Path Chap 17 Stomach
Monday, February 11, 2013
1:53 PM
Stomach
 Diseases related to gastric acid are about a third of health care spending on GI disease.
 Gastric cancer is a leading cause of death worldwide.
 Cardia and Antrum are lined mainly by mucin-secreting foveolar cells that form small glands.
 Acute Gastritis
o Transient mucosal inflammatory process that may be asymptomatic or cause degrees of
epigastric pain, nausea, and vomiting.
o Pathogenesis
 Mechanisms of Gastric Mucosa Protectino
 Mucin secreted by foveolar cells forms a thin layer, keeping large food pieces
from touching the epithelium.
 Mucous layer promotes "unstirred" layer of fluid that protects the mucosa and
has a neutral pH due to bicarb secretion from epithelial cells.
 Rich vascular supply to mucosa delivers oxygen and nutrients while washing
away back-diffused acid.
 NSAIDs may interfere with protection normally provided by prostaglandins or reduce
bicarb secretion.
 H.Pylori uses ammonium ions to block gastric bicarb transporters.
 Mitotic inhibitors (used in cancer chemo) cause generalized mucosal damage due to
insufficient epithelial regeneration.
o Morphology
 Histologically is difficult to recognize since the surface epithelium is intact.
 Large amounts of lymphocytes or plasma cells suggest chronic disease.
 Presence of neutrophils above the basement membrane in direct contact with
epithelial cells is abnormal in all parts of the GI Tract = Active inflammation
 Erosion: Loss of superficial epithelial, generating a defect in the mucosa limited to the
lamina propria.
 Seen with more severe mucosal damage.
o Acute Gastric Ulceration
 Stress Ulcers: common with shock, sepsis, or severe trauma.
 Curling Ulcers: Proximal duodenum associated with severe burns or trauma
 Cushing Ulcers: gastric, duodenal, and esophageal ulcers arising with intracranial
disease.
 Pathogenesis
 NSAID ulcers are related to cyclooxygenase inhibition.
 Prevents synthesis of prostaglandins
 Prostaglandins enhance bicarb secretion, inhibit acid secretion,
promote mucin synthesis, and increase vascular perfusion.
 Lesions with intracranial injury thought to cause direct vagal stimulation which
causes increased gastric acid.
 Morphology
 Ulcers range in depth from shallow erosions caused by superficial damage to
deeper lesions that penetrate the depth of the mucosa.
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Acute stress ulcers are found anywhere in the stomach.
 Sharply demarcated.
 Healing with complete re-epithelialization occurs after the injurious factors are
removed.
 Clinical Features
 H2 histamine receptor agonists or proton pump inhibitors may blunt the impact
of stress ulceration.
 Most important determinant of clinical outcome is the ability to correct the
underlying conditions.
 Complications
 Bleed is the most frequent complication and may be the first indication of
an ulcer.
 Perforation accounts for two thirds of ulcer deaths despite occurring in up
to 5% of patients.
 Obstruction
Chronic Gastritis
o Symptoms are usually less severe but more persistent.
o Most common cause of chronic gastritis is H. Pylori infection.
o Autoimmune Gastritis is the most common cause of atrophic gastritis and is the most
common form of chronic gastritis without H. Pylori infection.
o Helicobacter Pylori Gastritis
 Spiral shaped or curved bacilli are present in gastric biopsy of almost all patients with
duodenal ulcers and the majority of individuals with gastric ulcers or chronic gastritis.
 Infection increases acid secretion which may result in peptic ulcers.
 Also increases risk of gastric cancer.
 Epidemiology
 Associated with poverty, household crowding, limited education, AfricanAmerica, Mexican-American, residence in rural areas, and birth outside the US.
 Humans are the only known host, making oral-oral, fecal-oral, and
environmental spread the most likely routes of infection.
 Pathogenesis
 Most common cause of chronic gastritis.
 Presents most often as predominantly antral gastritis with high acid production,
despite hypogastrinemia.
 Four Factors linked to virulence
1. Flagella: allow motility.
2. Urease: generates ammonia to elevate pH.
3. Adhesions: enhance bacterial adherence to surface foveolar cells.
4. Toxins: cytotoxin-associated gene A (not well understood)
 Infection results in increased acid production and disruption of protective
mechanisms.
 May progress to pangastritis, resulting in multifocal atrophic gastritis.
 Severity may be influenced by genetic variation among H. Pylori strains.
 Morphology
 Organism is concentrated within the superficial mucus overlying epithelial cells
in the surface and neck regions.
 Within the stomach, H. Pylori typically found in the antrum.
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Mucosa is usually erythematous and has a coarse or even nodular
appearance.
 H. Pylori are uncommon in oxyntic mucosa of the fundus and body except in
heavy colonization.
 Intraepithelial neutrophils and subepithelial plasma cells are characteristic of H.
Pylori gastritis.
 Lymphoid aggregates, some with germinal centers, are frequently present and
represent an induced form of mucosa-associated lymphoid tissue (MALT) that
has the potential to transform into lymphoma.
 Clinical Features
 Diagnostic tests
 Serologic tests for antibodies to H. Pylori.
 Fecal bacterial detection
 Urea breath test
 Treated with antibiotics and proton pump inhibitors.
Autoimmune Gastritis
 Less than 10% of cases and typically spares the antrum and includes hypergastrinemia.
 Characterized by
 Antibodies to parietal cells and intrinsic factor
 Reduced serum pepsinogen I concentration
 Antral endocrine cell hyperplasia
 Vit B12 deficiency
 Defective Gastric Acid Secretion (achlorydia)
 Pathogenesis
 Associated with loss of parietal cells, which secrete gastric acid and IF.
 Lack of acid stimulates gastrin from G cells producing hypergastrinemia dn
hyperplasia of G cells.
 Lack of IF leads to B12 deficiency and slow-onset megaloblastic anemia
(pernicious anemia).
 Reduced pepsinogen comes from chief cell destruction.
 These are lost through gastric gland destruction during autoimmune
attacks on parietal cells.
 No evidence of autoimmunity to chief cells.
 CD4+ T cells are directed against parietal cell components like the H+/K+
ATPase.
 Morphology
 Characterized by damage of the oxyntic (acid producing) mucosa within the
body and fundus.
 Inflammatory infiltrate usually composed of lymphocytes, macrophages, and
plasma cells.
 Superficial lamina propria plasma cells of H. Pylori are typically absent.
 Small surface elevations may be apparent which correlate with intestinal
metaplasia.
 Include the presence of goblet cells and columnar absorptive cells (not
good in stomach!).
 Hypergastrinemia can stimulate endocrine cell hyperplasia in the fundus and
body.
 Clinical Features
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Antibodies to parietal cells and to IF are seen early in the course of disease.
Patients are generally diagnosed only after being affected for many years;
median age of 60 years.
 Autoimmune Gastritis stands apart from other autoimmune diseases in that
there is little evidence of linkage to specific HLA alleles.
 B12 Deficiency may cause atrophic glossitis (tongue becomes smooth and beefy
red), megaloblastosis, and malabsorptive diarrhea.
 May also cause peripheral neuropathy, spinal cord lesions, and cerebral
dysfunction.
 Most frequent mansfestations of peripheral neuropathy are
parasthesias and numbness.
o Uncommon Forms of Gastritis
 Reactive Gastropathy
 Marked by foveolar hyperplasia, glandular regenerative changes, and mucosal
edema.
 Neutrophils are not abundant.
 Common after gastric surgeries that bypass the pylorus.
 Endoscopy will show longitudinal stripes of red, edematous stripes alternating
with less severely injured mucosa, giving it the name of Watermelon Stomach.
 Esosinophilic Gastritis
 Tissue damage associated with eosinophils in the mucosa and muscularis.
 Associated with eosinophilia and increased serum IgE levels.
 Allergic reactions, Parasitic infections, H. Pylori infection, and systemic collagenvascular disease are causes of Eosinophilic Gastritis.
 Lymphocytic Gastritis
 Affects women more and produces nonspecific symptoms such as abdominal
pain, anorexia, nausea, and vomiting.
 Idiopathic but 40% of cases associated with celiac disease.
 Also called Varioliform Gastritis because of the appearance of thickened folds
covered by small nodules with central aphthous ulceration.
 Entire stomach affected in most cases.
 Has marked increase in intraepithelial T lymphocytes, mostly CD8+ cells.
 Granulomatous Gastritis
 Any gastritis that contains granulomas, or aggregates of epitheloid histiocytes.
 Most common specific cause is Crohn Disease.
 Second is Sarcoidosis.
 Also includes narrowing and rigidity of the gastric antrum secondary to
transmural granulomatous inflammation.
Complications of Chronic Gastritis
o Peptic Ulcer Disease
 Most often associated with H. Pylori-induced hypercholric chronic gastritis.
 Presence of chronic gastritis helps to distinguish peptic ulcers from erosive gastritis or
stress ulcers, since the adjacent mucosa in these two conditions is generally normal.
 Most common in the gastric antrum and first part of the duodenum.
 Pathogenesis
 The imbalance between mucosal defense and damaging forces that causes
chronic gastritis are also responsible for PUD.
 H. Pylori infection and NSAID use are the primary underlying causes of PUD.
 Both compromise defense and cause damage.
Gastric Hyperacidity of PUD may be cause by
 H. Pylori infection
 Parietal cell hyperplasia
 Excessive secretory responses
 Impaired inhibition of stimulatory mechanisms
 Zollinger-Ellison Syndrome: multiple ulcers caused by a gastrin
releasing tumor.
 NSAIDs cause direct chemical irritation while suppressing prostaglandin
synthesis needed for mucosal protection.
 Smoking impairs blood flow and healing.
 Duodenal ulcers found more with alcoholic cirrhosis, COPD, chronic renal
failure, and hyperparathyroidism.
 CRF and hyperparathyroidism both have high calcium which stimulate
gastrin.
 Morphology
 Peptic ulcers are four times more common in the proximal duodenum than in
the stomach.
 Gastric Peptic ulcers usually located along the lesser curvature of
stomach.
 Classic peptic ulcer is round to oval, with a sharply punched-out defect.
 Heaped-up margins are more characteristic of cancers.
 Perforation is a surgical emergency and can be identified by air under the
diaphragm.
 Base of ulcers is smooth and clean as a result of peptic digestion of exudate, and
blood vessels may be evident.
 Malignant transformation of peptic ulcers is very rare.
 Clinical Features
 Notoriously chronic, often diagnosed in middle-aged to older adults without
obvious precipitating conditions.
 Majority come to clinical attention because of epigastric burning or aching pain
relieved by alkali or food.
 Penetrating ulcer pain referred to the back, left upper quadrant, or the chest.
 Therapies aimed at H. Pylori eradication and neutralization of acid with PPIs and
H2 antagonists.
 These have reduced the need for surgical intervention which is reserved
for bleeding or perforated peptic ulcers.
Mucosal Atrophy and Intestinal Metaplasia
 Chronic gastritis can lead to significant loss of parietal cell mass or atrophy.
 Atrophy may be associated with metaplasia, characterized by goblet cells.
 Strongly associated with increased risk of gastric adenocarcinoma.
 Risk of adenocarcinoma is greatest with autoimmune gastritis.
 Intestinal metaplasia also occurs in chronic H. Pylori gastritis and may regress after
clearance of the infection.
Dysplasia
 Variations in epithelial size, shape, and orientation along with coarse chromatin
texture, hyperchromasia, and nuclear enlargement.
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Reactive epithelial cells mature as they reach the mucosal surface, while dysplastic
lesions remain cytologically immature.
o Gastritis Cystica
 Exuberant reactive epithelial proliferation associated with entrapment of epitheliallined cysts.
 Trauma Induced.
Hypertrophic Gastropathies
o Uncommon diseases characterized by giant cerebriform enlargement of the rugal folds due
to epithelial hyperplasia without inflammation.
 Linked to excessive growth factor release.
o Menetrier Disease
 Caused by excessive secretion of transforming growth factor α (TGF-α).
 Characterized by diffuse hyperplasia of the foveolar epithelium of the body and
fundus.
 Morphology
 Irregular enlargement of gastric rugae in the body and fundus.
 Histologically most characteristic is hyperplasia of foveolar mucous cells.
 The glands appear corkscrew-like and cystic dilation is common.
 Treated with intravenous albumin and parenteral nutritional supplementation.
 Agents that block TGF-α show promise.
o Zollinger-Ellison Syndrome
 Caused by gastrin-secreting tumors, gastrinomas, that are most commonly found in
the small intestine or pancreas.
 Patients present with duodenal ulcers or chronic diarrhea.
 In the stomach the most remarkable feature is a doubling of thickness of the mucosa
due to fivefold increase in parietal cells.
 Gastrin induces hyperplasia of mucous neck cells, mucin hyperproduction, and
proliferation of endocrine cells within oxyntic mucosa.
 Treatment includes blockage of acid hypersecretion and then tumor removal.
Gastric Polyps and Tumors
o Inflammatory and Hyperplasia of Polyps
 Approx 75% of all gastric polyps.
 Usually develop in association with chronic gastritis.
 Morphology
 Majority are smaller than 1 cm in diameter and are frequently multiple.
 Polyps are ovoid and have a smooth surface, thought superficial erosions are
common.
o Fundic Gland Polyps
 Occur sporadically and in people with familial adenomatous polyposis (FAP).
 Increased tons as a result of PPI therapy.
 Equals increased gastrin which equals glandular hyperplasia.
 Occur in the gastric body and fundus and are well-circumscribed lesions.
 Inflammation is typically absent or minimal.
o Gastric Adenoma
 Incidence increases with age.
 Patients usually between 50-60 years and are males 3x more.
 Incidences increases with FAP.
 Almost always happen with chronic gastritis with atrophy and intestinal metaplasia.
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Risk is related to the size of the lesion and is really elevated in lesions greater than 2
cm in diameter.
 Most commonly located in the antrum and are composed of intestinal-type columnar
epithelium.
 All GI adenomas have epithelial dysplasia.
 Low Grade or High Grade Dysplasia both present with
 Enlargement
 Elongation
 Hyperchromasia of epithelial cell nuclei
 Epithelial crowding
 Pseudostratification
Gastric Adenocarcinoma
 Most common malignancy of the stomach.
 Early symptoms similar to chronic gastritis: dyspepsia, dysphagia, and nausea.
 Epidemiology
 Cause of overall reduction in gastric cancer is unknown.
 Possible explanation is decreased consumption of dietary carcinogens.
 Intake of green, leafy vegies and citrus fruits, which contain antioxidants is
correlated with reduced risk of gastric cancers.
 Although gastric adenocarcinoma is reduced, cancer of the gastric cardia is
rising.
 Due to Barret Esophagus and may reflect increased GERD and obesity.
 Pathogenesis
 Mutations in CDH1, which encodes E-cadherin, (protein that contributes to
epithelial intercellular adhesion) are associated with familial gastric cancers.
 The loss of the E-cadherin function seems to be a key step in the
development of diffuse gastric cancer.
 Genetic variants of pro-inflammatory and immune response genes are
associated with elevated risk of gastric cancer when accompanied byH. Pylori
infection and p53 mutations.
 Chronic inflammation promotes neoplastic progression.
 Morphology
 Classified according to location and gross/histologic morphology.
 Most involve the antrum and the lesser curvature.
 Tumors with intestinal morphology tend to form bulky tumors composed of
glandular structures.
 Cancers with diffuse infiltrative growth patterns more often have signet-ring
cells.
 Typically grow along broad cohesive fronts to form either an exophytic mass or
an ulcerated tumor.
 Neoplastic cells often contain apical mucin vacuoles and have abundant mucin.
 Diffuse gastric cancer typically has large mucin vacuoles that expand the
cytoplasm and push the nucleus to the periphery, making a signet-ring cell
morphology.
 Infiltrative tumors often evoke a desmoplastic reaction that stiffens the gastric
wall.
 Large amounts of infiltration show diffuse rugal flattening and a rigid,
thickened wall that may look like a leather bottle, called linitis plastica.
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Clinical Features
 Decrease in gastric cancer applies only to the intestinal type, which is closely
associated with atrophic gastritis and intestinal metaplasia.
 Depth of invasion and extent of nodal and distant metastasis at the time of
diagnosis are the most powerful prognostic indicators for gastric cancer.
 May first be detected at the supraclavicular sentinel lymph node, also called
Virchow's node.
 Tumors can also metastasize to the periumbilical region to form a subcutaneous
nodule, termed a Sister Mary Joseph nodule.
Lymphoma
 Pathogenesis
 Extra-nodal marginal zone B-cell lymphomas usually are at sites of chronic
inflammation.
 More commonly arise in tissues normally devoid of organized lymphoid tissue.
 Common cause of "pro-lymphomatous" inflammation in the stomach is H. Pylori
infection.
 Biggest evidence linking the two is that getting rid of the infection leads to
durable remissions with low rates of recurrence.
 Features that predict antibiotic treatment failure include
 Transformation to large-cell lymphoma
 Tumor invasion to muscularis propria
 Lymph node involvement
 MALTomas have translocations associated that are highly predictive of response
failure.
 These all activate NF-κB, a transcription factor that promotes B-cell
growth and survival.
 Morphology
 Dense lymphocytic infiltrate in the lamina propria
 Neoplastic lymphocytes infiltrate the gastric glands focally to create diagnostic
lymphoepithelial lesions.
 Occasionally the tumor cells accumulate large amounts of pale cytoplasm which
is referred to as monocytoid change.
 MALTomas express B-cell markers CD19, CD20, and CD43 (in 25% of cases).
 Clinical
 Most common presenting symptoms are dyspepsia and epigastric pain.
Carcinoid Tumor
 Arise from components of endocrine system.
 Tend to have more lazy clinical course than GI carcinomas.
 Best considered to be well-differentiated neuroendocrine carcinomas.
 Morphology
 Intramural or submucosal masses that create small polyploid lesions.
 Tend to be yellow or tan and are very firm from demoplastic reactions which
may cause bowel kinks and obstruction.
 Most tumors have minimal pleomorphism, but anaplasia, mitotic activity, and
necrosis may be present in rare cases.
 Clinical Features
 Peak incidence is 60-70 years.
 Symptoms are determined by the hormones produced.
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Carcinoid tumor is caused by vasoactive substances secreted by the tumor into
systemic circulation.
 Most important prognostic factor for GI carcinoid tumor is LOCATION.
 Foregut: generally cured by resection.
 Midgut: tend to be aggressive.
 Greater depth, increased size, and presence of necrosis and mitosis
are associated with poor outcome.
 Hindgut: Not too bad.
Gastrointestinal Stromal Tumor (GIST)
 Most common mesenchymal tumor of the abdomen, more than half occur in the
stomach.
 Epidemiology
 Slightly more common in men.
 Carney Triad (children's disease):
 Typically in young females includes gastric GIST, paraganglioma, and
pulmonary chondroma.
 Pathogenesis
 75-80% of all GIST have oncogenic, gain-of-function mutations of the gene
encoding tyrosine kinase c-KIT, which is the receptor for stem cell factor.
 GISTs arise from interstitial cells of Cajal, which are located in the muscularis
propria and serve as pacemaker cells for gut peristalsis.
 c-KIT and PDGFRA receptor tyrosine kinases activate the RAS and PI3/AKT
pathways that promote tumor cell proliferation and survival.
 Morphology
 Usually form a solitary, well-circumscribed, fleshy mass.
 Composed of thin elongated cells classified as spindle cell type.
 Most useful diagnostic marker is c-KIT, which is detectable in 95% of gastric
GISTs.
 Clinical Features
 Symptoms are related to mass effects.
 Ulceration can cause blood loss and about half of GIST patients are
anemic.
 Complete resection is the primary treatment.
 Prognosis correlates with tumor size, mitotic index and location, with gastric
GISTs being less aggressive than intestinal.
 Patients with unresectable, recurrent, or metastatic disease often respond to
imatinib, a tyrosine kinase inhibitor that inhibits c-KIT and PDGFRA.