Gastro Intestinal

Pathology
Objectives
• Categorize the etiology of diseases of Gastrointestinal tract
• Explain the pathogenesis with regards to the etiology of diseases
• Describe the microscopic and macroscopic morphology of diseases of
the diseases of Gastrointestinal tract
• Explain the clinical manifestations based on the pathogenesis
Integrate the etiology, pathogenesis, morphology with the clinical
presentation/manifestation
Gastrointestinal Tract
CONGENITAL ABNORMALITIES
• Atresia: In esophageal atresia, a
portion of the conduit is replaced
by a thin, noncanalized cord, with
blind pouches above and below
the atretic segment
• Fistula: A connection between
the esophagus and the trachea
or a mainstem bronchus
CONGENITAL ABNORMALITIES
• Stenosis: An incomplete form of atresia; the lumen is
reduced by a fibrous thickened wall
• Congenital duplication cysts: Cystic masses with
redundant smooth muscle layers
Diaphragmatic Hernia, Omphalocele,
and Gastroschisis, Ectopia
• Diaphragmatic hernia occurs when incomplete formation of the
diaphragm allows cephalad displacement of abdominal viscera
• Omphalocele occurs when abdominal musculature is incomplete and
the viscera herniate into the ventral membranous sac
• Gastroschisis is similar to omphalocele except that all layers of the
abdominal wall (from peritoneum to skin) fail to develop.
• Ectopia
• most common site for gastric mucosa ectopia is the proximal esophagus,
leading to dysphagia and esophagitis
• Pancreatic heterotopia occurs in esophagus and stomach; in the pylorus, it can
cause inflammation, scarring, and obstruction.
Diaphragmatic Hernia, Omphalocele,
and Gastroschisis, Ectopia
Meckel Diverticulum
• A true diverticulum is a blind pouch leading off the alimentary tract, lined by mucosa
and including all three layers of the bowel wall
• the most common (2% of the population)—result from persistence of the vitelline
duct (connecting yolk sac and gut lumen):
• leaving a solitary outpouching within 85 cm of the ileocecal valve
• the male to female ratio is 2:1
• Rule of 2’s
• occur in 2% of the population
• are 2 inches (5 cm) long
• are 2 feet (60 cm) from the ileocecal valve
• 2/3 have ectopic mucosa
• 2 types of ectopic tissue are commonly present (mostly gastric and pancreatic)
• Most common age at clinical presentation is 2 years
Pyloric Stenosis
• Congenital hypertrophic pyloric stenosis
• there is a complex polygeneic inheritance and associations with Turner
syndrome and trisomy 18
• present with regurgitation and projectile vomiting within 3 weeks of birth
• Acquired pyloric stenosis is a complication of chronic antral gastritis,
peptic ulcers close to the pylorus, and malignancy
Hirschsprung Disease
• this disorder results from arrested migration of neural crest cells into
the gut, yielding an aganglionic segment lacking peristaltic
contractions
• genetic component in most cases.
• Heterozygous loss-offunction mutations in the RET tyrosine kinase receptor
accounts for 15% of sporadic cases and the majority of familial cases
• presents with neonatal failure to pass meconium or abdominal
distention with severely distended megacolon (up to 20 cm in
diameter);
• patients risk perforation, sepsis, or enterocolitis with fluid derangement
• Hirschsprung disease
Esophagus
Esophageal Obstruction
• Spasm can be short- or long-lived and focal or diffuse
• Diverticula if sufficiently large they can accumulate enough food to
present as a mass with food regurgitation
• Zenker (pharyngeoesophageal) diverticulum occurs immediately above the upper
esophageal sphincter
• Traction diverticulum occurs at the esophageal mid-point
• Epiphrenic diverticulum occurs immediately above the lower esophageal
sphincter
• Mucosal webs are ledgelike protrusions of fibrovascular tissue and
overlying epithelium
• Plummer-Vinson syndrome - webs, iron deficiency anemia, glossitis, and cheilosis
Achalasia
• Triad of incomplete relaxation of the lower esophageal sphincter (LES),
increased LES tone (due to cholinergic signaling), and esophageal
aperistalsis
• Primary achalasia
• Idiopathic and results from failure of distal esophageal neurons to induce LES
relaxation during swallowing
• Secondary achalasia
• Chagas disease (Trypanosoma cruzi)
• Disorders of the vagal dorsal motor nuclei
• Diabetic autonomic neuropathy
• Infiltrative disorders (e.g., malignancy, amyloidosis, sarcoidosis)
Esophagitis
• Mallory-Weiss tears are longitudinal lacerations (millimeters to
centimeters in length) at the gastroesophageal junction associated
with excessive vomiting
• Chemical and Infectious Esophagitis
• Dense neutrophilic infiltrates are most common
• Candidiasis, when severe, is associated with adherent grey-white
pseudomembranes
• Herpes viruses typically cause punched-out ulcers
• CMV presents with shallower ulcerations with characteristic viral inclusions
• Lesions associated with esophageal GVHD or blistering disorders
Esophagitis
• Reflux Esophagitis
• caused by decreased LES tone and/or increased abdominal pressure
• can be exacerbated by
• alcohol, tobacco use, obesity, central nervous system (CNS) depressants, pregnancy,
delayed gastric emptying, or increased gastric volume.
• Hiatal hernia is also a cause of GERD
• occurs when the diaphragmatic crura are separated and the stomach protrudes into the
thorax
• Symptoms include dysphagia, heartburn, and regurgitation of gastric contents
into the mouth.
• Complications of long-standing reflux include ulceration, hematemesis,
melena, stricture, or Barrett esophagus
Barrett Esophagus
• Gross: Patches of red, velvety mucosa extend up from the
gastroesophageal junction
• Microscopic: intestinal metaplasia within the esophageal squamous
mucosa
• When present, dysplasia is classified as low or high grade.
• Intramucosal carcinoma is characterized by neoplastic cell invasion into the
lamina propria
• Confers an increased risk of esophageal adenocarcinoma;
• pre-invasive dysplasia is detected each year in 0.2% to 2% of patients with
Barrett esophagus
Esophageal Varices
• Severe portal hypertension induces collateral bypass channels
between the portal and caval circulations leading to congested
subepithelial and submucosal veins in the distal esophagus (varices)
• Varices are clinically silent until they rupture with catastrophic
hematemesis;
• causes of rupture include inflammatory erosion, increased venous pressure,
and increased hydrostatic pressure associated with vomiting
Esophageal Tumors
• Adenocarcinoma
• largely evolve from dysplastic changes in Barrett mucosa
• Chromosomal and p53 abnormalities occur early; additional changes include
amplification of c-ERB-B2 and cyclin D1 and E genes and mutations in Rb and
the p16/INK4a cyclin-dependent kinase inhibitor

• Grossly:
• Lesions range from exophytic nodules to excavated and deeply infiltrative masses
• Microscopically:
• Tumors typically produce mucin and form glands, often with intestinal-type morphology;
• Diffusely infiltrative signet ring tumors are less common, and the histology rarely reveals
adenosquamous or small poorly differentiated cells.
Esophageal Tumors
• Squamous Cell Carcinoma
• Risk factors include alcohol and tobacco use, caustic esophageal injury,
achalasia, Plummer-Vinson syndrome, and frequent consumption of scalding
hot beverages

• Onset is insidious and symptom onset is late;

• Patients develop dysphagia, obstruction, weight loss, hemorrhage, sepsis
secondary to ulceration, or respiratory fistulae with aspiration.
• Superficial carcinomas have a 5-year survival rate of 75%, but the overall 5-
year survival rate is 9%.
Esophageal Tumors
• Squamous Cell Carcinoma
• Fungating / exophytic / polypoid
lesions (most common), Ulcerative
• Usually moderate to well
differentiated
• Tumor clusters may be present
distant from main mass (intramural
metastases) due to lymphatic
spread through submucosa
• Tumor cells often exhibit
keratinization and have
intercellular bridges
Other tumors
• Benign tumors are usually mesenchymal in origin and arise in the
esophageal wall; leiomyomas are most common, but fibromas,
lipomas, hemangiomas, neurofibromas, and lymphangiomas also
occur.
Stomach
Acute Gastritis
• Acute gastric ulceration refers to focal,
acute mucosal defects.
• These commonly occur as a complication
of NSAID use or as a consequence of
severe physiologic stress:
• Stress ulcers occur after shock, sepsis, or
severe trauma.
• Curling ulcers occur in the proximal
duodenum and are associated with burns
or trauma.
• Cushing ulcers are gastric, duodenal, and
esophageal ulcers arising in patients with
intracranial disease; they have a high risk of
perforation.
Acute Gastritis
Chronic Gastritis
• Helicobacter Pylori Gastritis
• H. pylori induces predominantly an antral gastritis, characterized by increased
acid production and disruption of the normal mucosal protection mechanisms
• Virulence factors in H. pylori infections include:
• Motility via flagella
• Urease production buffering gastric acid
• Bacterial adhesins to bind surface epithelial cells
• Toxins (e.g., cagA and vacA cytotoxins)
• H. pylori infection is a risk factor for peptic ulcer disease, gastric
adenocarcinoma, and gastric lymphoma.
• Chronic Gastritis • H. pylori
Chronic Gastritis
• Autoimmune Gastritis
• This form of gastritis typically spares the antrum and is associated with
hypergastrinemia
• CD4+ T cell-mediated autoimmune destruction of parietal cells is the major
pathogenic mechanism
• Autoantibodies are detected early in the course;
• Progression to gastric atrophy occurs over 20 to 30 years.
• Patients present with symptoms referable to anemia; B12 deficiency can also
manifest with atrophic glossitis, malabsorption, peripheral neuropathy, spinal
cord lesions, and cerebral dysfunction
Complications of Chronic Gastritis
• Peptic Ulcer Disease
• typically occurs in the first portion of the duodenum or the antrum (4:1 ratio).
• The most common causes are H. pylori–induced hyperchlorhydric chronic
gastritis and NSAID use
• Hyperacidity in PUD can be caused by infection, parietal cell hyperplasia,
excessive secretory response, or increased gastrin production
• NSAIDs and steroids block the normal prostaglandin cytoprotective effects
(discussed previously), and cigarette smoking impairs mucosal blood flow and
healing
Complications of Chronic Gastritis
• Dysplasia
• Long-standing, chronic gastritis exposes epithelium to inflammation- related
free radical damage and proliferative stimuli.
• Over time, the combination can lead to the accumulation of genetic
alterations resulting in carcinoma
• Pre-invasive in situ lesions can be recognized histologically as dysplasia
Hypertrophic Gastropathies
• Menetrier Disease
• There is diffuse foveolar cell hyperplasia, with a protein-losing enteropathy
that causes systemic hypoproteinemia.
• caused by overexpression of transforming growth factor-a (TGF-a).
• Risk of gastric adenocarcinoma is increased.
• Zollinger-Ellison Syndrome
• caused by gastrin-secreting tumors (gastrinomas) typically in the small bowel
or pancreas.
• Patients classically present with multiple duodenal ulcers and/or chronic
diarrhea
Gastric Polyps and Tumors
• Inflammatory and Hyperplastic Polyps
• most common between ages 50 and 60 years, and they typically arise in
association with chronic gastritis
• Risk of dysplasia increases with size; polyps more than 1.5 cm should be
resected.
• Fundic Gland Polyps
• occur sporadically (typically in women older than 50 years) or in the setting of
familial adenomatous polyposis (FAP)
• incidence is also increased by proton pump inhibitors and the consequent
increased gastrin secretion
• are single or multiple, smooth, well-circumscribed lesions composed of
irregular, cystically dilated glands with minimal inflammation
Gastric Polyps and Tumors
• Gastric Adenoma
• Almost always occur on a background of FAP or chronic gastritis with atrophy
and intestinal metaplasia
• Usually solitary and less than 2 cm, gastric adenomas all exhibit some degree
of dysplasia;
• 30% can harbor carcinoma, and lesions more than 2 cm are particularly
concerning.
Gastric Polyps and Tumors
• Gastric Adenocarcinoma
• The epidemiology suggests a role for environmental factors (e.g., H. pylori
infections). Diet also influences risk
• Divided into intestinal and diffuse forms with different risk factors, genetic
perturbations, and clinical and pathologic presentations
• Loss of intercellular adhesion is a key step in oncogenesis, particularly of
diffuse gastric cancer
• Intestinal- type gastric cancers are associated with FAP, mutations in proteins
that associate with E-cadherin (e.g., b-catenin), microsatellite instability, and
hypermethylation of TGFbRII, BAX, IGFRII, and p16/INK4a
Gastric Polyps and Tumors

Diffuse type Intestinal type

Gastric Polyps and Tumors
• Gastric Adenocarcinoma
• Prognosis critically depends on depth of invasion and the extent of nodal or
distant metastases.
• After surgical resection, the 5-year survival of early gastric cancer is more
than 90%, even with nodal spread; in comparison, advanced gastric cancer
has a 5-year survival of less than 20%.
• Overall, 5-year survival in the United States is 30%.
Gastric Polyps and Tumors
• Lymphoma
• Extranodal marginal B-cell lymphomas arise at sites of chronic inflammation.
In the stomach, this is typically associated with chronic H. pylori infection
• antibiotic treatment can induce tumor regression
• Antibiotic-resistant tumors often harbor a t(11;18) translocation
• these MALTomas can transform into the more aggressive diffuse large B-cell
lymphomas, often associated with inactivation of p53 and/or p16 tumor
suppressor genes.
Gastric Polyps and Tumors
• Carcinoid Tumor
• arise from diffusely distributed endocrine cells
• the cells of origin in the gastrointestinal tract are responsible for hormone
secretion that coordinates gastrointestinal function
• Carcinoids are usually indolent, slow-growing malignancies, and symptoms
are largely a function of the hormones produced.
• cutaneous flushing, bronchospasm, increased bowel motility, and right-sided cardiac
valve thickening (carcinoid syndrome)
• Carcinoid syndrome occurs in 10% or less of patients with gastrointestinal
carcinoid due to hepatic catabolism of the secreted products;
• presence of the syndrome is therefore usually associated with bulky hepatic metastatic
disease
Gastric Polyps and Tumors
• Gastrointestinal Stromal Tumor
• Peak age of GIST diagnosis is approximately age 60 years; incidence is
increased in patients with neurofibromatosis type I, and in children (usually
girls) with Carney triad
• appear to arise from the interstitial cells of Cajal in the muscularis propria
• 80% of all GISTs contain oncogenic gain-of-function mutations in the gene
coding for the tyrosine kinase c-KIT
• Symptoms are usually related to mass effects or blood loss. Surgical resection
is the primary treatment for localized gastric GIST. Metastases are rare when
tumors are less than 5 cm but common when more than 10 cm.
GIST
• C-kit
Small Intestine and Colon
Intestinal Obstruction
Ischemic Bowel Disease
• abrupt compromise of any major vessel can cause infarction of
several meters of intestine.
• Watershed zones between major vessel branches (e.g., the splenic
flexure between superior and inferior mesenteric artery circulations)
are most vulnerable
• causes of ischemia are:
• atherosclerosis, aortic aneurysm, hypercoagulable states, embolization, and
vasculitis; hypoperfusion can also be associated with cardiac failure, shock,
dehydration, or vasoconstrictive drugs.
• Mesenteric venous obstruction or thrombosis due to hypercoagulability,
masses, or cirrhosis can also cause ischemic disease
Ischemic Bowel Disease
• Typically occurring in older individuals with coexisting cardiac or
vascular disease, ischemic bowel presents with severe abdominal
pain, bloody diarrhea or gross melena, abdominal rigidity, nausea,
and vomiting.
• Patients can progress to shock within hours, and mortality can exceed
50%.
Angiodysplasia
• Lesions of angiodysplasia are tortuous, ectatic dilations of mucosal or
submucosal veins occurring in approximately 1% of the population;
most common in the cecum or ascending colon (usually after age 60),
• angiodysplasia accounts for 20% of major episodes of lower
gastrointestinal bleeding
Malabsorption
Celiac Disease
• gluten-sensitive enteropathy or celiac sprue, celiac disease is an
immune-mediated diarrheal disorder triggered by ingestion of gluten-
containing foods
• delayed-type hypersensitivity, specifically directed against a 33 amino acid a-
gliadin polypeptide resistant to digestive enzymes
Celiac Disease
• Morphology
• Diffusely flattened (atrophic) villi
and elongated regenerative crypts
are associated with intraepithelial
CD8þ T cells and exuberant lamina
propria chronic inflammation.
• Severity is greatest in the more
proximal intestine
Celiac Disease
• occurs in infants to middle-aged people who present with diarrhea,
flatulence, weight loss, and the effects of anemia.
• The most sensitive serologic test assesses the presence of
immunoglobulin A (IgA) antibodies to tissue transglutaminase, or IgA
or IgG to deamidated gliadin.
Tropical Sprue
• occurs almost exclusively in people inhabiting or visiting tropical
climes.
• The histology is similar to celiac disease, although the distal small
bowel is most severely affected.
• An infectious etiology is implicated, and broad-spectrum antibiotics
aid recovery
Autoimmune Enteropathy
• an X-linked disorder of children characterized by a persistent auto-
immune–driven diarrhea
• A severe familial form (immune dysregulation, polyendocrinopathy,
enteropathy, and X-linked [IPEX]) is due to germline mutations in the
FOXP3 gene, a transcription factor responsible for the differentiation
of CD4+ regulatory T cells.
• Autoantibodies to a variety of gastrointestinal epithelial cell types
may be present
Lactase (Disaccharidase) Deficiency
• With lactase deficiency, undigested and unabsorbed lactose exerts an
osmotic pull, causing diarrhea and malabsorption;
• Bacterial fermentation of lactose can also cause abdominal distention
and flatus.
Abetalipoproteinemia
• rare autosomal recessive disease caused by inability of lipids to egress
absorptive epithelial cells.
• The underlying defect is a mutation in the microsomal triglyceride
transfer protein (MTP)
• responsible for lipoprotein and fatty acid export from mucosal cells
• Affected infants present with failure to thrive, diarrhea, and
steatorrhea, as well as complete absence of all lipoproteins
containing apolipoprotein B
• Failure to absorb essential fatty acids leads to deficiencies of fat-
soluble vitamins as well as lipid membrane defects.
Reading Assignment: Infectious
Enterocolitis (Review your
Micro)
Irritable Bowel Syndrome
• is characterized by chronic, relapsing abdominal pain, bloating, and
changes in stool frequency or form;
• it is most common in women between the ages of 20 and 40 years.
• IBS results from interplay of psychologic stressors, diet, and abnormal
gastrointesinal motility, perhaps via disruption of signaling in the
brain-gut axis
Inflammatory Bowel Disease
• results from inappropriate mucosal immune responses to normal gut
flora; it comprises two disorders
• Ulcerative colitis (UC)—severe ulcerating inflammation extending into
the mucosa and submucosa, and limited to the colon and rectum.
• Crohn disease (CD; also called regional enteritis)—typically
transmural inflammation, occurring anywhere in the gastrointestinal
trac
Inflammatory Bowel Disease
• IBD results from a combination of defects in host interactions with
gastrointestinal flora, intestinal epithelial dysfunction, and aberrant
mucosal immunity.
• The current prevailing model is that transepithelial flux of microbes activates
innate and adaptive immune responses
Crohns vs UC (Gross and Microscopic)

Crohns UC
Sigmoid Diverticulitis
• Acquired colonic pseudodiverticular outpouchings (diverticulosis) are
uncommon in patients younger than 30 years but occur in 50% of
Western populations older than 60 years.
• Focal bowel wall weakness allows mucosal outpouching when there is
increased intraluminal pressure
• Diverticular disease is usually asymptomatic but may be associated
with cramping, abdominal discomfort, and constipation.
• Diverticulitis can result in pericolic abscesses, sinus tracts, and peritonitis.
Even without perforation, diverticulitis can cause fibrotic thickening and
stricture formation.
Polyps
• Inflammatory Polyps
• result from recurrent cycles of injury and healing; there is lamina propria
fibromuscular hyperplasia, mixed inflammatory cell infiltrates, and mucosal
erosion and/or hyperplasia.
• Hamartomatous Polyps
• (tumor-like growths of tissues normally present at the site) are important to
recognize because they usually occur in the setting of various genetic or
acquired syndromes
Polyps
• Hyperplastic Polyps
• polyps result from decreased epithelial turnover with delayed shedding; they
have no malignant potential.
• These are usually smaller than 5 mm and are composed of well-formed
mature, albeit crowded, glands
• Neoplastic Polyps
• Colonic adenomas are benign polyp precursors to the majority of colorectal
carcinomas; they are characterized by the presence of epithelial dysplasia
• Risk of malignancy is correlated to size and severity of dysplasia.
• Adenomatous polyp • Villous adenoma
Familial Adenomatous Polyposis
• an autosomal dominant disorder caused by mutations of the
adenomatous polposis coli (APC) gene.
• Patients in adolescence characteristically develop more than 100 colonic
adenomatous polyps; if untreated, colorectal carcinoma will develop in 100%
by age 30 years
• Some FAP patients without APC loss have mutations of the base-
excision repair gene MUTYH
Familial Adenomatous Polyposis
Hereditary Non-Polyposis Colorectal Cancer
• Also known as Lynch syndrome, hereditary non-polyposis colorectal
cancer (HNPCC) is caused by mutations in genes encoding proteins
responsible for the detection, excision, and repair of DNA replication
errors
• majority of cases involve mismatch repair genes MSH2 and MLH1
• patients inherit one defective copy and, when the second is lost by mutation
or epigenetic silencing, mutations accrue at rates up to 1000 times normal,
mostly in regions of microsatellite repeats, which leads to microsatellite
instability.
Hereditary Non-Polyposis Colorectal Cancer
Adenocarcinoma
• Develops insidiously and may go undetected for long periods.
• Fatigue, weakness, iron deficiency anemia, abdominal discomfort, progressive
bowel obstruction, and liver enlargement (metastases) eventually occur.
• Prognosis varies with the stage of disease at diagnosis; 5-year survival
rates are related to the depth of tumor penetration and lymph node
involvement
• Multiple genetic and epigenetic
events contribute to colorectal
carcinogenesis
• No single event or sequence of
events is requisite, but a multi-
hit genetic mechanism appears
to be operative
Adenocarcinoma
Hemorrhoids
• Hemorrhoids are variceal dilations of anal and perianal submucosal
venous plexi; they affect 5% of adults.
• Hemorrhoids are causally associated with constipation (straining at
stool), venous stasis during pregnancy, and cirrhosis
• Secondary thrombosis (with recanalization), strangulation, or
ulceration with fissure formation can occur
Acute Appendicitis
• Some 50% to 80% of appendicitis cases are associated with
obstruction of the appendiceal lumen by a fecalith, tumor, or worms
• Classically, there is periumbilical pain migrating to the right lower
quadrant, nausea and/or vomiting, abdominal tenderness, mild fever,
and leukocytosis
• Complications include pyelophlebitis, portal vein thrombosis, liver
abscess, and bacteremia
Acute Appendicitis