Far Eastern University Nicanor Reyes Medical Foundation
Pathology B Gastrointestinal Tract
Mari Karr Esguerra M.D.
Congenital Abnormalities
Atresia, Fistulae, and Duplications
When present within the esophagus, they are discovered shortly
after birth, usually due to regurgitation during feeding.
Without surgical intervention, these are incompatible with life.
Agenesis or absence of the organ is extremely rare.
Atresia or incomplete formation is more common.
A thin non-canalized cord replaces a segment causing
mechanical obstruction.
Occurs most commonly at or near the tracheal bifurcation.
Usually associated with fistula.
Fistula a connection between the upper or lower pouch of the
esophagus to a bronchus or the trachea.
Fistula can be present without atresia.
Complications are aspiration, suffocation, pneumonia, and
severe fluid and electrolyte imbalances.
Intestinal atresia is less common than esophageal atresia but
most commonly involves the duodenum.
Imperforate anus is the most common form of congenital
intestinal tract due to failure of cloacal diaphragm involution.
Stenosis is an incomplete form of atresia where in the lumen is
markedly reduced in caliber due to fibrous thickening of the wall.
Can be acquired as a consequence of inflammatory scarring
such as in GERD, irradiation, systemic sclerosis, or injury.
Can involve any part of GIT, most common is esophagus and
small intestines.
Congenital Duplication Cyst can be saccular or elongated cystic
masses that contain redundant smooth muscle layers.
Diaphragmatic Hernia
Occurs when incomplete formation of the diaphragm allows the
abdominal viscera to herniate into the thoracic cavity.
When severe, space-filling effect of the displaced viscera can
cause pulmonary hypoplasia that is incompatible with life.
Omphalocoele and Gastroschisis
Both results from incomplete closure of the abdominal
musculature leading to herniation of the abdominal viscera.
Omphalocoele herniates into the ventral membranous sac, can
be surgically repaired.
Gastroschisis involves all the layers of the abdominal wall,
from the peritoneum to the skin.
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Ectopia
Most frequent site of ectopic gastric mucosa is the upper third of
the esophagus, referred to as an inlet patch.
Generally asymptomatic but the acid produced by the gastric
mucosa within the esophagus can cause dysphagia, Barrett
esophagus, or adenocarcinoma.
Ectopic Pancreatic Tissue occurs less frequently, located in the
esophagus or stomach.
Can be asymptomatic or produce local inflammation.
If present in the pylorus, can cause inflammation and
scarring leading to obstruction.
Gastric Heterotropia small patches of ectopic gastric muscosa
in the small bowel or colon, may present with occult blood due
to peptic ulceration of adjacent mucosa.
Meckels Diverticulum
A true diverticulum (a blind outpouching of the GIT that
communicates with the lumen and includes 3 layer of bowel wall)
Occurs in the Ileum.
Occurs as a result of failed involution of the vitelline duct.
Rule of 2s for the characteristics of Meckels diverticulum:
Occurs in 2% of the population.
Generally present within 2 feet (60cm) of the ileocecal valve.
Approximately 2 inches long.
Twice common in males.
Most often symptomatic at the age of 2.
Mucosal lining is the same but ectopia may be present; acid
secretion can cause ulceration and resemble acute appendicitis.
Congenital Hypertrophic Pyloric Stenosis
3-5 times more common in males (polygenic inheritance).
Monozygotic twins have high rate of concordance.
Consistent with genetic basis, Turner syndrome and trisomy
18 also confer increased risk.
rd th
Presents between the 3 6 weeks of life as new-onset
regurgitation, projectile, non-bilious vomiting after feeding.
On PE, there is a firm, ovoid, 1-2 cm abdominal mass and
hyperperistalsis.
These stems from hyperplasia of pyloric muscularis propria,
which obstructs the gastric outflow tract, edema and
inflammation, may aggravate the narrowing.
Myotomy or surgical splitting of the muscularis is curative.
Hirschsprung Disease (Congenital Aganglionic Megacolon)
Pathogenesis
Results when normal migration of neural crest cells from cecum
to rectum is arrested prematurely or when ganglion cells
undergo premature death.
This produces a distal intestinal segment lacks both Messners
and Myenteric (Auerbach) Plexus, coordinated peristalsis is
absent and functional obstruction occur, resulting to dilation of
the proximal to the affected segment.
Most common heterozygous loss of function mutations in the
receptor tyrosine kinase RET.
Diagnosis requires documenting the absence of ganglion cells
within the affected segment.
Morphology
The ganglion cells can be identified in immunohistochemical
stains for acetylcholinesterase, diagnosis is the absence of
ganglion cells within the affected segments.
Rectum is always affected.
The aganglionic region may have normal appearance, but the
normally innervated proximal colon may undergo progressive
dilation and become massively distended (megacolon)
May stretch and thin the colonic wall to the point of rupture,
most frequently near the cecum.
Clinical Features
Presents with a failure to pass meconium in the immediate
postnatal period.
Obstruction or constipation follows, often with visible,
ineffective peristalsis, may progress to abdominal distention and
bilious vomiting.
Complications are enterocolitis, fluid and electrolyte
disturbances, perforation, and peritonitis.
Primary mode of treatment is surgical resection.
Acquired Megacolon
Occur at any age as a result of Chagas Disease, neoplastic
obstruction, inflammatory stricture.
Complication of ulcerative colitis, visceral myopathy or
functional psychosomatic disorders.
Esophagus
rd
Develops from cranial portion of foregut, recognizable during 3
week of gestation.
ESOPHAGEAL OBSTRUCTIONS
Can be due to mechanical or functional (peristaltic) obstruction.
3 forms of esophageal dysmotility:
1. Nutcracker Esophagus high amplitude contractions of
distal esophagus, due to loss of normal coordination of
inner circular and outer longitudinal smooth muscles.
2. Diffuse Esophageal Spasm repetitive, simultaneous
contractions of the distal esophageal muscles.
3. Hypertensive Lower Esophageal Sphincter absence of
altered patterns, can be distinguished from achalasia the
latter includes reduced esophageal peristalsis.
Pharyngoesophageal Diverticulum
Epiphrenic Diverticulum
Due to increased wall stress, esophageal dysmotility can
result in the development of small diverticulae
Located above the lower esophageal sphincter.
Zenkers Diverticulum
Impaired relaxation of the cricopharyngeus muscle after
swallowing can result to increased pressure in distal pharynx.
Located immediately above the upper esophageal sphincter.
Larger Zenker diverticulae may accumulate significant
amount of food, producing a mass and symptoms of
regurgitation and halitosis.
Traction Diverticulum
Located near the middle portion of the esophagus
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Benign Esophageal Stenosis
Narrowing of the lumen caused by fibrous thickening of the
submucosa and atrophy of muscularis propria.
Most often due to inflammation and scarring in chronic GERD.
Esophageal Mucosal Webs
Idiopathic, ledge-like protrusions of mucosa that may cause
obstruction, encountered most frequently in women over age 40
Associated with GERD, Chronic GVHD, or blistering skin disease.
Most common in the upper esophagus where they are semi-
circumferential, eccentric, that protrudes less than 5mm, and
has 2-4mm thickness.
Microscopically composed of fibrovascular connective tissue and
overlying epithelium.
Accompanied by iron deficiency anemia, glossitis, and cheilosis
as part of Patterson-Brown-Kelly or Plummer Vinson Syndrome.
Main symptom is non-progressive dysphagia with incompletely
chewed food.
Esophageal / Schatzki Rings
Similar to webs but are circumferential, thicker, and include
mucosa, submucosa, and hypetrophic muscular propria.
A Rings if present in the distal esophagus, above the
gastroesophageal junction, covered by squamous epithelium.
B Rings if present at the squamocolumnar junction of the
lower esophagus may have a gastric cardia-type mucosa.
ACHALASIA
Normally, during swallowing, release of Nitric Oxide and
vasoactive intestinal polypeptides from inhibitory neurons along
with interruption of normal cholinergic signaling causes
relaxation of LES during swallowing.
Increased tone of LES as a result of impaired smooth muscle
relaxation leads to esophageal obstruction.
Characterized by a triad:
Incomplete LES relaxation
Increased LES tone
Aperistalsis of esophagus
Primary Achalasia idiopathic, failure of distal esophageal
inhibitory neurons (ganglion cell degeneration). Degenerative
changes in the extraesophageal vagus nerve or dorsal motor
nucleus of the vagus may occur.
Secondary Achalasia may arise from Chagas disease caused by
Trypanosoma cruzi leading to destruction or myenteric plexus.
Duodenal, colonic, and ureteric plexi can also be affected.
Symptoms include dysphagia, diffulty in belching, and chest pain.
Achalasia-like disease may be caused by diabetic autonomic
neuropathy, infiltrative disorders such as malignancy, amyloidosis or
sarcoidosis & lesions of dorsal motor nuclei, particularly polio or
surgical ablation.
Treatments include laparoscopic myotomy and pneumatic
balloon dilation.
Botulinum neurotoxin injection to inhibit LES cholinergic neurons
can also be effective.
ESOPHAGITIS
Lacerations
Normally, a reflex relaxation of the gastroesophageal
musculature precedes the antiperistaltic contractile wave
associated with vomiting.
It is speculated that the relaxation fails during prolonged
vomiting, with the result of gastric acid reflux contents
overwhelm the gastric inlet and cause the esophageal wall to
stretch and tear.
Mallory-Weiss Syndrome
Longitudinal mucosal tears near gastroesophageal junction.
Most often associated with severe retching or vomiting
secondary to acute alcohol intoxication.
Up to 10% of GI Bleeding often presenting as hematemesis is
due to superficial esophageal lacerations.
Does not require surgery, healing is rapid and complete.
Boerhave Syndrome
Less common but more serious, characterized by transmural
tearing and rupture of the distal esophagus.
Produces severe mediastinitis.
Require surgical intervention, presents with chest pain,
tachypnea, and shock (initial d/dx is myocardial infarction).
Chemical and Infectious Esophagitis
May be damaged by variety of irritants like alcohol, erosive acids
or alkalis, excessive hot fluids, and heavy smoking.
Symptoms range from self-limited pain on swallowing
(odynophagia) to hemorrhage, stricture or perforation.
Pills lodge and dissolve in the esophagus causing injury.
Iatrogenic esophageal injury may be caused by cytotoxic
chemotherapy, radiation therapy, or GVHD.
Esophageal infection is uncommon in healthy individuals.
Infections in patients who are debilitated or immunosuppressed
which can be caused by herpes simplex virus, CMV, or fungi.
Herpesvirus punched out ulcers, biopsy demonstrates
nuclear viral inclusions within the rim of degenerating
epithelial cells at the ulcer margin.
CMV causes shallower ulcerations and characteristic
nuclear and cytoplasmic inclusions within capillary
endothelium and stromal cels. IHC stains are also sensitive.
Candida - adherent, gray-white pseudomembranes
composed of densely matted fungal hyphae and
inflammatory cells.
Morphology
Morphology of esophagitis varies with the etiology.
Chemicals outright necrosis of the esophageal wall.
Pill-induced occurs at site of strictures that impede passage
of luminal contents, presents with ulceration with superficial
necrosis, granulation tissue and fibrosis.
Irradiation intimal proliferation and luminal narrowing of
submucosal and mural blood vessels.
Infection by fungi or bacteria, non-pathogenic oral bacteria
are frequently found in ulcer beds, may invade lamina
propria and cause necrosis of overlying mucosa.
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Reflux Esophagitis
Stratified squamous epithelium is resistant to abrasion but
sensitive to acids; submucosal glands abundant in the proximal
and distal esophagus contribute to mucosal protection by
secreting mucin and bicarbonate.
The constant tone of LES prevents reflux of acidic gastric
contents, which is the most frequent cause of esophagitis and
most common outpatient GI diagnosis, the associated clinical
condition is termed gastroesophageal reflux disease (GERD).
Pathogenesis
Most common cause is transient LES relaxation, mediated via
vagal pathways and can be triggered by gastric distention.
Other conditions that decrease LES tone or increase abdominal
pressure that contribute to GERD include alcohol, tobacco use,
obesity, CNS depressants, pregnancy, and hiatal hernia.
Morphology
Hyperemia.
Intraepithelial eosinophils followed by PMN in more severe cases
Basal zone hyperplasia exceeding 20% of the total epithelial
thickness and elongation of the lamina propria papillae.
Clinical Features
Heartburn, dysphagia, and regurgitation of sour-tasting gastric
contents and chest pain.
Treatment with proton pump inhibitors, which have replaced
H2-receptor antagonists, to reduce gastric acidity.
Complications include ulceration, hematemesis, melena (black
colored stool), stricture development, and Barrett esophagus.
Hiatal Hernia
Separation of diaphragmatic crura and protrusion of the
stomach into the thorax through a gap.
Give rise to symptoms such as heartburn and regurgitation of
gastric juices, similar to GERD.
Symptomatic in fewer than 10% of adults.
Barrett Esophagus
A complication of chronic GERD characterized by intestinal
metaplasia with esophageal squamous mucosa.
Increased risk for esophageal adenocarcinoma.
Morphology
Can be recognized as one or several tongues or patches of red,
velvety mucosa extending upward the junction.
Alternates with residual smooth, pale squamous mucosa and
interfaces with light-brown columnar mucosa.
Can be classified as:
Long segment more than 3 cm
Shot Segment less than 3 cm
Diagnosis requires endoscopic evidence of metaplastic columnar
mucosa above the gastroesophageal junction.
Intestinal-type metaplasia is seen as replacement of the
squamous esophageal epithelium with goblet cells.
 These are diagnostic of Barrett Esophagus, and have distinct
mucous vacuoles that stain plate blue in H&E and impart the
shape of a wine-goblet.
Non-goblet columnar cells, like gastric type foveolar cells may
also be present, but are insufficient for diagnosis.
Epithelial dysplasia, considered to be pre-invasive lesion, is
detected in 0.2% to 2% of persons with Barrett esophagus each
year associated with prolonged symptoms and increased age.
When dysplasia is present it is classified as low or high grade.
Atypical mitoses, nuclear hyperchromasia, irregularly
clumped chromatin, increased N/C ratio, and failure of
epithelial cells to mature as they migrate to esophageal
surface are present in both grades.
Gland architecture is frequently abnormal and characterized
by budding, irregular shapes, and cellular crowding.
High-grade dysplasia exhibits more severe cytologic and
architectural changes
With progression of epithelial cells may invade the lamina
propria, a feature that defines intramucosal carcinoma.
Clinical Features
Can only be identified via endoscopy and biopsy, which are
usually prompted by GERD symptoms.
Treatment options include esophagectomy, or photodynamic
therapy, laser ablation and endoscopic mucosectomy.
Esophageal Varices
Venous blood from GIT passes through the liver via the portal
vein before returning to the heart, this is responsible for the
first-pass effect in drugs and food.
Disease that impedes this flow causes portal hypertension and
can lead to development of esophageal varices.
Pathogenesis
Portal HTN results in the development of collateral channels at
sites where the portal and caval systems communicate.
They allow some drainage to occur but at the same time lead
to development of congested sub epithelial and submucosal
venous plexi in the distal esophagus & proximal stomach.
These varices develop in vast majority of cirrhotic patients
most commonly associated with alcoholic liver disease.
Hepatic schistosomiasis is the second most common.
Morphology
Varices are tortuous dilated veins lying primarily within the
submucosa of the distal esophagus and proximal stomach.
Varicieal rupture results in hemorrhage into the lumen of the
esophageal wall, in which the overlying mucosa appears
ulcerated and necrotic.
Clinical Features
Variceal hemorrhage is an emergency that can be treated by
inducing splanchnic vasoconstriction or endoscopically
sclerotherapy (injection of thrombotic agents), endoscopic
balloon tamponade, or endoscopic rubber band ligation.
Page 4 of 18
As many half of the patients die from the first bleeding episode
either as a direct consequence of hemorrhage or following
hepatic coma triggered by hypovolemic shock.
Factors that lead to rupture:
Thinned overlying mucosa
Increased Tension in the progressively dilated veins.
Increased vascular hydrostatic pressure.
Esophageal Adenocarcinoma
Most arise from Barrett esophagus, increased rates may be
partly due to increased incidence of obesity related GERD.
H. pylori infection reduces the risk of esophageal
adenocarcinoma due to atrophy of the gastric mucosa.
Occurs most frequently in Caucasians more commonly in men.
Pathogenesis
Progression of Barrett esophagus to adenocarcinoma occurs
over an extended period through stepwise acquisitions of
genetic and epigenetic changes.
Chromosomal abnormalities, mutation of TP53 and
downregulation of CDKN2A.
Morphology
Usually occurs in the distal third of the esophagus and may
invade adjacent gastric cardia.
Initially appearing as flat or raised patches in otherwise intact
mucosa, large masses of 5 cm or more in diameter.
Microscopically, Barrett esophagus is present adjacent.
Commonly produces mucin and form glands, often with
intestinal-type morphology.
Clinical Features
Commonly present with pain, difficulty in swallowing,
progressive weight loss, hematemesis, chest pain, & vomiting.
Overall 5-year survival is less than 25%.
5 year survival is 80% in patients with adenocarcinoma limited to
the mucosa or submucosa.
Esophageal Squamous Cell Carcinoma
Pathogenesis
Linked to tobacco and alcohol, nutritional deficiencies (polycyclic
hydrocarbons, nitrosamines), mutagenic compounds, HPV.
Molecular pathogenesis is linked to SOX2 amplification,
overexpression of cyclin D1, and loss-of-function mutations in
TP53, E-cadherin, and NOTCH1.
Morphology
rd
Occurs in the middle 3 of the esophagus.
Begins as an in situ lesion termed squamous dysplasia.
Early lesions appear as small, gray-white, plaque-like thickenings.
Grows into poluypoid, or exophytic tumor, and protrude into
and obstruct the lumen.
Most are moderately to well differentiated.
Sites of lymph node metastasis:
rd
Upper 3 Cervical lymph nodes
rd
Middle 3 Mediastinal, Paratracheal, Tracheobronchial
rd
Lower 3 Gastric and Celiac lymph nodes.
Clinical Features
Onset is insidious, most commonly presents with dysphagia,
odynophagia, or obstruction.
Prominent weight loss and debilitation results from both
impaired nutrition and effects of the tumor itself.
5 year survival rates are 65% in patients with superficial
esophageal squamous cell carcinoma.
Leiomyoma
Benign tumors of the esophagus are generally of mesenchymal
origin, leiomyoma being the most common.
Stomach
GASTROPATHY AND ACUTE GASTRITIS
Gastritis is a mucosal inflammatory process.
If PMNs are present, it is termed as acute.
If inflammatory cells are rare or absent, gastropathy is used.
Pathogenesis
Disruption of the normal protective mechanisms.
NSAIDs (Non-steroidal anti-inflammatory drugs)
Inhibits COX dependent synthesis of prostaglandins E2 and
I2, which supposedly stimulates the defense mechanisms of
the stomach.
COX-1 plays a larger role than COX-2, thus non-specific
inhibition by aspirin & ibuprofen poses greater gastric injury
rather than selective COX-2 inhibition such as celecoxib.
Helicobacter pylori & Uremic Patients
Due to inhibition of gastric bicarbonate transporters by
ammonium ions.
In older adults, decreased mucin and bicarb secretions.
Decreased O2 delivery may account for people at high altitudes.
Morphology
Difficult to recognize histologically, since the lamina propria
shows only moderate edema and slight vascular congestion.
Surface is intact, but foveolar cell hyperplasia with characteristic
corkscrew profiles and epithelial proliferation are present.
Page 5 of 18
Presence of neutrophils in the basement membrane signifies
active inflammation (gastritis).
More severe mucosal damage: erosions & hemorrhage develops
Concurrent erosion and hemorrhage is termed acute erosive
hemorrhagic gastritis.
Clinical Features
Varies according to the etiology.
NSAID-induced gastropathy may be asymptomatic or have
persistent epigastric pain that responds to antacids or PPIs.
Pain associated with bile reflux is refractory to therapy and may
be accompanied by bilious vomiting.
STRESS-RELATED MUCOSAL DISEASE
Occurs in patients with severe trauma, burns, intracranial
disease, major surgery, and other forms of severe physiologic
stress.
75% develop gastric lesions during the first 3 days of illness.
Stress Ulcers most common in shock, sepsis, and trauma.
Curling Ulcers in the proximal duodenum, associated with
severe burns or trauma.
Cushing Ulcers duodenal and esophageal ulcers in patients
with intracranial diseases, carry high incidence of perforation
Pathogenesis
Most often related to local ischemia, due to systemic
hypotension or reduced blood flow caused by splanchnic
vasoconstriction.
Upregulation of NO Synthase and increased release of
vasoconstriction endothelin-1 contributes.
COX-2 expression appears to be protective.
Lesions associated with intracranial injury are caused by direct
stimulation of vagal nuclei, causing acid hypersecretion.
Morphology
Ranges from shallow erosions caused by superficial epithelial
damage to deep lesions that penetrate the depth of the mucosa.
Acute ulcers are rounded, <1 cm, frequently stained brown to
black by acid digestion of extravasated blood.
Unlike peptic ulcers, acute stress ulcers are found anywhere in
the stomach, most often multiple.
Clinical Features
Bleeding from erosions or ulcers may require transfusions.
Prophylactic PPIs may blunt the impact of stress ulcerations.
Other, non-stress-related causes of gastric bleeding:
1.) Dieulafoy Lesion
Caused by submucosal artery that does not branch properly.
This has 3 mm diameter, or 10 times larger than mucosal
capillaries, most commonly found along the lesser curvature,
near the gastroesophageal lesions.
2.) Gastric Antral Vascular Ectasia (GAVE)
Longitudinal strips of edematous erythematous mucosa that
alternate with less severely injured, paler mucosa.
Referred sometimes as watermelon stomach.
The erythematous mucosa is made by ectatic mucosal vessels.
Associated with cirrhosis and systemic sclerosis, often idiopathic
CHRONIC GASTRITIS
Most common cause is H. pylori infection.
Autoimmune gastritis, the most common cause of diffuse
atrophic gastritis, represents the less common (10%) cases of
chronic gastritis.
Symptoms are less severe compared to acute gastritis.
Helicobacter pylori Gastritis
H. pylori is a spiral shaped or curved bacilli.
Acute infection does not produce sufficient symptoms.
Pathogenesis
Most predominantly presents as antral gastritis with normal or
increased acid production.
When inflammation is limited to the antrum, increased acid
production results to greater risk of duodenal peptic ulcer.
May progress to involve gastric body and fundus.
Multifocal atrophic gastritis associated with patchy mucosal
atrophy, reduced parietal cell mass and acid secretion, intestinal
metaplasia, increased risk of gastric adenocarcinoma.
H. pylori virulence factors:
Flagella allow it to be motile in viscous mucus
Urease generates ammonia, elevating local gastric pH and
enhances bacterial survival.
Adhesins enhance bacterial adherence to foveolar cells.
Toxins cytotoxin associated gene A (CagA).
Morphology
Antral biopsy is the preferred site; the organism is concentrated
within the superficial mucus overlying epithelial cells.
Distribution can be irregular, with areas of heavy colonization
adjacent to those with few organisms.
H. pylori display tropism for gastric mucosa cells and are
generally not associated with intestinal or duodenal epithelium.
More common in the antrum and cardia, less common in the
oxyntic mucosa of the fundus and the body.
Grossly appears as erythematous mucosa.
Intraepithelial infiltrates including neutrophils within the lamina
propria, plasma cells in the lamina propria.
Mucosa may be atrophic.
When intense, the infiltrates may create thickened rugal folds,
mimicking the appearance of early cancers.
Lymphoid aggregates, with some germinal centers, are present,
represents an induced form of mucosa-associated lymphoid
tissue (MALT) that has a potential to transform to lymphoma.
Page 6 of 18
Clinical Features
Urea Breath Test detection of ammonia in the breath is a
useful diagnostic tool for H. pylori infection.
Effective treatments include combinations of antibiotics and PPIs
Autoimmune Gastritis
Spares the antrum and associated with hypergastrinemia.
Characterized by:
Antibodies to parietal cells and intrinsic factor that can be
detected in serum and gastric secretion.
Reduced serum pepsinogen I concentration
Endocrine cell hyperplasia
Vitamin B12 deficiency
Defective gastric acid secretion (achlorhydria).
Pathogenesis
Associated with loss of parietal cells, which are responsible for
secretion of gastric acid and intrinsic factor.
Absence of acids production stimulates gastrin release, hence
the hypergastrinemia, and hyperplasia of antral gastrin-
producing G cells.
Lack of intrinsic factors disables ileal B12 absorption, leading to
slow-onset megaloblastic anemia (pernicious anemia).
Reduced pepsinogen I concentration due to chief cell destruction
CD4+T cells directed against parietal cell components, including
+ +
H K -ATPase, are considered to be the principal agents of injury.
Morphology
Diffuse mucosal damage of the oxyntic (acid-producing) mucosa
within the body and the fundus, mucosa appears thin and rugal
folds are lost.
Inflammation is deep and centered on the glands, primarily
composed of lymphocytes.
Inflammatory infiltrates is primarily composed of lymphocytes,
macrophages and plasma cells.
Endocrine hyperplasia can be demonstrated with immunostains
for proteins such as chromogranin A.
Glandular atrophy.
Intestinal metaplasia (goblet cells) is associated with increased
risk of gastric carcinoma.
COMPLICATIONS OF CHRONIC GASTRITIS
Peptic Ulcer Disease (PUD)
PUD refers to chronic mucosal ulceration affecting the
duodenum or stomach.
Nearly all are associated with H. pylori infection, NSAIDs, or
cigarette smoking.
Most common form occurs in the antrum or duodenum as a
result of chronic H. pylori induced antral gastritis, associated
with increased gastric acid and decreased bicarb secretion.
Pathogenesis
Imbalances between mucosal defense mechanism and damaging
factors cause chronic gastritis.
Morphology
Peptic ulcers in the setting of chronic gastritis are most common
in the proximal duodenum.
Gastric peptic ulcers are predominantly located along the lesser
curvature near the interface of body and antrum.
Solitary (80%), less than 0.3cm in diameter tends to be shallow,
those greater than 0.6 tends to be deeper.
Classically round to oval, sharply punched-out defect.
Headed-up margins are more characteristic of cancers.
Perforation to the peritoneal cavity is a surgical emergency.
Other complications of Chronic Gastritis
Mucosal Atrophy and Intestinal Metaplasia
Dysplasia
Gastritis Cystica exuberant reactive epithelial proliferation
associated with enlargement of epithelial-lined cysts.
HYPERTROPHIC GASTROPATHIES
Giant cerebriform enlargement of the rugal folds due to
epithelial hyperplasia without inflammation.
Menetrier Disease
Excessive secretion of TGF- characterized by diffuse hyperplasia
of the foveolar epithelium of the body and fundus, and
hypoproteinemia due to protein-losing enteropathy.
Irregular enlargement of the gastric rugae in the body & fundus
Histologically, glands are elongated with a corkscrew-like
appearance and cystic dilation is common.
Treatment is supportive, with IV albumin.
Zollinger-Ellison Syndrome
Caused by gastrin-secreting tumor.
These gastrinomas are most commonly found in the small
intestine or pancreas.
Often presents with duodenal ulcers or chronic diarrhea.
Within the stomach, there is doubling of oxyntic mucosal
thickness due to five-fold increase in parietal cell number.
60% - 90% of gastrinomas are malignant.
Treatment include blockade of acid hypersecretion by PPIs.
Tumors are sporadic (75%), tend to be solitary and can be
surgically resected.
The remaining 25% have Multiple Endocrine Neoplasia Type I
(MEN I).
Page 7 of 18
GASTRIC POLYPS AND TUMORS
Inflammatory and Hyperplastic Polyps
Up to 75% of all gastric polyps are of this type.
Chronic inflammation drives the development of such polyps.
Most common in individuals between 50-60 years old.
Usually develop in association with chronic gastritis.
Majority are smaller than 1 cm in diameter, frequently multiple,
ovoid, and have smooth surfaces.
It has irregular, cystically dilated, and elongated foveolar glands.
The lamina propria is edematous with surface ulceration.
Fundic Gland Polyps
Occurs sporadically in individuals with familial adenomatous
polyposis (FAP).
Increased incidence due to use of proton pump inhibitors, since
gastric acid secretion is inhibited, gastrin production increases
and oxyntic gland growth is also increased.
Occurs in gastric body and fundus, well-circumscribed with
smooth surface. May be single or multiple.
Composed of cystically dilated, irregular glands lined by flattened
parietal cells.
Inflammation is absent or minimal.
Gastric Adenoma
Represent up to 10% of all gastric polyps.
Frequency increases with age.
Patients are usually between 50 and 60 years of age, males are
more affected.
Also increased incidence in patients with FAP.
Usually solitary lesions less than 2 cm, most commonly located in
the antrum.
Composed of intestinal-type columnar epithelium that exhibits
varying degrees of dysplasia (low/high grade)
Almost always associated with chronic gastritis with atrophy and
intestinal metaplasia.
Gastric Adenocarcinoma
Most common malignancy of the stomach (90%).
Can be either: intestinal or diffuse.
Strongly associated with germline loss-of-function mutation in
CDH1 (a tumor suppressor gene), that encodes for E-cadherin.
Sporadic type is strongly associated with mutations that result in
increased signaling via Wnt pathway.
Morphology
Most involve the antrum; lesser curvature is more involved than
the greater curvature.
Elevated mass with headed up margins and central ulceration.
Infiltrative tumors often evoke a desmoplastc reaction that
stiffens the gastric wall.
When there are large areas of infiltration, diffuse rugal
flattening and a rigid thickened wall may impart a leather
bottle appearance termed linitis plastic.
Intestinal type, Gastric Adenocarcinoma
Tends to form bulky tumors, composed of glandular
structures with mucin secretion.
Closely associated with gastritis and intestinal metaplasia.
 Diffuse infiltrative type, Gastric Adenocarcinoma
More often composed of signet-ring cells.
Composed of discohesive cells due to E-cadherin loss.
These cells do not form glands but instead have large mucin
vacuoles that expand the cytoplasm and push the nucleus to
the periphery, hence the signet ring appearance.
Clinical Features
Intestinal type usually develops from precursor lesions such as
flat dysplasia and adenomas.
Most important prognostic indicators at the time of diagnosis:
Depth of invasion
Nodal Metastasis
Local invasion into the duodenum, pancreas, and
retroperitoneum is common.
Virchows node Supraclavicular sentinel lymph node.
Sister Mary Joseph Nodule Periumbilical region subcutaneous
Gastric Lymphoma
Extranodal lymphomas can arise in any tissue, but most
commonly in the GIT, particularly the stomach.
These tumors are often reerred to as lymphomas of mucosa-
associated lymphoid tissues (MALT) or MALTomas.
Pathogenesis
In the stomach, MATL is induced as a result of chronic gastritis.
H. pylori is the most common inducer in the stomach.
Can transform to diffuse large B cell lymphomas.
Associated with 3 translocations:
t(11;18)(q21;q21) most common
t(1;14)(p22;q32)
t(14;18)(q32;q31)
Morphology
Forms dense lymphocytic infiltrates in the lamina propria
Neoplastic lymphocytes infiltrate the gastric flands fcally to
create diagnostic lymphoepithelial lesions.
Tumor cells accumulate large amount of cytoplasm (monocytoid)
MALTomas express B-cell markers:
(+) CD19, CD20, CD42 (25%)
(-) CD5, CD10
Clinical Features
Most common are dyspepsia and epigastric pain.
Hematemesis, melena, and weight loss may be present.
Since MALTomas and H. pylori infection often coexist and have
overlapping symptoms and endoscopic appearances, diagnosis
difficulties may arise.
Carcinoid Tumors
Arise from diffuse components of the endocrine system, now
referred to as well-differentiated neuroendocrine tumors.
Most are found in the GI tract, more than 40% occur in the small
intestine. The tracheobronchial tree and lungs are the next most
commonly involved site.
Maybe associated with endocrine cell hyperplasia, MEN-I, and
Zollinger Syndrome.
Page 8 of 18
Morphology
Grossly, can be intramural or submucosal that create small
polypoid lesions, tends to be yellow or tan in color and are very
firm due to desmoplastic reaction.
In the stomach, they arise within oxyntic mucosa.
Histologically composed of islands, trabeculae, strands, glands or
sheets of uniform cells with scant, pink, granular cytoplasm and
a round to oval stippled nucleus.
Immunohistochemical markers are positive for endocrine
granule markers such as synaptophysin and chromogranin A.
Clinical Features
th
Peaks in the 6 decade.
Symptoms are determined by the hormones produced.
Ex: Tumors that produce gasrin may cause Zollinger syn.
Generally requires tumor to secrete hormones into non-portal
venous circulation and strongly associated with metastatic dse.
Most important prognostic factor is location:
Foregut Carcinoid
From esophagus to stomach to duodenum proximal to
ligament of Treitz.
Rarely metastasize, generally cured by resection.
Midgut Carcinoid
Arise in the jejunum and ileum
Often multiple and tend to be aggressive.
Greater depth of local invasion, increased size, and
presence of necrosis and mitoses indicates worse outcome
Hindgut Carcinoid
Arise in the appendix and colorectum.
Discovered incidentally.
Rarely more than 2 cm, almost always benign.
Rectal carcinoids produce polypeptide hormones, presents
with abdominal pain and weight loss
Gastrointestinal Stromal Tumors (GIST)
Most common mesenchymal tumor of the abdomen.
More than 50% occurs in the stomach.
75-80% has oncogenic gain-of-function mutation in receptor
tyrosine kinase c-KIT (CD 117).
Morphology
Primary GISTS can be large up to 30cm, usually soliraty, well-
circumscribed, fleshy mass covered by ulcerated/ intact mucosa.
May project outward the serosa.
Shows whorled appearance.
May be composed of thin elongated cells (spindle cell type), or
may be dominated by epithelial appearing termed epitheloid
type, or it can be mixed.
Most useful diagnostic marker is KIT, detectable in Cajal cells.
Clinical Features
May be related to mass effects.
Mucosal ulceration can cause blood loss, presenting with anemia
It can also be an incidental finding on radiographs.
Prognosis correlates with tumor size, mitotic index, and location.
Gastric GISTs being less aggressive.
Complete surgical resection is the primary treatment.
Small Intestine and Colon
INTESTINAL OBSTRUCTION
Mechanical obstructions account for 80% of obstructions.
Hernia, Adhesions, Intussusception, Volvulus
Tumors and Infarct account for 10-15% of obstructions.
Hernias
Any weakness or defect in the abdominal wall may permit
protrusion of serosa-lined pouch of peritoneum (hernia sac)
Typically occur anteriorly via the inguinal and femoral canals,
umbilicus, or sites of surgical scars.
Obstruction occurs due to visceral protrusion (external hernia)
Most frequently associated with inguinal hernias with narrow
orifices and large sacs.
Pressure at the neck of the pouch may impair venous drainage, resultant
stasis and edema increases the bulk of herniated loop, leading to permanent
entrapment (incarceration) and overtime arterial and venous compromise
(strangulation) and infarction.
Adhesions
Surgical procedures, infections, peritoneal inflammation (e.g.
endometriosis) may result in development of adhesions between
bowel segments.
These fibrous bridge create closed loops through which the
other viscera may slide and become entrapped (internal hernia)
Obstruction and strangulation are much the same with external.
Volvulus
Twisting of a loop of bowel about its mesenteric point of
attachment, results in luminal and vascular compromise.
Features of obstruction and infaraction.
Occurs most often in large redundant loops of sigmoid colon.
Intussusception
Occurs when a segment telescopes into the distal segment due
to constricted wave of peristalsis.
Once trapped, the invaginated segment is propelled by
peristalsis and pulls the mesentery along.
May progress to intestinal obstruction, compression of vessels
and infarction if left untreated.
Page 9 of 18
ISCHEMIC BOWEL DISEASE
Interconnections between arcades, as well as collaterals from
proximal celiac and distal pudendal, and iliac make it possible for
the small intestine and colon to tolerate slowly progressive
blood loss from one artery.
Chronic, progressive hypoperfusion, acute compromise of any
major vessel can lead to infarction of several meters of intestine.
Damage can range from:
Mucosal no deeper than muscularis
Mural mucosa and submucosa
Transumural involves the three layers
Major variables in IBD are severity of vascular compromise,
timeframe during which it develops, and the vessels affected.
Acute Arterial Obstruction
Atherosclerosis Aortic Aneurysm
Hypercoagulable states
Intestinal Hypoperfusion
Cardiac Failure, Shock
Dehydraion, Vasoconstrictive Drugs
Mesenteric Venous Thrombosis
Uncommon
Inherited or Acquired Hypercoagulable State
Invasive Neoplasm
Cirrhosis, Trauma, Masses that compress portal system
Pathogenesis
Intestinal responses to ischemia occur in two phases: Hypoxic
Injury and Reperfusion Injury.
Hypoxic Injury
Occurs at the onset of vascular compromise.
Epithelial cells of the intestine are relatively resistant to
transient hypoxia.
Reperfusion injury
Initiated by restoration of blood supply.
It is at this time the greatest damage occurs.
Morphology
Colon is the most common site of GI Ischemia.
Lesions can be continuous, most often patchy and segmental.
Mucosa is hemorrhagic and may be ulcerated.
Bowel wall is also thickened by edema.
Atrophy and sloughing of the surface epithelium.
Coagulative necrosis of muscularis propria within 1-4 days, and
perforation may occur.
Serositis, with purulent exudates and fibrin deposition may be
prominent.
Bacterial superinfection and enterotoxin release may induce
pseudomembrane formation, resembling C. difficile colitis.
Clinical Features Celiac Disease / Celiac Sprue
Most common in patients older than 70 y/o,
Slightly more often in women.
Acute colonic ischemia presents with sudden onset of cramping,
left lower abdominal pain, desire to defecate, and passage of
blood or bloody diarrhea.

ANGIODYSPLASIA
Malformed submucosal and mucosal blood vessels.
Occurs most often in the cecum or right colon.
th
Presents after 6 decade of life.
Accounts for 20% of major episodes of lower intestinal bleeding.
Intestinal hemorrhage may be chronic and intermittent, or acute
and massive.
Pathogenesis remains undefined but attributed to mechanical
and congenital factors.

MALABSORPTION SYNDROME
Presents most commonly as chronic diarrhea, characterized by Gluten-sensitive enteropathy.
defective absorption of fats, fat- and water-soluble vitamins, An immune-mediated enteropathy triggered by the ingestion of
proteins, carbohydrates, electrolytes, and water. gluten-containing foods such as wheat, rye, or barley in
Accompanied by weight loss, anorexia, abdominal distention, genetically predisposed individuals.
borborygmi (rumbling sound), and muscle wasting.
Pathogenesis
Hallmark of malabsorption is steatorrhea.
The alcohol-soluble fraction of gluten gliadin, contains most of
Malabsorption results from disturbance of at least one of 4
the disease producing components.
phases of nutrient absorption:
Gluten is digested into amino acids including gliadin which is
Intraluminal Digestion
resistant to digestion.
Terminal Digestion
Gliadin peptides may induce epithelial cells to express IL15.
Transepithelial transport
IL-15 triggers CD9 proliferation expressing NKG2D marker
Lymphatic transport of absorbed lipids
and receptor for MIC-A.
Enterocytes express surface MIC-A and are attacked by
Diarrhea
NKG2D-expressing lymphocytes.
Defined as increase in stool mass, frequency, or fluidity.
Silent (+) serology and villous atrophy without symptoms.
Typically greater than 200g / day/
Latent (+) serology, (-) villous atrophy
Painful, bloody, small-volume diarrhea is called dysentery.
Can be classified as:
Morphology
Secretory diarrhea isotonic stool, during fasting.
Biopsy of specimens from second portion of duodenum or
Osmotic diarrhea occurs with lactase deficiency, due to
proximal jejunum which are exposed to highest gluten conc.
excessive osmotic forces of unabsorbed luminal solutes.
Characterized by intraepithelial lymphocytosis (CD8+).
Malabsorptive diarrhea generalized failure of nutrient
Crypt hyperplasia and villous atrophy.
absorption, associated with steatorrhea, relieved by fasting.
Loss of mucosal and brush-border surface area accounts for
Exudative diarrhea due to inflammatory bowel disease,
malabsorption.
characterized by purulent, bloody stools.
Increased Plasma cells, mast cells, eosinophils.
Associated with T-cell lymphoma and small cell intestinal
Cystic Fibrosis
adenocarcinoma.
Due to absence of epithelial cystic fibrosis transmembrane
conductance regulator (CFTR), individuals have defects in
Clinical Features
chloride, and bicarbonate ion secretion.
Typically begins at the introduction of gluten to diet between
Interferes with bicarb, sodium, and water secretion resulting
ages of 6-24 months.
defective luminal hydration.
Presents with irritability, distention, anorexia, diarrhea, failure to
Reduced hydration can occasionally lead to intestinal obstruction
thrive, weight loss, muscle wasting.
Result is failure of the intraluminal phase of nutrient absorption.
Serologic tests:
Can be treated with oral enzyme supplementation.
Presence of IgA to tissue transglutaminase most sensitive
Presence of IgA or IgG to deamidated gliadin
Anti-endomysial antibody highly specific but less sensitive

Page 10 of 18
Tropical Sprue (Environmental Enteropathy)
Prevalent in areas of poor hygiene and sanitation.
Individuals suffer from malabsorption and malnutrition, stunted
growth, and defective intestinal immune function.
Overgrowth of aerobic enteric bacteria.
Autoimmune Enteropathy
An X-linked disorder characterized by severe persistent diarrhea.
Occurs most often in young children.
Severe familial form IPEX, (Immune dysregulation,
Polyendocrinopathy, Enteropathy, X-linked).
Due to germline mutation of FOXP3 a transcription factor
expressed in CD4+ regulatory T cells, individuals with IPEX have
defect with this protein.
Lactase (Dissacharidase) Deficiency
Dissacharidases are located in the apical brush border
membrane of the villus absorptive epithelial cells.
Two types:
1.) Congenital Lactase Deficiency
Mutation in the gene encoding for lactase.
Autosomal recessive.
Presents as explosive diarrhea with atery, frothy stools and
abdominal distention upon milk ingestion.
Symptoms abate when exposure to milk is terminated.
2.) Acquired Lactase Deficiency
Caused by down-regulation of lactase gene expression.
Develop following enteric viral or bacterial infections.
Abetalipoproteinemia
Autosomal recessive disease characterized by inability to secrete
triglyceride rich protein.
Mutation in the microsomal triglyceride transfer protein (MTP)
that catalyzes transfer of lipids to specialized domains of the
nascent apopliprotein B polypeptide within the RER.
INFECTIOUS ENTEROCOLITIS
Enterocolitis can present with a broag range of symptoms
including diarrhea, abdominal pain, urgency, perianal
discomfort, incontinence, and hemorrhage.
E. coli is frequently responsible.
Cholera
Vibrio cholorae, a comma-shaped, gram-negative causes cholera.
Despite severe diarrhea, vibrios are non-invasive and remain
within the intestinal lumen.
Cholera toxin encoded by a virulence phage and released by the
organism causes the disease, composed of 5 B subunits and 1 A
subunit.
B units bind to GM1 ganglioside and carried via endocytosis to the
ER, the A subunit is reduced, unfolded, and released. The fragments
interacts with cytosolic ADP ribosylation factors (ARFs) to ribosylate
and activate G protein to stimulate adenylyl cyclase and increase
intracellular cAMP that opens CFTR allowing efflux of Cl- ions and
prevents its absorption. This results to osmotic diarrhea.
Page 11 of 18
The flagellar protein is for motility and attachment.
Hemagglutinin used for bacterial detachment and shedding.
Clinical Features
There is an abrupt onset of watery diarrhea and vomiting.
Voluminous stools resemble rice water and have fishy odor.
Rate of diarrhea may reach 1L / hour and may lead to
hypotension and dehydration.
Campylobacter Enterocolitis
Campylobacter jejuni is the most common bacterial enteric
pathogen and an important cause of travelers diarrhea.
Most are associated with ingestion of improperly cooked chiken.
Pathogenesis
Remains poorly defined but 4 virulence factors contribute:
Motility - flagella
Adherence
Toxin Production cytotoxins that cause epithelial damage,
and a cholera toxin-like enterotoxin.
Invasion
Enteric fever occurs when bacteria proliferate within lamina
propria and mesenteric lymph nodes.
Can result in reactive arthritis in patients with HLA-B27.
Diagnosis is primarily by stool culture, since biopsy findings are
non-specific and reveals acute self-limited colitis, cryptitis, and
crypt abscess.
Clinical Features
As few as 500 organisms can cause disease after 8 days.
Watery diarrhea, influenza-like prodrome.
Antibiotic therapy not required.
Shigellosis
Gram-negative, unencapsulated, non-motile, facultative aerobes.
Highly transmissible by fecal-oral route, infective dose of less
than 100 organisms.
Pathogenesis
Resistant to harsh acidic environment of the stomach, explaining
the extremely low infective dose.
Organisms are taken up by M, or microfold cells (epithelial cells
that do sampling and presentation of luminal antigens).
Proliferates intracellularly, escape into the lamina propria, and
are phagocytosed in which they induce apoptosis.
All species carry virulence plasmids that enode a Type III
secretion system, capable of directly infecting bacterial proteins.
Morphology
Most prominent in the left colon due to abundance of M cells in
the dome epithelium over Peyer patches
Mucosa is hemorrhagic and ulcerated.
Pseudomambranes may be present.
Clinical Features
1 week incubation period.
Causes self-limited disease characterized by 1 week of diarrhea,
fever, and abdominal pain.
Initially watery diarrhea progresses to a dysenteric phase.
Complications are uncommon includes a triad:
Sterile Reactive Arthritis
Urethritis
Conjunctivitis
Hemolytic Uremic Syndrome occurs after infection of S.
dysenteria serotype 1 that secretes Shiga Toxin.
Salmonellosis
Salmonella is a gram negative bacilli divided into:
S. typhi causative agent of typhoid fever
S. enteritidis non-typhoid salmonella, causes Salmonellosis
Virulence genes encode a Type III secretions system that
transport bacterial proteins to M cells that active host Rho
GTPases triggering actin rearrangement & bacterial endocytosis
Flagellin activates TLR5 on host cells and increase inflammation.
Salmonella also triggers release of eicosanoid hepatoxilin A3,
drawing neutrophils potentiating mucosal damage.
Diagnosis is via stool culture.
Symptoms range from loose stools to cholera-like diarrhea to
dysentery, fever often resolves in 2 days.
Typhoid Fever (Enteric Fever)
Caused by Salmonella enterica.
Majority are due to S. yyphi, infections among travelers are
caused by S. paratyphi. Humans are the sole reservoir.
Pathogenesis
Able to survive in gastric acid, once in the small intestine they
are taken up by M cells.
Engulfed by mononuclear cells in the underlying lymphoid tissue.
S. typhi is able to disseminate via lymphatics and blood and can
cause hyperplasia of lymphoid tissue and phagocytes.
Morphology
Infection causes Peyer patches in the terminal ileum to enlarge
to sharply delineated, plateau-like elevations up to 8 cm.
Neutrophils accumulate within the superficial lamina.
Mucosal damage creates oval ulcers oriented along the ileal axis
that may perforate.
Liver shows small, randomly scattered foci of parenchymal
necrosis in which hepatocytes are replaced by macrophage
aggregates called typhoid nodules.
Spleen in enlarged, soft with uniformly pale red pulp, obliterated
follicular markings, and prominent phagocyte hyperplasia.
Page 12 of 18
Clinical Features
Anorexia, abdominal pain, bloating, bloody diarrhea.
Rose spots, small erythematous maculopapular rashes seen on
chest and the abdomen.
Extraintestinal complications encephalopathy, endocarditis,
meningitis, serizures, myocarditis, pneumonia, cholecystitis.
Gallbladder colonization S. typhi or S. paratyphi associated
with gallstones and chronic carrier state.
Yersinia
Three Yersinia species are known human pathogens:
Y. enterocolitica GI disease
Y. pseudotuberculosis GI disease
Y. pestis bubonic and pulmonic plague
Y. enterocolitica is more common than Y. tuberculosis.
Invades M cells and use specialized bacterial proteins called
adhesins to bind to host cell 1-integrins.
A pathogenicity island encodes an iron uptake system that
mediates iron capture and transport, Iron enhances virulence
and systemic dissemination.
Morphology
Involves the ileum, appendix and right colon.
Multiple extracullarly in lymphoid tissue, resulting in hyperplasia
as well as bowel thickening.
Mucosa may become hemorrhagic and aphthous-like erosions
and ulcers may develop.
Eschecrichia coli
Gram negative bacilli that colonizes the healthy GI tract.
Most are non-pathogenic.
Classificed according to morphology, mechanism of pathogensis,
and in vitro behavior:
Enterotoxigenic E. coli (ETEC)
Enteropathogenic E. coli (EPEC)
Enterohemorrhagic E. coli (EHEC)
Enteroinvasive E. coli (EIEC)
Enteroaggregative E. coli (EAEC)
ETEC principal cause of travelers diarrhea produces heat labile
and heat stable toxin that both induce chloride and water
secretion while inhibiting intestinal fluid absorption.
EPEC- characterized by their ability to produce attachment and
effacement lesions (A/E).
EHEC categorized as E. coli O157:H7 or nonO157:H7 serotype,
produces Shiga-like toxins.
EIEC bacteriologically similar to shigella, they do not produce
toxin but hey invade epithelial cells.
EAEC Unique pattern of adherence to epithelial cells.
Pseudomembranous Colitis
Caused by Clostridium difficile, can also be referred to as
antibiotic-associated colitis, or antibiotic-associated diarrhea.
Disruption of normal colonic microbiota by antibiotics (most
rd
commonly 3 gen cephalosporins), allows C. difficile overgrowth
Toxins released cause ribosylation of GTPases and lead to
disruption of epithelial cytoskeleton, right junction barrier los,
cytokine release, and apoptosis.
Morphology
Formation of pseudomembranes, made up of adherent layer of
inflammatory cells and debris at site of mucosal injury.
May occur with ischemia or necrotizing infections.
Histopathology is pathognomonic.
Surface epithelium is denuded; superficial lamina propria
contains dense infiltrates and occasional fibrin thrombi with
capillaries.
Mucopurulent exudate that forms an eruption (volcano-like)
Clinical Features
Risk for hospitalization is advanced age, hospitalization, and
antibiotic treatment.
Protein loss can give rise to hypoalbuminemia.
Diagnosis is accomplished by detection of toxin.
Metronidazole or Vancomycin is treatment of choice.
Whipples Disease
Rare, multivisceral chronic disease.
Cause by gram-positive Tropheryma whippelil
Malbsorptive diarrhea is due to impaired lymphatic transport.
Morphology
Hallmark is dense accumulation of distended, foamy
macrophages in the small intestinal lamina propria.
The macrophages contain periodic acid-Schiff (PAS)-positive,
diastase-resistant granules that represent lysosomes stuffed
with partially digested bacteria.
Accumulate within mesenteric lymph nodes, synovial
membranes, cardiac valves, and brain.
Villous expansion imparts a shaggy gross appearance of to the
mucosal surface.
Viral Enterocolitis
Norovirus (Norwalk-like virus) causes half of gastroenteritis
outbreaks, common cause of sporadic gastroenteritis.
Rotavirus most common cause of severe childhood diarrhea
and diarrheal mortality worldwide.
Adenovirus second most common cause of pediatric diarrhea.
Parasitic Enterocolitis
Ascaris lumbricoides
Nematode that infects via fecal-orgal contamination.
Ingested eggs hatch in the intestine and larvae penetrate the
intestinal mucosa, which migrate from splanchnic to systemic
circulation, enters the lungs to grown and coughed up or
swallowed 3 weeks later.
Strongyloides
Live in fecally contaminated ground soil and can penetrate
unbroken skin.
Migrates through the lungs and induce inflammatory infiltrates,
and then reside in the intestine.
Strongyloides egg can hatch within the intestine and release
larvae that penetrate the mucosa to cause autoinfection.
Page 13 of 18
Other parasitic worms:
Necator duodenale, Ancylostoma duodenale
Enterobius vermicularis
Trichuris trichiura
Schistosoma
Diphyllobothrium latum
Taenia solium, Taenia saginata
Hymenolepis nana
Entamoeba hystolitica
Causes amebiasis, spread via oral fecal route.
Have chitin wall and four nuclei, resistant to gastric acid.
Most frequently affects the cecum and ascending colon.
Dysentery develops when amebae attach to the epithelium,
induce apoptosis, invade crypts, and burro laterally into the
lamina propria.
Creates a flask-shaped ulcer with narrow neck and broad base
Penetrates splanchnic vessels and embolize to the liver
producing abscesses.
Giardia lamblia
Most common pathogenic parasitic infection in human,
transmitted via fecally contaminated water.
Infection may occur after ingestion of as few as 10 cysts.
Cysts are resistant to chlorine.
They are flagellated protozoans that cause decreased expression
of brush-border enzymes, they also cause microvilli damage and
apoptosis of intestinal cells.
Secretory IgA and mucosal IL-6 are important for clearance.
Cryptosporidium
Humans are infected by C. hominis and C. parvum.
Causes acute, self-limited diarrhea in normal hosts.
Causes chronic diarrhea in AIDS patient.
Most common mode of transmission is via contaminated water
Ingested encysted oocyte of which 10 are sufficient to infect.
Concentrated in the terminal ileum and proximal colon.
IRRITABLE BOWEL SYNDROME
Characterized by chronic, relapsing abdominal pain, bloating,
and changes in bowel habits.
Gross and microscopic evaluations are normal.
It should be recognized that IBS is a syndrome, and the multiple
illnesses are represented under this global descriptor.
IBS is divided into different criteria defined using Rome Criteria.
Pathogenesis remains poorly understood.
Peak prevalence is 20-40 y/o and variability in diagnostic criteria
makes it difficult to establish incidence.
INFLAMMATORY BOWEL DISEASE
A chronic condition resulting from inappropriate mucosal
immune activation.
Two disorders that comprise IBD are:
Crohn Disease Regional enteritis, frequent ileal
involvement, and may involve any area of the GI tract,
typically transmural.
Ulcerative Colitis limited to the colon and rectum, extends
only into the mucosa and submucosa.
Page 14 of 18
Pathogenesis
IBD is idiopathic
Most believe that IBD results from combined effects of
alterations in host interactions with intestinal microbiota,
intestinal epithelial dysfunction, and altered gut microbiome.
Crohn Disease
May occur in any area of the GI tract, most common sites
involved are the terminal ileum, ileocecal valve, and cecum.
Limited to small intestine alone (40%), involvement of both large
and small intestine (30%).
Skip lesions multiple, separate, sharply delineated areas.
Earliest lesion is aphthous ulcer, may coalesce into elongated,
serpentine ulcers along the axis of the bowel.
Results in coarsely textured, cobblestone appearance.
Fissures frequently develop between mucosal folds.
In extensive transmural disease, mesenteric fat frequently
extends around serosal surfaces (Creeping Fat).
Abundant neutrophils that infiltrate and damage crypt
epithelium, referred to as crypt abscesses.
Repeated cycles of crypt destruction and regeneration leads to
distortion of mucosal architecture.
Paneth Cell metaplasia may also occur in the left colon where it
is normally absent.
Non-caseating granulomas is the hallmark of Crohn disease.
Cutaneous granulomas form nodules that are referred to as
metastatic Crohn disease.
Clinical Features
Intermittent attacks of relatively mild diarrhea, fever, and
abdominal pain.
20% experience RLQ pain, fever, and bloody diarrhea.
May mimic acute appendicitis or bowel perforation.
Periods of active disease are typically interrupted by
asymptomatic periods that last for weeks to many months.
Iron deficiency anemia may develop in individuals with colonic
disease, while extensive small bowel disease may result in
protein loss and hypoalbuminemia.
Malabsoprtion of B12 and Bile Salts.
Fibrosing strictures particularly at the terminal ileum
Extraintestinal manifestations Uveitis, Polyarhtritis, Acroilitis,
Ankylosing Spondylitis, Clubbing of fingers.
Ulcerative Colitis
Always involves the rectum and extends proximally.
Disease of the entire colon is termed pancolitis.
Limited distal disease may be referred as ulcerative proctitis or
ulcerative proctosigmoiditis.
Grossly, involved colonic mucosa may be slightly red and
granular, or have extensive, broad-based ulcers.
Isolated islands of regenerating mucosa bulge into the lumen to
create pseudopolyps the tips may fuse & create mucosal bridges
Chronic disease may lead to mucosal atrophy with a flat smooth
muscle surface that lacks normal folds.
Mural thickening is NOT present, serosal surface is normal, and
strictures do NOT occur.
Inflammatory infiltrates is diffuse and limited to the mucosa and
submucosa, can damage the muscularis propria and disturb
neuromuscular function leading to colonic dilation and toxic
megacolon that carries a significant risk of perforation.
Crypt abscess, architectural crypt distortion is also present.
Pseudopyloric epithelial metaplasia is present.
Granulomas are NOT present.
Clinical Features
A relapsing disorder characterized by attacks of bloody diarrhea
with stringy mucoid material, lower abdominal pain, cramps
relieved by defecation.
Persists for days, weeks, or months before subsiding.
Most have clinically mild disease.
At least one experience relapses during a 10 year period.
SIGMOID DIVERTICULITIS
Diverticular disease generally refers to acquires pseudo-
diverticular outpouchings of the colonic mucosa and submucosa.
They are not invested by all three layers of the colonic wall.
Results from unique structure of colonic muscular propria and
elevated intraluminal pressure of the sigmoid colon.
Morphology
Small, flask-like outpouchings, usually 0.5 to 1 cm in diameter.
Occurs in regular distribution alongside the taeniae coli (epiploic
appendages), most common in the sigmoid colon.
Histologically thin walled, composed of flattened atrophic
mucosa, compressed submucosa, attenuated or, most often
absent muscularis propria, hypertrophy of the circular layer.
POLYPS
Most common in the colo-rectal region.
Polyps are begin as small elevations of the mucosa, referred to
as sessile, as it enlarge, proliferation adjacent to the mass and
the effects of traction create a stalk, not called pedunculated.
Most common neoplastic polyp is the adenoma, which has the
potential to progress to cancer.
The non-neoplastic polyps can be further classified into:
inflammatory, hamartomatous, or hyperplastic.
Page 15 of 18
Non-neoplastic polyps
Hyperplastic Polyps
Benign epithelial proliferations that are typically discovered on
th th
6 to 7 decade of life.
Thought to result from decreased epithelial cell turnover and
delayed shedding of surface epithelial cells, leading to pilling up.
Chief significance is that they must be distinguished from
serrated adenomas which have malignant potential.
Commonly found in the left colon, less than 5mm.
Smooth nodular protrusions of the mucosa, often on the crests
of mucosal folds.
Composed of mature goblet cells and absorptive cells.
Hallmark is serrated surface architecture.
Inflammatory Polyps
Form as part of the solitary rectal ulcer syndrome is an example.
Presents with clinical triad:
Rectal bleeding
Mucus discharge
Inflammatory lesion of the anterior rectal wall.
Underlying cause is impaired relaxation of the anorectal
sphincter that creates a sharp angle at the anterior rectal shelf
leading to recurrent abrasion.
Entrapment of this polyp leads to mucosal prolapse.
Distinctive feature is a typical inflammatory polyp include mixed
inflammatory infiltrates, erosion, and epithelial hyperplasia.
Hamartomatous Polyps
Occur sporadically or as a component of various genetically
determined or acquired syndromes.
Juvenile Polyps
Focal malformations of the epithelium and lamina propria.
Vast majority occur in children younger than 5 y/o.
Most are located in the rectum and typically present with rectal
bleeding, or sometimes intussusception or polyp prolapse.
Usually solitary, also called retention polyps.
Most common mutation is SMAD4.
Typically less than 3 cm, pedunculated, smooth-surfaced,
reddish lesions with cystic spaces after sectioning.
Histologically, has dilated glands filled with mucin and
inflammatory debris and mixed inflammatory infiltrates.
Peutz-Jeghers Syndrome
Rare autosomal dominant syndrome presents at a median age of
11 years with multiple GI hamartomatous polyps and
mucocutaneous hyperpigmentation.
Hyperpigmentation takes the form of dark blue to brown
macules on lips, nostrils, buccal mucosa, palmar surface.
Associated w/ a markedly increased risk of several malignancies
Germline heterozygous loss-of-function mutations in STK11.
Polyps are most common in the small intestine.
Grossly, large and pedunculated with a lobulated contour.
Histologically demonstrates an arborizing network of connective
tissue, smooth muscle, lamina propria, and glands lined by
normal-appearing intestinal epithelium.
Cowden Syndrome, Bannayan-Ruvalcalba-Riley Syndrome Patterns of Colorectal Carcinoma
Autosomal dominant hamartomatous polyp syndrome. Etiology Molecular Defect Gene Transmission
Loss of function mutation in PTEN. FAP (70%) APC/WNT Pathway APC Autosomal
GI hamartomatous polyps, lipoma, macrocephaly, hemangiomas, dominant
and pigmented macules on gland penis In males. FAP (<10%) DNA mismatch repair MUTYH None, Autosomal
BRR Syndrome mental deficiency and developmental delays. recessive
HNPCC DNA mismatch repair MSH2, Autosomal
Cronkhite-Canada Syndrome MLH1 dominant
Unknown cause Sporadic APC/WNT pathway APC None
Hamartomatous polyps of the stomach, small intestine, and Colonic CA
colorectum. (80%)
Non-polypoid intervening stroma shows crypt dilation and Sporadic DNA mismatch repair MSH2, None
lamina propria edema and inflammation. Colonic CA MLH1
Nail atrophy and splitting, hair loss, cutaneous hyper- and (10-15%)
hypopigmentation.
HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (HNPCC)
Neoplastic Polyps Also known as Lynch Syndrome.
Any neoplastic lesion may produce mucosal protrusion. Tends to occur at younger ages in the right colon.
Most common neoplastic polyps are colonic adenomas which HNPCC is caused by inherited mutations in genes that encode
precursor to majority of colorectal adenocarcinoma. proteins responsible for the detection, excision, and repair of
errors during DNA replication.
Adenomas
Small, often pedunculated with fibromuscular stalks to sessile. ADENOCARCINOMA
Typically range from 0.3-10 cm in diameter.
Presence of epithelial dysplasia: nuclear hyperchromasia,
elongation, and stratification.
Can be classified as:
Tubular small, pedunculated with small rounded glands.
Tubulovillous
Villous larger and sessile, with slender villi
Sessile Serrated Adenomas overlap histologically with
hyperplastic polyps, but are more commonly found in the right
colon.
Intramucosal carcinoma occurs when dysplastic epithelial cells
breach the basement membrane to invade the lamina propria or
muscularis mucosa.
Size is the most important characteristic that correlates with risk
of malignancy. Adenocarcinoma is the most common malignancy of GI tract.
The classic adenoma-carcinoma sequence accounts up to 80% of
ADENOMATOUS POLYPOSIS sporadic colon tumors, typically includes mutation of APC early
Familial Adenomatous Polyposis is an autosomal dominant in the neoplastic process.
disorder in which patients develop numerous colorectal Both copies of the APC genes must be functionally inactivated
adenomas as teenagers. either by mutation or epigenetics, for adenomas to develop,
Mutations of the adenomatous polyposis coli or APC gene. APC is a key negative regulator of -catenin, a component of
At least 100 polyps are necessary for diagnosis of classic FAP. the Wnt signaling pathway.
Colorectal adenocarcinoma develops in 100% of untreated FAP, APC promotes degradation of -catenin, loss of function results
often develops often before age 30. to accumulation of -catenin and translocates it to the nucleus
Potential neoplasia at other sites: Ampulla of vater and Stomach where it activates MYC transcription and cyclin D1 that
Extraintestinal manifestations: Hypertrophy of retinal pigment promotes proliferation.
epithelium. This is followed by K-RAS mutations that promote growth and
Variants: prevent apoptosis.
Gardner Syndrome Neoplastic progression is associated with SMAD2 and SMAD4
Osteoma of mandible, skull, long bones, epidermal cysts, which leads to loss of TGF- signaling pathway, allowing
desmoid tumors, thyroid and dental abnormalities. unrestrained cell growth.
Turcot Syndrome P53 is mutated and loss of function together with other tumor
Intestinal adenoma suppressor gene is often caused by chromosomal deletions.
CNS tumors medullobastomas. Expression of telomerase increases as the lesion advances.

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Colon Carcinogenesis
In patients with DNA mismatch repair, mutations accumulate in
microsatellite repeats a condition referred to as microsatellite
instability (MSI).
The microsatellite sequences are located in the promoter or
coding regions of genes involved in regulation of cell growth.
Mutation of Type II TGF- receptor contributes to
uncontrolled cell growth.
Loss of BAX enhances survival of abnormal clones.
BRAF Mutations
Methylation of specific targets such as MLH1
A subset called CpG island hypermethylation phenotype (CIMP)
has a hypermethylated MLH1 promoter region, thereby reducing
MLH1 expression and repair function.
Morphology
Overall distributed approximately equally over the entire length
of the colon.
Proximal Colon often polypoid, exophytic that extend along
one wall of the cecum and asc. colon, may cause obstruction.
Distal Colon tend to be annular lesions having a napkin-ring
constrictions and luminal narrowing.
Most tumors are composed of columnar cells that resemble
dysplastic epithelium found in adenomas.
Invasive component of these tumors elicit a strong stromal
desmoplastic response, which is responsible for its firmness.
May or may not produce mucin that may accumulate.
Clinical Features
Right sided adenocarcinomas fatigue, weakness due to iron
deficiency anemia.
Left sided adenocarcinoma may produce occult bleeding,
changes in bowel habits, or cramping and LLQ pain.
Two most important prognostic factors:
Depth of Invasion
Presence or absence of lymph node metastasis
The liver is the most common site of metastatic lesions.
(See last page for grading and staging system)
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TUMORS OF THE ANAL CANAL
The anal canal can be divided into thirds:
Upper zone lined by columnar rectal epithelium
Middle zone lined by transitional epithelium
Lower zone lined by stratified squamous epithelium
Carcinomas of the anal canal may have typical glandular or
squamous patterns of differentiation.
Basaloid pattern is present in tumors populated by immature
cells derived from the basal transitional epithelium, may be
mixed with squamous or mucinous differentiation.
Cloacogenic carcinoma the entire tumor displays basaloid
pattern.
Pure Squamous Cell Carcinoma of the anal canal is related to
HPV infections.
Hemorrhoids
Develop secondary to persistently elevated venous pressure
within the hemorrhoidal plexus.
Most frequent predisposing factors are straining on defecation
due to constipation, and venous stasis in pregnancy.
Can also occur in portal hypertension.
Often presents with pain and rectal bleeding, particularly bright
red blood.
Can be treated by sclerotherapy, rubber band ligation, or
infrared coagulation. Severe cases undergo hemorrhoidectomy.
Morphology
Collateral vessels within the inferior hemorrhoidal plexus below
the anorectal line are termed external hemorrhoids.
Dilation of the superior hemorrhoidal plexus within the distal
rectum is termed internal hemorrhoids.
Consists of thin-walled, dilated, submucosal vessels.
ACUTE APPENDICITS
Appendix is a normal true diverticulum of the cecum that is
prone to acute and chronic inflammation.
Acute appendicitis is initiated by progressive increases in
intraluminal pressure that compromise venous outflow.
In 50-8)% of cases, it is associated with overt obstruction usually
caused by stone-like mass of stool, fecalith, gallstone, tumor, or
mass of worms (Oxyuriasis vermicularis).
Stasis of luminal contents favors bacterial proliferation,
triggering ischemia and inflammatory responses.
Morphology
Early acute appendicitis subserosal vessels are congested,
modest perivascular neutrophilic infiltrate in all layers.
Diagnosis of acute appendicitis requires neutrophilic infiltration
of the muscularis propria.
Focal abscesses may form within the wall (acute suppurative).
Further compromise of vessels lead to gangrenous appendicitis.
Clinical Features
Periumbilical pain, localized to RLQ, nausea, vomiting, low grade
fever, mild leukocytosis.
Mc Burneys Sign deep tenderness 2/3 from umbilicus to the
right anterior superior iliac spine.
 Complications: Pyelophlebitis, Portal Vein Thrombosis, Liver TUMORS OF THE PERITONEAL CAVITY
Abscess, and bacteremia. Primary tumors
Mesothelioma asbestos exposure
TUMORS OF THE APPENDIX Desmoplastic Small Round cell tumor aggressive tumor
Most common is a carcinoid tumor. that occurs in children and young adults, resembles Ewing
Most commonly involves the distal tip of the appendix. sarcoma, characterized by reciprocal chromosomal
It produces solid bulbous swelling, 2-3 cm in diameter. translocation t(11;12)(p13q12)
Secondary Tumors
Mucocele Peritoneal carcinomatosis direct spread or metastasis.
A dilated appendix filled with mucin. Ovarian and pancreatic adenocarcinoma
May simply represent obstructed appendix containing mucin. Appendicieal mucinous carcinoma produces
May be a consequence of mucinous cystadenoma or mucinous pseudomyxoma peritonei.
cystadenocarcinoma. ________________________________________________________
Pseudomyxoma peritonei in severe cases, the abdomen fills
with tenacious, semisolid mucin.

Peritoneal Cavity
Inflammatory Disease
Peritonitis may result from bacterial invasion or chemical
irritation most often due to:
Leakage of bile or pancreatic enzymes (Sterile Peritonitis)
Perforation or rupture of biliary system
Acute hemorrhagic pancreatitis
Foreign material induces foreign-body type granulomas
and fibrous scarring.
Endometriosis can cause hemorrhage into the cavity
Ruptured dermoid cysts releases keratins and induce
intense granulomatous reaction
Perforation of the viscera

Peritoneal Infection
Occurs when bacteria from the lumen are released to the
abdominal cavity most commonly following perforation.
Most common pathogens: E. coli, Streptococci, S. aureus,
enterococci, C. perfringens.
Spontaneous bacterial peritonitis develops in the absence of
obvious source of contamination.
Bacterial peritonitis occurs most commonly as a complication of
acute appendicitis, peptic ulcer, cholecystitis, diverticulitis and
intestinal ischemia, acute salpingitis, abdominal trauma and
periotoneal dialysis.
Dense collections of neutrophils and fibrinopurulent debris that
coat the viscera and abdominal wall.
Subhepaic and subdiaphragmatic abscesses may be formed.

Sclerosing Retroperitonitis (Ormond Disease)

Also known as idiopathic retroperitoneal fibrosis.
Dense fibrosis that may extend and involve the mesentery.
Related with IgG4-related sclerosis diseases.

CYST IN THE ABDOMINAL CAVIY

Blind lmphatic channels.
Foregut or hindgut diverticula that pinch off during development
Urogenital ridge or its derivatives.
Walled-off infection
Sequealae of pancreatitis (pseudocyst)

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