ celiac disease = positive serology and villous atrophy without symptoms, or ‘latent’
celiac disease = positive serology without villous atrophy)
o Children, M=F: classically symptoms occur after introduction of gluten to diet between 6-24
months of age, manifesting as irritability, abdominal distension, anorexia, chronic diarrhoea,
failure to thrive, weight loss or muscle wasting. Extraintestinal complaints include arthritis
or joint pain, aphthous stomatitis, iron deficiency anemia, delayed puberty and short
stature. 10% of patients may have dermatitis herpetiformis, an itchy blistering skin lesion
Diagnostic noninvasive serologic tests (generally performed prior to biopsy): IgA antibodies against
tissue transglutaminase (most sensitive), anti-endomysial antibodies. Presence of HLA-DQ2 and DQ8
does not confirm diagnosis, but useful if absent for its negative predictive value
Diagnostic biopsies: usually taken from the 2nd duodenal segment or proximal jejunum, which are
exposed to the highest concentrations of dietary gluten
Complications: Risk of malignancy - enteropathy-associated T cell lymphoma (an aggressive
lymphoma of intraepithelial T cells), small intestinal adenocarcinoma. Thus, when symptoms of
abdominal pain, diarrhoea and weight loss develop despite a strict gluten-free diet, cancer or
refractory sprue (in which response to a gluten-free diet is lost) must be considered.

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Treatment: gluten-free diet → resolution of symptoms, decreasing titers of anti-tissue

transglutaminase antibodies and restoration of mucosal histology within 6-24 months. May also
reduce the risk of long-term complications e.g. anaemia and cancer
• Histology: Intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy (but not specific: can
be seen in other diseases e.g. viral enteritis – correlation with serology is important)

Environmental enteropathy (aka tropical enteropathy / tropical sprue): disorder prevalent in areas and
populations with poor sanitation and hygiene, and may contribute to a large number of childhood
deaths. Presently no accepted clinical, lab or histopathologic criteria that allows diagnosis. Reported
histologic features are more similar to severe celiac disease than infectious enteritis

Autoimmune enteropathy: X-linked disorder characterized by severe persistent diarrhoea and

autoimmune disease that occurs most often in young children, caused by FOXP3 gene mutation,
resulting in defective function of regulatory T cells

Lactase (disaccharidase) deficiency: Osmotic diarrhoea due to inability to break down or absorb lactase.
Can be congenital (rare autosomal recessive disorder caused by mutation in gene encoding lactase) or
acquired (common in adults, caused by down-regulation of lactase gene expression, which can develop
following enteric viral or bacterial infections and may resolve over time). Defect is biochemical so
histology is generally unremarkable

Infectious enterocolitis

Aetiology varies with age, nutrition, and host immune status as well as environmental influences.
Paediatic infectious diarrhoea is often caused by enteric viruses, while cholera is common in areas with
poor sanitation. Enterocolitis can present with a broad range of symptoms including diarrhoea,
abdominal pain, urgency, perianal discomfort, incontinence and dysentery

Bacterial
Cholera: Vibrio cholerae (comma-shaped gram-negative bacteria, non-invasive)
- Endemic in India and Bangladesh, with several epidemics in other countries. Primarily water-borne
infection (can also be present in food)
- Cholera toxin released by the organism causes accumulation of chloride, bicarbonate and sodium
within the intestinal lumen, creating an osmotic driving force (secretory diarrhoea)
- Most individuals asymptomatic / mild diarrhoea. Severe disease: abrupt onset of watery diarrhoea
and vomiting following an incubation period of 1-5 days (voluminous ‘rice-water’ stools)
- Complications: dehydration, hypotension, shock and death (usually within first 24 hours).
Treatment: timely fluid replacement (oral rehydration often sufficient)
Campylobacter enterocolitis: Campylobacter jejuni (comma-shaped flagellated gram negative)
- Most common bacterial enteric pathogen in developed countries, cause of traveler’s diarrhoea.
Usually a/w contaminated chicken, also unpasteurized milk or contaminated water
• Bacteria produces toxin and a minority also invade (latter associated with dysentery)
• Most patients have watery diarrhoea, either acute or following an influenza-like prodrome after an
incubation period of up to 8 days. Dysentery in 15% of adults and more than 50% in children
• Complications: Reactive arthritis (primarily in patients with HLA-B27), erythema nodosum, Guillain-
Barre syndrome. Treatment: Supportive (antibiotics generally not required)
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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Shigellosis: Shigella sp. (gram negative facultative anaerobe, belongs to Enterobacteriaceae family)
• One of the most common causes of bloody diarrhoea. Extremely low infective dose → highly
transmissible via fecal-oral route (contaminated water/ food). Usually in children <5 yo.
• Self-limited disease ~1 week of diarrhoea, fever and abdominal pain. Minority have subacute
presentation (several weeks of waxing and waning diarrhoea); mimics new-onset ulcerative colitis
Typhoid fever: Salmonella typhi/paratyphi and Salmonellosis: Salmonella enteritidis etc. (gram negative
bacilli of Enterobacteriaceae family)
• Typhoid fever: person-person transmission or via contaminated food/water. Febrile phase with
bacteraemia. Antibiotics can prevent disease progression.
• Salmonellosis: Ingestion of contaminated food esp. raw/undercooked meat, poultry, eggs and milk.
Vaccines available for both humans and farm animals. Most infections are self-limited.
Escherichia coli: gram-negative bacilli, mostly nonpathogenic but a subset cause human disease
• Enterotoxigenic E.coli (ETEC): major cause of traveler’s diarrhoea; via contaminated food or water
• Enteropathogenic E.coli (EPEC): endemic diarrhoea and diarrhoea outbreaks in children <2yo
• Enterohaemorrhagic E.coli (EHEC): O157:H7 and non-O157-H7 serotypes; produce Shiga-like toxin
• Enteroinvasive E.coli (EIEC): similar to Shigella; invades epithelial cells but do not produce toxin
• Enteroaggregative E.coli (EAEC): may cause traveler’s diarrhoea
Yersinia: Yersinia enterocolitia>> Yersinia pseudotuberculosis
• Ingestion of pork, raw milk and contaminated water. Preferentially involves ileum, appendix and
right colon with Peyer patchy and regional lymph node hyperplasia, mimicking acute appendicitis.
Pseudomembranous colitis: morphologic diagnosis (can also be seen in ischaemia or necrotizing
infections) but usually caused by Clostridium difficile (anaerobe)
• Risk factors are advanced age, hospitalization and antibiotic treatment (almost any antibiotic may
be responsible). Antibiotics disrupt normal colonic microbiota, allowing C.difficile overgrowth, which
releases toxins that lead to epithelial damage. Diagnosis of C.difficile-associated colitis is via
detection of the toxin rather than culture. Treatment: Metronidazole or vancomycin.
• Pseudomembranes are an adherent layer of inflammatory cells and debris at sites of colonic
mucosal injury, that are seen endoscopically as a tan-grey-white coating. Histologically, there is
surface epithelial denudation of the colonic mucosa with distension of the superficial portions of the
crypts by a mucopurulent exudate (‘volcanic eruption’) that coaelesce to form pseudomembranes
Mycobacterial: Mycobacterium tuberculosis, Mycobacterium bovis
• Intestinal tuberculosis: (primary involvement) drinking of contaminated milk in countries where
bovine tuberculosis is present and milk is not pasteurized; or (secondary involvement) caused by
swallowing of coughed-up infective material in patients with advanced pulmonary disease
• Organisms are seeded to mucosal lymphoid aggregates of small and large bowel, which undergo
granulomatous inflammation that can lead to ulceration of the overlying mucosa, esp. ileocaecal
region. Healing can cause strictures. Mimics Crohn’s disease
Viral
Norovirus: ~50% of all gasteroenteritis outbreaks worldwide, usually related to contaminated food or
water. Sporadic cases usually due to person-person transmission. Self-limiting disease
Rotavirus: common cause of severe childhood diarrhoea and diarrhoeal mortality (esp. 6-24 mths age)
Adenovirus: common cause of paediatric diarrhoea and in immunocompromised patients
HSV, CMV: systemic infections that can also infect the GIT
Parasitic
Nematodes (roundworms Ascaris and Strongyloides, hookworms and pinworms), cestodes (flatworms
and tapeworms), trematodes (flukes)
Protozoa: Entamoeba histolytica (amebiasis)
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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

• Fecal-oral transmission. Mostly affects the caecum and ascending colon. Causes dysentery
• Amoeba attach to the colonic epithelium, induce apoptosis, invade crypts and burrow laterally
creating a ‘flask-shaped’ ulcer. Parasites can also penetrate splanchnic vessels and embolize to the
liver to produce abscesses in ~40% of patients
Protozoa: Giardia lamblia (giardiasis)
• Most common parasitic pathogen in humans; spread by fecally contaminated water or food.
Presentation can be subclinical or acute/chronic diarrhoea, malabsorption and weight loss
• Identified in duodenal biopsies as pear-shaped organisms tightly bound to the brush border of
villous enterocytes. No invasion.
Protozoa: Cryptosporidium parvum (cryptosporidiosis)
• First discovered as a cause of chronic diarrhoea in AIDS patients; also a cause of acute self-limited
diarrhoea or persistent diarrhoea in immunocompetent hosts. Usu. via contaminated drinking water
• Usually identified in terminal ileum and proximal colon. Intracellular, epithelial apical membrane
Fungal
Candida, Aspergillus, Mucormycosis, Histoplasma: systemic infections that can affect the GIT

Irritable bowel syndrome (IBS)

Chronic relapsing abdominal pain, bloating and changes in bowel habits, but normal gross and
microscopic evaluation – diagnosis depends on clinical symptoms and functional testing. Pathogenesis is
poorly defined, with interplay between psychological stressors, diet, perturbation of the gut
microbiome, increased enteric sensory responses to gastrointestinal stimuli and abnormal GI motility.
Not associated with serious long-term sequelae; prognosis is most closely related to symptom duration,
with longer duration correlating with reduced likelihood of improvement

Inflammatory bowel disease (IBD)

• Chronic inflammation of the GI tract resulting from inappropriate mucosal immune activation,
usually referring to either Ulcerative Colitis (UC) or Crohn Disease (CD)
• Pathogenesis: Likely due to combined effects of alterations in host interactions with intestinal
microbiota, intestinal epithelial dysfunction, aberrant mucosal immune responses and altered
composition of the gut microbiome
o Genetics: risk of disease is increased when there is an affected family member. Over 160
IBD-associated genes have been identified, with each gene conferring only a small increase
in risk e.g. NOD2 (for CD) which is involved in recognition and response to intracellular
pathogens (supporting the hypothesis that inappropriate immune reactions to luminal
bacteria are an important component of IBD pathogenesis)
o Mucosal immune responses: T helper cells are activated in Crohn disease (response
polarized to the TH1 type; TH17 cells most likely contribute to disease pathogenesis). Many
other pro-inflammatory cytokines including TNF and immunoregulatory molecules e.g. IL-10
also appear to play a role. Immunosuppressive agents remain the mainstay of treatment

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

o Epithelial defects: defects in intestinal epithelial tight junction barrier function in CD (a/w
specific disease-associated NOD2 polymorphisms); inhibition of matrix metalloproteinase 9
in UC (a/w polymorphisms involving ECM1)
o Microbiota: as mentioned earlier, linkage to NOD2 points to the involvement of microbes in
the causation of CD. The presence of antibodies against bacterial progetin flagellin are also
seen in CD. Clinical trials suggest that probiotic bacteria or even fecal microbial transplants
from healthy individuals may benefit IBD patients
It has been theorized that IBD is a result of a self-amplifying cycle that gives rise to maladaptive and
injurious immune responses, by which transepithelial flux of luminal bacterial components activates
innate and adaptive immune responses. In a genetically susceptible host, the subsequent release of
TNF and other immune-mediated signals direct the epithelium to increase tight junction
permeability, causing further increase in the influx of luminal material, resulting in a vicious cycle.
The hygiene hypothesis suggests improved food storage conditions, decreased food contamination
and changes in gut microbiome composition results in inadequate development of regulatory
processes that limit mucosal immune responses. This in turn allows some mucosa-associated
microbial organisms to trigger persistent and chronic inflammation in susceptible hosts
• Clinical features: Teens and young adults. Caucasians but increasing incidence in other regions e.g.
Africa, South America and Asia. Distinction between CD and UC is based largely on the distribution
of affected sites and morphologic expression of disease at these sites. Extraintestinal
manifestations may also be present.

Crohn disease Ulcerative colitis

Recurrent granulomatous, fibrosing inflammatory Recurrent acute-on-chronic ulcero-inflammatory
disorder affecting terminal ileum (or colon) +/- other disease affecting mainly rectum and distal colon
systemic manifestations
Clinical features
Relapsing disorder: intermittent attacks of (bloody) diarrhoea with stringy mucoid material, lower
abdominal pain, cramps that are temporarily relieved by defecation +/- fever; can also present acutely.
Asymptomatic periods may last for weeks to months
Disease re-activation by triggers include physical or Triggers may include episode of infectious
emotional stress, specific dietary items and cigarette enteritis, psychological stress, after smoking
smoking (a strong exogenous risk factor for cessation
development of Crohn disease; initiation of smoking
may be associated with disease onset but smoking
cessation does not result in disease remission)
Extraintestinal manifestations: uveitis, ankylosing Similar; also primary sclerosing cholangitis (PSC)
spondylitis, migratory polyarthritis
Saccharomyces cerevisiae antibodies positive pANCA+ (75%)
Complications
Fistulae between bowel loops and with other organs Nil
e.g. bladder, vagina, skin (esp. perianal);
perforations and peritoneal abscesses
Fibrosing strictures (particularly of the terminal Nil
ileum; require surgical resection)

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Common recurrence after surgery No. Colectomy cures intestinal disease (although
extraintestinal manifestations may persist)
Fat/vitamin malabsorption, iron deficiency and Nil
hypoalbuminaemia (in extensive small bowel
disease)
Increased malignancy risk (in colonic disease) Yes
No toxic megacolon Toxic megacolon occurs due to damage of the
muscularis propria by inflammatory mediators,
and disturbance of neuromuscular function.
Significant risk of perforation
Gross and microscopy
Skip lesions (i.e. separate sharply delineated areas Diffuse continuous involvement. Rarely ‘caecal
of disease) patch’ in L-sided UC
Frequently ileum; any other area of the GI tract Disease limited to Rectum +/- part or all of
colon. Small intestine normal apart from mild
mucosal inflammation of the distal ileum
(‘backwash ileitis’) in severe pancolitis
Transmural inflammation and oedema – thickened Mucosa +/- submucosa – usually thin wall, mild
wall with marked fibrosis +/- strictures. In extensive or no fibrosis / serositis; strictures are rare
transmural disease, serositis and mesenteric fat
extending around the serosal surface (‘creeping fat’)
‘Cobblestone’ appearance of mucosa (due to patchy Slightly red granular friable mucosa; Frequent
sparing of mucosa interspersed with deep ulcers) mucosal pseudopolyps (isolated islands of
regenerating mucosa that bulge into lumen
amongst broad-based ulcers). Mucosal atrophy in
chronic disease with a flat and smooth mucosal
surface that lacks normal folds
Aphthous ulcer (earliest lesion) → coalesce into Superficial broad-based ulcers along the long
elongated serpentine ulcers oriented along the axis axis of the colon; no fistula/sinuses
of the bowel. Deep fissuring ulcers between
mucosal folds, with fistulae/sinuses/perforation
Microscopy: Active chronic colitis
Activity: cryptitis, crypt abscesses (clusters of neutrophils within crypts), erosions, ulceration
Chronicity: distortion of mucosal architecture due to repeated cycles of crypt destruction and
regeneration, epithelial metaplasia (pseudopyloric metaplasia and (in the left colon) Paneth cell
metaplasia), crypt atrophy/shortening
Non-caseating granulomas (~35% of cases) is the Nil
hallmark – may occur in areas of active disease, or
uninvolved regions in any layer of the intestinal wall
or mesenteric lymph nodes

Indeterminate colitis: ~10% of IBD patients without definitive features of either UC or CD. Serologic
studies for p-ANCA (UC) and antibodies to Saccharomyces cerevisiae (CD) may help differentiate, but
despite diagnostic uncertainty, patients with indeterminate colitis often still can be treated effectively
due to extensive overlap in medical management of UC and CD

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Colitis-associated neoplasia

• One of the most feared long-term complications of UC and colonic CD

• Risk of dysplasia is related to: (i) duration of disease (risk increases sharply 8-10 years after disease
onset); (ii) extent of disease (patients with pancolitis are at greater risk than those with only L-sided
disease); (iii) nature of the inflammatory response (greater frequency and severity of active
inflammation confers increased risk)
• To facilitate early detection of neoplasia, patients usually undergo frequent endoscopic surveillance
approximately 8 years after diagnosis of IBD (earlier for patients with both IBD and PSC who have
even greater risk of developing cancer). The goal of surveillance biopsies is to identify dysplastic
epithelium, which is a precursor to colitis-associated carcinoma. Dysplasia can occur in flat areas of
mucosa that are not grossly recognized as abnormal. Dysplasia can be low grade or high grade, and
may be multifocal. Sporadic colonic adenomas can also occur in IBD patients and may be difficult to
distinguish from polypoid foci of IBD-associated dysplasia. Treatment depends on the distinction as
IBD-associated dysplasia may prompt colectomy due to association with invasive carcinoma while
sporadic adenomas can be excised via polypectomy.

Diversion colitis

• Inflammation developing in a segment of colon diverted away from the normal faecal flow e.g. in
surgical treatment of intestinal disorders (like UC) which may require creation of a temporary or
permanent ostomy and a blind distal segment of colon
• Pathogenesis: Not well understood; possibly due to changes in the luminal microbiota and diversion
of the fecal stream that provides nutrients to colonic epithelial cells. Treatment: enemas containing
short-chain fatty acids, a product of bacterial digestion in the colon and an important energy source
for colonic epithelial cells, can promote mucosal recovery in some cases. Ultimate cure is re-
anastomosis of the diverted segment. Histology: Numerous mucosal lymphoid follicles. In severe
cases, may mimic IBD (crypt abscesses, mucosal architectural distortion or rarely granulomas)

Microscopic colitis

• Idiopathic disease, presenting with chronic non-bloody watery diarrhoea and with normal radiologic
and endoscopic findings. Encompasses 2 entities: collagenous colitis and lymphocytic colitis
• Collagenous colitis: middle-aged and older women; characterized by a dense subepithelial collagen
layer +/- increased numbers of intraepithelial lymphocytes
• Lymphocytic colitis: strong association with celiac disease and autoimmune disease; increased
intraepithelial lymphocytes (>20 T-cells per 100 colonocytes)

Graft vs host disease

• Occurs following haematopoietic stem cell transplantation, usually involving small bowel and colon.
Presents as watery diarrhoea but may become bloody in severe cases

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

• Occurs secondary to donor T cells targeting antigens on the recipient’s GI epithelial cells. Histology
shows epithelial apoptosis (particularly of the crypt cells) with sparse inflammation in the lamina
propria. Rarely, total gland destruction occurs

Diverticular disease

• Acquired pseudodiverticular outpouchings of colonic mucosa and submucosa (unlike true diverticula
e.g. Meckel diverticulum, which includes all 3 layers of the colonic wall). Usually multiple
(diverticulosis)
• Pathogenesis: results from the elevated intraluminal pressure usually in the sigmoid colon
(probably due to exaggerated peristaltic contractions with spasmodic sequestrations of bowel
segments, which may be enhanced by diets low in fiber which reduce stool bulk, particularly in the
sigmoid colon). This causes outpouchings in the focal discontinuities in the colonic muscle wall
where nerves, arterial vasa recta and their connective tissue sheaths penetrate the inner circular
muscular coat. The external longitudinal layer of the MP is unable to reinforce these gaps as they
are gathered into the 3 bands (taenia coli) in the colon
• Clinical features: Prevalence increases with age (common in those over 60yo); less common in Japan
and developing countries ? dietary differences. R-sided disease more common in Asia but
uncommon in Western countries. Most individuals are asymptomatic, but ~20% present with
intermittent cramping, continuous lower abdominal discomfort, constipation, distension, sensation
of incomplete defecation or occasionally chronic / intermittent per rectal bleeding (with erosion into
blood vessels). Complications: Obstruction of diverticula leads to inflammation, resulting in
diverticulitis and peri-diverticulitis, which can lead to perforation, pericolonic abscesses, sinus
tracts, fistulae and occasionally peritonitis. Diverticulitis may also cause segmental diverticular
disease-associated colitis (SCAD), fibrotic thickening in and around the colonic wall or stricture
formation. Treatment: Increased dietary fiber may help symptoms. Even when diverticulitis occurs,
it most often resolves spontaneously; relatively few patients require surgical intervention
• Gross: small flask-like outpouchings ~0.5-1 cm in diameter that occur alongside the taenia coli
• Histology: thin wall composed of flattened / atrophic mucosa, compressed submucosa and
attenuated or totally absent muscularis propria. Hypertrophy of the circular layer of the muscularis
propria in the affected bowel segment is common

Polyps
• Gross morphology: sessile (broad-based) vs pedunculated (narrow base +/- stalk)
• Non-neoplastic (inflammatory, hamartomatous or hyperplastic) vs neoplastic (usually adenoma)

Non-neoplastic polyps

• Hyperplastic: benign epithelial proliferations, usually in left colon, often multiple. Serrated surface
architecture (serrations restricted to upper third of the crypt)
• Inflammatory: can form as part of the solitary rectal ulcer syndrome due to impaired relaxation of
the anorectal sphincter, leading to recurrent abrasion and ulceration of the overlying rectal mucosa;
an inflammatory polyp develops as a result of the chronic cycles of injury and healing. Entrapment of
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the polyp in the fecal stream subsequently leads to mucosal prolapse. Histology = mixed
inflammatory infiltrates, surface erosion, and epithelial hyperplasia +/- lamina propria fibromuscular
hyperplasia (in mucosal prolapse)
• Hamartomatous: occur sporadically or as part of various genetically determined or acquired
syndromes (some of which are associated with increased cancer risk either within the polyps or at
other intestinal or extra-intestinal sites)
o Juvenile polyps: morphology of sporadic vs syndromic forms are indistinguishable. Usually
in children <5 yo, in the rectum and typically present with PR bleeding. Sporadic juvenile
polyps are usually solitary (aka ‘retention polyps’) and rarely associated with dysplasia, while
individuals with the AD syndrome of juvenile polyposis have multiple in the colon, may have
dysplasia both within the juvenile polyp and in separate adenomas, and may also have
polyps in the stomach and small bowel that can undergo malignant transformation.
Histology: dilated cystic glands filled with mucin and inflammatory debris within an inflamed
oedematous lamina propria. Most common mutation is SMAD4 and BMPR1A in the TGF-B
signaling pathway.
o Peutz-Jeghers syndrome: AD syndrome due to germline loss-of-function mutations in the
tumour suppressor gene STK11, presents at a median age of 10-15 yo with multiple GI
hamartomatous polyps and mucocutaneous hyperpigmentation (including buccal mucosa).
PJ polyps can be complicated by intussusception. PJS is associated with a markedly
increased risk of several malignancies e.g. colon (can develop at sites without PJ polyps),
breast, lung, pancreas and thyroid – regular surveillance is thus recommended. Most PJ
polyps are in the small intestine, large and pedunculated. Histology: characteristic
arborizing network of connective tissue, smooth muscle, lamina propria and glands lined by
normal-appearing intestinal epithelium

Neoplastic: any neoplastic mass lesion in the GI tract may produce a mucosal protrusion or polyp,
including adenocarcinoma, neuroendocrine tumours, stromal tumours, lymphomas and even metastatic
cancers from distant sites. Most common neoplastic polyps are colonic adenomas, which are precursors
to the majority of colorectal adenocarcinomas

• Adenomas are intraepithelial neoplasms, ranging from small often pedunculated polyps to large
sessile lesions, characterized by the presence of epithelial dysplasia. Dysplasia is characterized by
cytologic and architectural atypia, and can be low grade or high grade
• Although they are precursor lesions, the majority of adenomas do not progress to become
adenocarcinomas, and it may be that transformation is stochastic, being dependent on acquisition
of oncogenic mutations merely by chance. A small proportion of adenomas may harbour invasive
cancer at the time of detection; risk of malignancy is greater with size, presence of high grade
dysplasia, higher proportion of villous architecture and increased numbers of adenomas. Most
adenomas are clinically silent, with the exception of large polyps that produce occult bleeding and
anaemia and rare villous adenomas that cause hypoproteinemic hypokalemia by secreting large
amounts of protein and potassium. Therefore, regular surveillance colonoscopy and polyp removal
is needed to reduce the incidence of colorectal adenocarcinoma

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

• Histology: Conventional adenomas are classified as tubular, tubulovillous or villous based on their
architecture. Other forms include serrated adenomas e.g. traditional serrated adenomas, sessile
serrated lesion/polyp

Colorectal cancer syndromes

Adenomatous polyposis syndromes like FAP and non-polyposis syndromes like HNPCC typify distinct
pathways of neoplastic transformation and progression that also contribute to the majority of sporadic
colon cancers

Adenomatous polyposis

• Familial adenomatous polyposis (FAP): AD disorder in which patients develop numerous colorectal
adenomas as teenagers, caused by mutations of the adenomatous polyposis coli (APC) gene in
chr5q21, a key negative regulator of the Wnt signaling pathway. Classic FAP require at least 100
polyps. The polyps are morphologically indistinguishable from sporadic adenomas, although flat or
depressed adenomas as well as microscopic adenomas consisting of only 1 or 2 dysplastic crypts are
also frequently observed in otherwise normal-appearing mucosa. Colorectal adenocarcinoma
develops in 100% of untreated FAP patients, often below age 30 and nearly always by age 50.
Prophylactic colectomy is thus the standard treatment for individuals with APC mutations, although
there remains a risk for neoplasia at other sites e.g. stomach and ampulla of Vater. Variants:
Gardner syndrome and Turcot syndrome (associated with other extraintestinal manifestations)
• MYH-associated polyposis: AR disorder with bi-allelic mutations of the base-excision repair gene
MYH; colonic phenotype is similar to attenuated FAP, with polyp development at later ages, fewer
than 100 adenomas and delayed appearance of colon cancer (usually later than 50yo). Serrated
polyps with KRAS mutations are also frequently present

Hereditary non-polyposis colorectal cancer (HNPCC) / Lynch Syndrome (LS)

• Most common syndromic form of colon cancer (2-4% of all colorectal cancers)
• AD; caused by inherited mutations in genes that encode mismatch repair proteins (MMR)
(responsible for the detection, excision and repair of errors that occur during DNA replication).
Defects in mismatch repair lead to the accumulation of mutations at rates up to 1000 times higher
than normal, mostly in regions containing short repeating sequences referred as microsatellites
(microsatellite instability)
• HNPCC refers to the clinical phenotype of familial colon cancer; LS refers to individuals with (genetic)
germline MMR mutation. Patients with LS have increased risk of extra-colonic malignancies
• Colon cancers tend to occur at younger ages than sporadic colon cancers, often right sided. Extra-
colonic malignancies include endometrium, stomach, ovary, ureters, brain, hepatopancreatobiliary
tract, small bowel and skin
• Important to identify these patients because of the implications for genetic counselling, the elevated
risk of a second malignancy of the colon or other organs, and differences in prognosis and therapy

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

Colorectal adenocarcinoma (CRC)

• Nearly all colonic cancers are adenocarcinomas. It is the most common GI tract malignancy and a
major cause of morbidity and mortality worldwide (10% of all cancer deaths). In contrast, the small
intestine is an uncommon site for benign and malignant tumours despite accounting for 75% of the
overall length of the GI tract
• Risk factors: Diet – increased risk with low intake of unabsorbable vegetable fiber and high intake
of refined carbohydrates. It is believed that reduced fiber content leads to decreased stool bulk and
altered composition of the intestinal microbiota, which may increase synthesis of potentially toxic
oxidation by-products of bacterial metabolism, which would be expected to remain in contact with
the colonic mucosa for longer periods of time as a result of reduced stool bulk. High fat intake also
enhances hepatic synthesis of cholesterol and bile acids, which can be converted into carcinogens by
intestinal bacteria. Epidemiologically, the incidence of CRC is highest in North America, is common in
Australia, New Zealand, Europe and increasingly Japan with changes in lifestyle and diet.
• Pharmacologic chemoprevention: epidemiologic studies suggest that aspirin or other NSAIDS have a
protective effect, possibly mediated by inhibition of the enzyme cyclooxygenase-2 (COX-2), which is
highly expressed in 90% of colorectal carcinomas and 40-90% of colorectal adenomas. COX2 is
necessary for production of prostaglandin E2, which promotes epithelial proliferation, particularly
after injury
• Pathogenesis: heterogeneous combination of molecular events that includes genetic and epigenetic
abnormalities, resulting in the stepwise accumulation of multiple mutations. At least 2 genetic
pathways:
(1) APC/b-catenin pathway (80% of sporadic colon tumours): activated in the classic adenoma-
carcinoma sequence; chromosomal instability is the hallmark (Vogelstein’s hypothesis)
o Typically includes APC gene mutation (chr 5q21) early in the neoplastic process. Both copies
of APC must be functionally inactivated, either by mutation or epigenetic events, for
adenomas to develop. APC is a key negative regulator of b-catenin, a component of the Wnt
signaling pathway. The APC protein normally binds to and promotes degradation of b-
catenin. With loss of APC function, b-catenin accumulates and translocates to the nucleus,
where it forms a complex with the DNA-binding factor TCF and activates the transcription of
genes, including MYC and cyclin D1, that promote proliferation. Colon cancers without APC
mutations harbour b-catenin mutations that allow them to avoid APC-dependent
degradation, thereby having the same impact as loss of APC function
o Additional mutations accumulate, including activating KRAS mutations that promote
growth and prevent apoptosis (often a late event in carcinoma development), mutations in
other tumour suppressor genes e.g. SMAD2 and SMAD4 (effectors of TGF-b signalling),
TP53 (mutated in 70-80% of colon cancers, probably a late event in carcinoma
development). Loss of functions of these genes are often caused by chromosomal deletions,
but may also be silenced by methylation of a CpG-rich zone (or CpG island), a 5’ region of
some genes that frequently includes the promoter and transcriptional start site
o Expression of telomerase also increases as lesions become more advanced

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(2) Microsatellite instability (MSI) pathway: associated with defects in DNA mismatch repair and
accumulation of mutations in microsatellite repeat regions of the genome (MSI-high tumours)
o Some microsatellite sequences are located in the coding or promoter regions of genes
involved in regulation of cell growth e.g. TGFR-b receptor and the pro-apoptotic protein
BAX, contributing to uncontrolled cell growth and enhanced survival of tumour cells
o MSI-H tumours can be identified by loss of immunohistochemical staining for mismatch
repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2) or by molecular genetic analysis of
microsatellite sequences
o These tumours often have prominent mucinous differentiation and peritumoral lymphocytic
infiltrates, and are frequently in the R colon
(3) A subset of microsatellite unstable colon cancers without mutations in DNA mismatch repair
enzymes demonstrate the CpG island hypermethylation phenotype (CIMP). In these tumours,
the MLH1 promoter region is typically hypermethylated, thereby reducing MLH1 expression and
repair function. Activating mutations in the oncogene BRAF are common in these cancers,
while KRAS and TP53 (seen in the chromosomal instability pathway) are not typically mutated
(4) A small group of colon cancers display increased CpG island methylation in the absence of
microsatellite instability. Many of these tumours harbour KRAS mutations, but TP53 and BRAF
mutations are uncommon. In contrast, TP53 mutations are common in colon cancers that do not
display a CpG island methylator phenotype
• Clinical features: Peaks at 60-70 yo. R-sided colon cancers often present with symptoms of iron-
deficiency anaemia (fatigue and weakness) while L-sided colon cancers may product occult bleeding,
changes in bowel habits, cramping and left lower quadrant discomfort. As CRCs may be insidious
and undetected for long periods, endoscopic screening and polyp removal (as most carcinomas arise
within adenomas) is important for cancer prevention. Prognostic factors: depth of tumour invasion,
presence of lymph node metastases and systemic metastases (AJCC TNM staging), and poor
histologic differentiation. Systemic metastases frequently include liver due to portal drainage of the
colon (except for rectum - does not drain via portal circulation), lung and bones. However,
regardless of stage, some patients may still do well for years following resection of solitary or
oligometastatic tumour foci
• Gross:
o Proximal colon: polypoid exophytic masses; because the caecum
and ascending colon are of large caliber, they rarely cause
obstruction
o Distal colon: annular lesions that produce ‘napkin-ring’
constrictions and luminal narrowing, sometimes to the point of
obstruction
• Histology: Both right and left-sided colonic adenocarcinomas are similar. Most tumours are
composed of irregular glands, typically cribriform architecture (grade of differentiation depends on
extent of gland formation), lined by tall columnar cells with dirty necrotic luminal debris. The
invasive component elicits a strong desmoplastic response which is responsible for their firm
consistency. Some tumours have abundant mucin, and may be composed of signet-ring cells

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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

V. ANAL CANAL

Anal canal is divided into thirds – the upper zone is lined by columnar rectal epithelium, the middle third
by transitional epithelium, and the lower third by stratified squamous epithelium

Haemorrhoids

• Thin-walled dilated submucosal vessels (varices) that protrude beneath the anal or rectal mucosa
o External haemorrhoids: inferior haemorrhoidal plexus located below the anorectal line
o Internal haemorrhoids: superior haemorrhoidal plexus within the distal rectum
• Affect about 5% of the general population and develop secondary to persistently elevated venous
pressure within the haemorrhoidal plexus. Risk factors: straining at defecation because of
constipation, venous stasis of pregnancy, portal hypertension (similar pathogenesis to oesophageal
varices – variceal dilations of the anal and perianal venous plexues form collaterals that connect the
poral and caval venous systems, thereby relieving the venous hypertension). Usually in older
patients (except pregnant ladies). Complications: In their exposed position, they can be traumatized
and can bleed, become inflamed, ulcerated, thrombosed and recanalized. Patients thus often
present with pain and PR bleed (bright red blood seen on toilet tissue). Treatment: sclerotherapy,
rubber band ligation, infrared coagulation or surgical excision (haemorrhoidectomy)

Carcinomas of the anal canal

May have typical glandular (adenocarcinoma) or squamous (squamous cell carcinoma) patterns of
differentiation, recapitulating the normal epithelium of the upper or lower thirds of the anal canal,
respectively. Pure squamous cell carcinoma of the anal canal is frequently associated with HPV infection,
which also causes precursor lesions e.g. condyloma acuminatum. An additional pattern, basaloid
pattern, is present in tumours populated by immature cells derived from the basal layer of transitional
epithelium

VI. VERMIFORM APPENDIX

Normal true diverticulum of the caecum. Prone to acute and chronic inflammation; tumours
(adenocarcinoma, neuroendocrine tumours) can also develop here

Acute appendicitis

• Acute inflammation of the appendix; most common in adolescents, young adults (lifetime risk 7%)
• Pathogenesis: thought to be initiated by progressive increases in intraluminal pressure that
compromise venous outflow. In 50-80% of cases, acute appendicitis is associated with overt luminal
obstruction, usually caused by a small stone-like mass of stool (faecolith) or less commonly, a
gallstone, tumour or mass of worms (oxyuriasis vermicularis). Stasis of luminal contents, which
favours bacterial proliferation, triggers ischaemia and inflammatory responses, resulting in tissue
oedema and neutrophilic infiltration of the wall
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Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY

• Clinical features: periumbilical pain that subsequently localizes to the right iliac fossa (RIF),
associated with nausea, fever, vomiting and mildly elevated peripheral white cell count. Classic
physical examination finding is the McBurney sign, deep tenderness located 2/3rd of the distance
from the umbilicus to the right anterior superior iliac spine (McBurney point). However, classic signs
and symptoms may be absent (esp. in the very young and old) e.g. retrocaecal appendix, malrotated
colon. Clinical differential diagnoses include mesenteric lymphadenitis (often due to unrecognized
Yersinia infection or viral enterocolitis), acute salpingitis, ectopic pregnancy, mittelschmerz (pain
caused by minor pelvic bleeding at the time of ovulation) and Meckel diverticulitis. Complications:
perforation and peritonitis, abscesses / phlegmon, pyelophlebitis, portal venous thrombosis, liver
abscess and bacteraemia. Treatment: Surgery (appendectomy)
o Gross: Congested turgid oedematous appendix with dull granular erythematous serosa +/-
serosal fibrinopurulent exudates. Lumen may contain fecolith or purulent material
o Histology: mucosal ulceration, transmural acute inflammation (involving muscularis propria)
+/- focal abscesses within the wall (acute suppurative appendicitis), subserosal vascular
congestion, acute serositis and serosal fibrinopurulent reaction. Further compromise of
appendiceal vessels leads to large areas of haemorrhagic ulceration and gangrenous
necrosis that extends to the serosa (acute gangrenous appendicitis), which can be followed
by rupture and suppurative peritonitis

Tumours of the appendix

• Most common tumour is the well-differentiated neuroendocrine tumour, usually discovered

incidentally at the time of surgery or examination of a resected appendix. Usually at the tip of the
appendix, with mostly benign behaviour (very infrequent nodal metastasis; distant spread is
exceptionally rare)
• Conventional adenomas or non-mucin-producing adenocarcinomas can also occur in the appendix
and may cause obstruction and enlargement that mimics acute appendicitis
• Mucocele: dilated appendix filled with mucin. This may simply represent an obstructed appendix
containing inspissated mucin, or be a consequence of a low grade appendiceal mucinous neoplasm
(LAMN) or mucinous adenocarcinoma, whereby involvement of the serosa can lead to
intraperitoneal seeding and spread (pseudomyxoma peritonei or mistaken for mucinous ovarian
tumours – the abdomen fills with tenacious semisolid mucin)

VII. PERITONEAL CAVITY

Houses the abdominal viscera and is lined by a single layer of mesothelial cells; these cover the visceral
and parietal surfaces and are supported by a thin layer of connective tissue to form the peritoneum

• Sterile peritonitis: Chemical irritation causing inflammation e.g. due to leakage of bile (e.g. from
perforation of rupture of the biliary system) or pancreatic enzymes (e.g. in acute haemorrhagic
pancreatitis). Endometriosis can cause haemorrhage into the peritoneal cavity where it acts as an

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irritant. Foreign material introduced surgically also induces foreign body-type granulomas and
fibrous scarring e.g. talc, sutures. Ruptured dermoid cysts release keratins and also induce an
intense granulomatous reaction
• Infection: Bacterial peritonitis occurs when bacteria (e.g. E.coli) from the GI lumen are released into
the abdominal cavity, most commonly following perforation/damage to the bowel. Spontaneous
bacterial peritonitis occurs without an obvious source of contamination, seen most often in patients
with cirrhosis and ascites and less frequently in children with nephrotic syndrome, possible due to
gut translocation of bacteria
• Sclerosing retroperitonitis (idiopathic retroperitoneal fibrosis): characterized by dense fibrosis that
may extend to involve the mesentery. Many cases through to be related to IgG4-related sclerosing
disease, an immune-inflammatory disorder that can lead to fibrosis in a wide variety of tissues
• Tumours: (Primary) Mesotheliomas are malignant tumours arising from the peritoneal lining, similar
to tumours of the pleura and pericardium. Peritoneal mesotheliomas are almost always associated
with significant asbestos exposure. Rarely, primary benign and malignant soft tissue tumours may
also develop within the peritoneum and retroperitoneum e.g. desmoplastic small round cell tumour.
(Secondary) Tumours from other primary sites may involve the peritoneum by direct spread or
metastatic seeding, resulting in peritoneal carcinomatosis. Mucinous carcinomas particularly of the
appendix may cause pseudomyxoma peritonei

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