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GASTROINTESTINAL DISORDERS Fe A. Bartolome, MD, FPASMAP Department of Pathology Our Lady of Fatima University

Impaired Digestion & Absorption Diseases of the stomach, intestine, biliary tree & pancreas  disrupt nutrient digestion and absorption Examples: Gastric hypersecretory syndromes (e.g. Zollinger-Ellison syndrome) Damage intestinal mucosa Impair pancreatic enzyme activation Lactase deficiency Most common intestinal maldigestion syndrome Biliary obstruction from stricture or neoplasm Chronic pancreatitis or pancreatic CA

Altered Secretion Gastric acid hypersecretion Zollinger-Ellison syndrome, G cell hyperplasia, duodenal ulcer disease Decreased or absent gastric acid secretion Atrophic gastritis or pernicious anemia Fluid loss through impaired absorption or enhanced secretion Inflammatory and infectious small-intestinal and colonic diseases Laxative abuse Endocrine neoplasias with secretion of vasoactive intestinal polypeptide (VIP)

Altered Gut Transit Mechanical obstruction Esophagus – acid-induced stricture or neoplasm Stomach – PUD or gastric cancer Small intestines Adhesions – most common Crohn’s disease, radiation-induced strictures, malignancy Colon Colon cancer – most common Inflammatory strictures in patients with inflammatory bowel disease

Altered Gut Transit Disordered gut motor function Achalasia – impaired esophageal body peristalsis Gastroparesis – symptomatic delay in gastric emptying of solid or liquid meals due to impaired gastric motility Injury to enteric nerves or intestinal smooth muscle  intestinal pseudo- obstruction Impaired colonic propulsion  constipation

Immune Dysregulation Celiac disease – mucosal inflammation due to ingestion of gluten-containing grains Eosinophilic esophagitis and gastroenteritis Ulcerative colitis & Crohn’s disease Bacterial, viral, and protozoal ileitis and colitis in selected patients

Impaired Gut Blood Flow Gastroparesis may result from blockage of the celiac and superior mesenteric arteries Intestinal and colonic ischemia – more common; may be due to: Arterial thrombosis or embolus Venous thrombosis Hypoperfusion from dehydration, sepsis, hemorrhage or reduced cardiac output

Neoplastic Degeneration All GI regions are susceptible to malignant degeneration to varying degrees Most GI cancers are carcinomas, but lymphomas & tumors of other cell types are also observed Colorectal CA – most common in U.S. Gastric CA – worldwide & esp. in certain regions in Asia Esophageal CA – associated with chronic acid reflux & extensive alcohol and tobacco use

Disorders without Obvious Organic Abnormalities Irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, functional heartburn  no abnormalities on biochemical or structural testing With altered gut motor function Exaggerated visceral sensory responses to noxious stimulation may cause discomfort Patients may exhibit significant emotional disturbances on psychometric testing

Symptoms of Gastrointestinal Disease Common Causes of Common GI Symptoms Abdominal Pain Appendicitis Gallstone disease Pancreatitis Diverticulitis Ulcer disease Esophagitis GI obstruction Nausea & Vomiting Medications GI obstruction Motor disorders Functional bower d.o. Enteric infection Pregnancy Endocrine disease Diarrhea Infection Poorly absorbed sugars Inflam. Bowel dse. Microscopic colitis Fxnal bowel disorder Celiac dse. Pancreatic insuff. GI Bleeding Ulcer disease Esophagitis Varices Vascular lesions Neoplasm Diverticula Hemorrhoids Obstructive Jaundice Bile duct stones Cholangio- carcinoma Cholangitis Sclerosing cholangitis Ampullary stenosis Ampullary CA Pancreatitis

Symptoms of Gastrointestinal Disease Common Causes of Common GI Symptoms Abdominal Pain Inflammatory bowel dse. Functional bowel d.o. Vascular disease Gynecologic causes Renal stone Nausea & Vomiting Motion sickness CNS disease Diarrhea Hyper- thyroidism Ischemia Endocrine tumor GI Bleeding Fissures Inflammatory bowel dse. Infectious colitis Obstructive Jaundice Pancreatic tumor

Abdominal Pain GI disease and extraintestinal conditions involving the GUT, abdominal wall, thorax or spine Visceral pain  midline in location and vague in character Parietal pain  localized and precisely described Most common causes are IBS and functional dyspepsia

Abdominal Pain Other causes: Inflammatory Peptic ulcer, appendicitis, IBD, diverticulitis, infectious enterocolitis Gallstone disease, pancreatitis Non-inflammatory Mesenteric ischemia Neoplasia

Heartburn Burning sub-sternal sensation Result from excess gastroesophageal reflux of acid Nausea and Vomiting Mechanical obstruction of upper gut Others: gastroparesis & intestinal pseudo-obstruction; IBS and functional disorders of upper gut

Altered Bowel Habits Constipation Infrequent defecation Straining with defecation Passage of hard stools Sense of incomplete fecal evacuation Causes: Obstruction Motor disorders of colon Medications Endocrine diseases (hypothyroidism and hyperparathyroidism)

Altered Bowel Habits Diarrhea Frequent defecation Passage of loose or watery stools Fecal urgency Sense of incomplete evacuation Causes: Inflammatory – (+) pus in stool IBS – constipation, diarrhea, or alternating bowel pattern; (+) fecal mucus Infectious Malabsorption – (+) steatorrhea Medications

GI Bleeding Upper GI bleed – (+) melena or hematemesis Most common causes are: ulcer disease, gastroduodenitis, and esophagitis Lower GI bleed – passage of bright red or maroon stools Most common causes are: hemorrhoids, anal fissures, diverticula, ischemic colitis, and arteriovenous malformations Chronic slow GI bleed  (+) iron deficiency anemia

Other Symptoms Dysphagia, odinophagia & unexplained chest pain  esophageal disease Weight loss, anorexia, fatigue  neoplastic, inflammatory, gut motility, pancreatic, small bowel mucosal, and psychiatric conditions Extraintestinal symptoms IBD – hepatobiliary dysfunction, skin & eye lesions, arthritis Celiac disease – dermatitis herpetiformis

Signs and Symptoms of Esophageal Disease Heartburn Most commonly due to GERD Dysphagia for solids alone Symptom of an obstructive lesion Examples: esophageal cancer, esophageal web, stricture Dysphagia for solids and liquids Signify motility disorder Oropharyngeal (upper esophageal) Striated muscle dysmotility Dermatomyositis, myasthenia gravis, stroke Lower esophageal Smooth muscle dysmotility Systemic sclerosis, achalasia

Esophageal Atresia Incomplete development Thin, non-canalized cord replaces a segment of esophagus, causing mechanical obstruction Proximal and distal blind pouches connect to the pharynx and stomach, respectively Occurs most commonly at or near the tracheal bifurcation  usually associated with fistula connecting the upper or lower esophageal pouches to a bronchus or the trachea

EA with distal TEF EA with proximal TEF Isolated EA EA with double TEF Isolated TEF

Esophageal Atresia Fistulae can lead to aspiration, suffocation, pneumonia, and severe fluid and electrolyte imbalances Abdominal distention in NB  air in stomach from fistula Regurgitation of food EA associated with congenital heart defects, GU malformations, and neurologic disease

Esophageal Stenosis Incomplete form of atresia Esophageal lumen markedly reduced in caliber due to fibrous thickening of the wall  partial or complete obstruction May involve any part of the GIT  esophagus & SI most commonly affected

Esophageal Stenosis Associated with atrophy of the muscularis propria & secondary epithelial damage Causes: Congenital – occasional Inflammation and scarring Most common Due to GERD, irradiation or caustic injury Progressive dysphagia

Congenital esophageal stenosis in a young man with long-standing dysphagia and occasional superimposed food impactions. Double-contrast esophagogram shows an area of mild narrowing in the mid-esophagus with distinctive ring-like indentations (“ringed esophagus”) (arrows) in the region of the stricture.

Nutcracker Esophagus High-amplitude esophageal contractions Outer longitudinal layer of smooth muscle contracts before the inner circular layer of smooth muscles  lack of coordination Cause periodic short-lived esophageal obstruction

Diffuse esophageal spasm Cause increased esophageal wall stress Result in functional obstruction Can cause small diverticulae to form

Diffuse esophageal spasm produces intermittent contractions of the mid and distal esophageal smooth muscle, associated with chest symptoms. Patient experienced chest pain during examination

Esophageal diverticulae Small mucosal outpouchings True diverticulae – with true muscularis Pseudodiverticulae – lack true muscularis

Esophageal diverticulae: Types Zenker’s Diverticulum Pharyngoesophageal diverticulum Occurs in older women Posteriorly at site of Killian's dehiscence = superior boundary is thyropharyngeal muscle and inferior boundary is cricopharyngeal muscle Pulsion diverticulum False diverticulum = herniation of mucosa and submucosa through muscular layer

Traction Diverticulum Mid-esophageal diverticulum May be formed in response to pull from fibrous adhesions following lymph node infection (usually TB) Or, may form from increased intraluminal pressure and be pulsion diverticula True diverticulum = contains all 3 esophageal layers

Epiphrenic Diverticulum Location is usually in distal esophagus on lateral esophageal wall, right > left Often associated with hiatal hernia Pulsion diverticulum False diverticulum

Esophageal mucosal webs Uncommon ledge-like protrusions of mucosa Women > 40 y/o Often associated with: Gastroesophageal reflux Chronic graft-versus-host disease Blistering skin diseases Most common in upper esophagus (at level of cricopharyngeus or C5-C6) Main symptom is dysphagia associated with incompletely chewed food

Barium esophagram demonstrates a thin membrane arising from the anterior wall of the cervical esophagus at the level of C5-C6 without circumferential involvement of the lumen characteristic for an esophageal web An upper esophageal web (arrow) in a patient with Plummer-Vinson syndrome.

Esophageal mucosal webs Patterson-Brown-Kelly or Plummer-Vinson Syndrome Iron deficiency anemia Stomatitis Glossitis Dysphagia Spoon-shaped nails Esophageal webs

Atrophic glossitis Esophageal web Hypochromic, microcytic anemia

Koilonychia (spoon-shaped fingernails) Cheilitis (rhagades, angular stomatitis)

Esophageal rings Similar to webs but circumferential and thicker Include mucosa, submucosa, and in some cases, hypertrophic muscularis propria If present in distal esophagus, above the gastroesophageal junction; covered by squamous mucosa  A rings If located at squamocolumnar junction (Z line) of lower esophagus & with gastric cardia-type mucosa on undersurface  B rings (Schatzki rings)

Esophageal A-ring due to muscular contraction. It varies during examination and may not persist.

The esophageal B-ring is located at the squamocolumnar junction, also termed the 'Z' line. The appearance does not change during the examination.

Achalasia Triad: Incomplete LES relaxation Increased LES tone Aperistalsis of the esophagus Impaired smooth muscle relaxation  increased tone of LES Primary – idiopathic; failure of distal esophageal inhibitory neurons Secondary – Chaga’s disease, diabetic autonomic neuropathy, malignancy, amyloidosis, polio, surgical ablation

LEFT: Dilated esophagus (arrows) appears as long, well-defined structure paralleling heart RIGHT: Dilated esophagus usually deviates to right, narrowing (arrow) at hiatus.

Esophageal Causes of Hematemesis

Mallory-Weiss Syndrome Longitudinal tears near the gastro-esophageal junction; superficial lacerations Usually associated with severe retching or vomiting due to acute alcohol intoxication

Boerhaave Syndrome Distal esophageal rupture and mediastinitis Occurs rarely; catastrophic Causes: Endoscopy (~75% of cases) Retching Bulimia Complications: Pneumomediastinum Air dissects into subcutaneous tissue Produces a crunching sound (Hamman’s crunch) on P.E. Pleural effusion contains food, acid, amylase

Chemical Esophagitis Alcohol, corrosive acids or alkalis, excessively hot fluids, heavy smoking Generally causes only self-limited pain, particularly with swallowing Complications: hemorrhage, stricture, perforation

Corrosive esophagitis. This is a vinegar-induced esophageal burn. The patient had a fish bone in her throat. She ingested vinegar in an attempt to dissolve the fish bone but to no avail; this led to corrosive esophagitis.

Pill-induced Esophagitis Occurs when medicinal pills lodge and dissolve in the esophagus rather than passing into the stomach Frequently occurs at the site of strictures that prevent passage of luminal contents

Infectious Esophagitis Frequently in debilitated or immunocompromised individuals  commonly HSV, CMV, or fungi (Candidiasis most common) HSV – punched-out ulcers CMV – shallower ulcerations + char. nuclear and cytoplasmic inclusions Candida – adherent, gray-white pseudomembranes

This is Candida esophagitis. Tan-yellow plaques are seen in the lower esophagus, along with mucosal hyperemia. The same lesions are also seen at the upper right in the stomach.

Candidiasis (thrush) of the esophagus. A ‘pseudomembrane’ is present (top) on the surface of the stratified squamous epithelium. It consists of desquamated epithelial cells and thin filament-like fungi. The fungi has penetrated the superficial layer of the squamous epithelium which is separated from relatively unaffected basal layer.

Here are two sharply demarcated "punched out" ulcerations of the mid esophagus in an immunocompromised patient with herpes simplex infection.

A herpetic ulcer is seen microscopically to have a sharp margin. The ulcer base at the left shows loss of overlying squamous epithelium with only necrotic debris remaining. Biopsies of these lesions reveals intranuclear inclusions in squamous epithelial cells indicative of herpes simplex virus esophagitis. This patient was immune compromised from chemotherapy.

Cytomegalovirus Infection. Microscopic sections reveal typical intranuclear inclusions Viral particles confirmed by electron microscopy

Reflux Esophagitis Reflux of gastric contents into the lower esophagus  called gastroesophageal reflux disease (GERD) Due to conditions that increase abdominal pressure or decrease lower esophageal sphincter tone Alcohol and tobacco use Obesity CNS depressants Pregnancy Hiatal hernia Delayed gastric emptying Increased gastric volume

Reflux Esophagitis Morphology: Simple hyperemia may be the only alteration Mild GERD  histology unremarkable Severe GERD Eosinophils & neutrophils in squamous mucosa Basal zone hyperplasia > 20% of the total epithelial thickness Elongation of lamina propria papillae

Reflux Esophagitis Gross appearance of a severe case of reflux esophagitis. Marked hyperemia with focal hemorrhage is present in the area of reflux.

Reflux Esophagitis Gastroesophageal Reflux with Ulceration. A common pattern of reflux are longitudinal ulcers arising from the gastroesophageal junction

Reflux Esophagitis Intra-epithelial eosinophils

Reflux Esophagitis Degrees of Gastroesophageal Reflux. In response to acid reflux, the squamous epithelium becomes thicker with basal cell hyperplasia and elongated rete papillae.

Reflux Esophagitis Clinical Features: Most common in adults > 40 Most common clinical symptoms: Dysphagia Heartburn Other symptoms may include: regurgitation of sour-tasting gastric content; attacks of severe chest pain (chronic)

Reflux Esophagitis Clinical Features: Complications: Esophageal ulceration Hematemesis Melena Stricture development Barrett esophagus Treatment: proton pump inhibitors or H 2 histamine receptor antagonists  symptomatic relief

Eosinophilic Esophagitis Majority of affected individuals are atopic  with atopic dermatitis, allergic rhinitis, asthma, or modest peripheral eosinophilia Symptoms: adults  food impaction and dysphagia Children  feeding intolerance and GERD-like symptoms Essentials for diagnosis: Large numbers of intraepithelial eosinophils Failure of high-dose proton pump inhibitor treatment Absence of acid reflux

Eosinophilic Esophagitis A, Reflux esophagitis shows papillary lengthening, basal hyperplasia, and rare intraepithelial eosinophils (IEEs) (hematoxylin-eosin, original magnification ×20). B, Eosinophilic esophagitis shows prominent IEEs, aggregates of eosinophils, and superficial eosinophils (hematoxylin-eosin, original magnification ×20)

Hiatal Hernia Characterized by separation of the diaphragmatic crura and protrusion of the stomach into the thorax through the resulting gap  part of stomach protrudes through the diaphragm and up to the chest Symptomatic in < 10% of adults  associated with other causes of LES incompetence Symptoms include heartburn and regurgitation of gastric juices, similar to GERD

Hiatal Hernia Other potential contributing factors: Permanent shortening of esophagus due to inflammation and scarring from reflux of gastric acid  pulls stomach up Abnormally loose attachment of esophagus to diaphragm  allow esophagus and stomach to slip upward

Hiatal Hernia: Types Sliding Hernia Most common type Gastroesophageal junction + part of stomach protrude into the chest Para-esophageal Hernia Gastroesophageal junction stays where it belongs (attached at level of diaphragm) but part of stomach protrudes into the chest beside the esophagus

With sliding or axial hiatal hernia there is thinning and elongation of the phrenoesophageal membrane leading to herniation of the stomach into the posterior mediastinum. As such, there is no potential for incarceration or strangulation. With paraesophageal herniation, visceral elements herniate through a focal weakness in the phrenoesophageal membrane with the potential to lead to the usual array of complications associated with visceral herniation through a constricted aperture. (Source: Modified from Skinner. 15 with permission from American Gastroenterological Association.)

Barrett Esophagus Complication of chronic GERD Characterized by intestinal metaplasia within the squamous mucosa  (+) goblet cells  necessary for diagnosis Most common in white males, between 40 – 60 yrs old Increased risk of esophageal adenoCA  pre-malignant condition

Patients with Barrett's esophagus have a 30- to 125-fold increased risk of the development of esophageal cancer in comparison with the general population. The disease is most common in white males.

Barrett Esophagus Gross: tongues or patches of red, velvety mucosa extending upward from gastro-esophageal junction alternating with residual smooth, pale squamous mucosa Classification: Long segment - > 3 cm of esophagus involved Short segment - < 3 cm of esophagus involved

Barrett Esophagus Microscopic: (+) goblet cells Gland architecture: budding, irregular shapes, and cellular crowding Classification if with dysplasia: Low grade High grade

Barrett Esophagus Clinical Features: Identified only through endoscopy and biopsy Usually prompted by GERD symptoms Treatment options: surgical resection or esophagectomy

Esophageal Varices Due to diseases that impede venous blood flow from GIT to the liver via portal vein before reaching IVC ( first-pass effect ) Alcoholic liver disease – 90% of cirrhotic patients Schistosomiasis – second most common cause worldwide Congested sub-epithelial and sub-mucosal venous plexus within the distal esophagus

Esophageal Varices Tortuous dilated veins lying within the submucosa of the distal esophagus and proximal stomach Variceal rupture  (+) hemorrhage into the lumen or esophageal wall  overlying mucosa appears ulcerated and necrotic

Esophageal Varices Cirrhotic patient with portal hypertension, in whom upper endoscopy shows large esophageal varices with red spots on their surface - indicating a high risk of bleeding.

Esophageal Varices Clinical Features: Often asymptomatic Rupture  massive hematemesis Contributory factors include: Inflammatory erosion of thinned overlying mucosa Increased tension in progressively dilated veins Increased vascular hydrostatic pressure associated with vomiting

Esophageal Varices Treatment: medical emergency Sclerotherapy – endoscopic injection of thrombotic agents Endoscopic balloon tamponade Endoscopic rubber band ligation 50% die from first bleeding episode either as (1) direct consequence of hemorrhage, or (2) following hepatic coma triggered by hypovolemic shock

Esophageal Tumors: Adenocarcinoma Typically arises in a background of Barrett esophagus and long-standing GERD Risk further increased by: Tobacco use Obesity Prior radiation therapy Risk reduced by diets rich in fresh fruits and vegetables, and some H. pylori serotypes

Esophageal Tumors: Adenocarcinoma Epidemiology: Caucasians 7x more common in males 50% of esophageal cancers in the U.S. Pathogenesis: Step-wise acquisition of genetic and epigenetic changes Mutation or over-expression of p53 Amplification of c-ERB-B 2 , cyclin D1 & cyclin E genes Allelic loss of p16INK4α by hyper-methylation Increased expression of TNF and NF κβ

Esophageal Tumors: Adenocarcinoma Morphology: Distal 3 rd of esophagus  may invade gastric cardia Initially flat or raised patches  large masses May infiltrate diffusely or ulcerate and invade deeply Barrett esophagus usually present adjacent to the tumor Most commonly produce mucin and form glands with intestinal-type morphology

Esophageal Tumors: Adenocarcinoma Endoscopic image of patient with esophageal adenocarcinoma seen at gastro-esophageal junction.

Esophageal Tumors: Adenocarcinoma H & E stain, Top - Low magnification, Bottom - High magnification, Esophageal Adenocarcinoma.

Esophageal Tumors: Adenocarcinoma Clinical Features: More commonly presents with: pain or difficulty in swallowing, progressive weight loss, hematemesis, chest pain, or vomiting Tumor spread to submucosal lymphatic vessels by the time symptoms appear  5-year survival < 25% 5-year survival ~ 80% if limited to mucosa or submucosa

Esophageal Tumors: Squamous Cell CA Epidemiology: U.S. – adults > 45 yrs old; 6x more common in African-Americans 4x more common in males Risk factors: Alcohol and tobacco use Poverty – more common in rural and under-developed areas Caustic esophageal injury Achalasia Plummer-Vinson syndrome Frequent consumption of very hot beverages Previous radiation therapy to mediastinum

Esophageal Tumors: Squamous Cell CA Pathogenesis: Alcohol and tobacco synergize to increase risk Nutritional deficiencies, polycyclic hydrocarbons, nitrosamines, fungus-contaminated foods, HPV infection  in areas where alcohol and tobacco use is uncommon Loss of tumor suppressor genes, including p53 and p16INK4 α

Esophageal Tumors: Squamous Cell CA Morphology: 50% occur in middle third Begins as in situ lesion called squamous dysplasia  early lesions small, gray white, plaque-like  tumor masses (polypoid or exophytic) over months to years  protrude into and obstruct lumen Most are moderately to well-differentiated LN metastases vary with tumor location: Upper 3 rd  cervical LN Middle 3 rd  mediastinal, paratracheal, and tracheobronchial nodes Lower 3 rd  gastric & celiac nodes

Esophageal Tumors: Squamous Cell CA Ulcerating Squamous cell carcinoma of the lower end of the esophagus. Malignant tumor of the esophageal squamous mucosa, most common in the middle and lower third of the esophagus, and strongly associated with tobacco and alcohol use.

Esophageal Tumors: Squamous Cell CA Clinical Features: Onset insidious Dysphagia, odynophagia (pain on swallowing), and obstruction Extreme weight loss & debilitation Tumor ulceration  (+) hemorrhage and sepsis Overall 5-year survival = 9%

Normal pH of gastric lumen close to 1 Normal defensive forces include: Mucin – secreted by gastric foveolar cells Forms a thin layer of mucus  prevents large food particles from directly touching epithelium Promotes formation of a layer of fluid over the epithelium  protects mucosa & has neutral pH Rich vascular supply  delivers oxygen, bicarbonate, and nutrients while washing away acid that has back-diffused into the lamina propria

Signs & Symptoms of Stomach Disease Hematemesis Vomiting of blood Most commonly due to PUD Other causes: esophageal varices, hemorrhagic gastritis Melena Dark, tarry stool Hemoglobin is converted into hematin by gastric acid Signifies bleed proximal to duodeno-jejunal junction

Signs & Symptoms of Stomach Disease Gastric analysis includes measurement of: Basal acid output (BAO) Acid output of gastric juice collected via NGT over a 1-hour period on an empty stomach Normal = < 5 mEq/hr Maximal acid output (MAO) Acid output of gastric juice that is collected over 1 hour after pentagastrin stimulation Normal = 5 – 20 mEq/hr BAO:MAO ratio - normally 0.20:1

Congenital Hypertrophic Pyloric Stenosis Also known as gastric outlet obstruction 3-4x more common in males; 1:300-900 live births Monozygotic twins with high rate of concordance  (+) genetic basis Progressive hypertrophy of the circular muscles in the pyloric sphincter Associated with Turner syndrome and trisomy 18

Congenital Hypertrophic Pyloric Stenosis

Congenital Hypertrophic Pyloric Stenosis Presents in 2 nd or 3 rd week of life as new-onset regurgitation and persistent, projectile, non-bilious vomiting P.E.: hyperperistalsis + firm, ovoid abdominal mass May be acquired in adults  due to antral gastritis or peptic ulcers near the pylorus, and CA of distal stomach and pancreas

Gastroparesis Decreased stomach motility, usually due to autonomic neuropathy (e.g. DM) May also be due to previous vagotomy Manifestations include Early satiety and bloating Vomiting of undigested food a few hours after eating

Acute Gastritis Transient mucosal inflammation brought about by disruption to protective mechanisms Elderly – reduced mucin synthesis NSAIDs – interfere with cytoprotection provided by PGs or reduce secretion of bicarbonate Uremic patients & those with H. pylori infection  (+) inhibition of gastric bicarbonate transporters by ammonium ions Ingestion of harsh chemicals (acids and alkalis), excessive alcohol consumption, NSAIDs, radiation therapy, and chemotherapy  direct cellular injury Decreased oxygen delivery

Acute Gastritis Morphology: Mild, acute gastritis: Intact surface epithelium with scattered neutrophils among epithelial cells or within mucosal glands Moderate edema and slight vascular congestion Neutrophils above basement membrane in direct contact with epithelial cells  active inflammation

Acute Gastritis Morphology: Severe acute gastritis: Development of Erosions – loss of superficial epithelium  (+) defect in the mucosa limited to lamina propria and accompanied by pronounced neutrophilic infiltrates + purulent exudate Hemorrhage – dark punctae in a hyperemic mucosa Hemorrhage + erosion  acute erosive hemorrhagic gastritis

Acute Gastritis This is a more typical acute gastritis with a diffusely hyperemic gastric mucosa.

Acute Gastritis At high power, gastric mucosa demonstrates infiltration by neutrophils. This is acute gastritis.

Acute Gastritis Here are some larger areas of gastric hemorrhage that could best be termed "erosions" because the superficial mucosa is eroded away.

Acute Gastritis Gross appearance of hemorrhagic gastritis as seen at autopsy. The entire gastric mucosa is involved by fresh hemorrhage.

Acute Gastric Ulceration Types: Stress ulcers Most common in individuals with shock, sepsis, or severe trauma Curling ulcers Proximal duodenum; severe burns or trauma Cushing ulcers Gastric, duodenal, and esophageal ulcers in patients with intracranial disease High incidence of perforation

Acute Gastric Ulceration Pathogenesis: NSAID-induced  cyclooxygenase inhibition  prevent PG synthesis Intracranial injury  direct stimulation of vagal nuclei  gastric acid hypersecretion Systemic acidosis  decreased intracellular pH of mucosal cells Stress-induced splanchnic vasoconstriction  hypoxia and reduced blood flow

Acute Gastric Ulceration Morphology: Acute stress ulcers Rounded, < 1 cm in diameter Found anywhere in the stomach Gastric rugal folds normal Margin and base of ulcers are not indurated Usually multiple Microscopically: sharply demarcated, with essentially normal adjacent mucosa

Acute Gastric Ulceration Acute stress ulcers Multiple acute ulcers of the stomach, occurring in a chronically debilitated patient. Microscopically, there was very little fibrous reaction in the ulcer bed.

Acute Gastric Ulceration Curling's ulcer is an acute peptic ulcer of the duodenum resulting as a complication from severe burns.

Acute Gastric Ulceration Clinical: Bleeding 10 – 20% of patients Most common complication 25% of ulcer deaths May be the first indication of an ulcer Perforation Up to 5% of patients 2/3 of ulcer deaths Rarely the first indication of an ulcer

Acute Gastric Ulceration Clinical: Obstruction Mostly in chronic ulcers Secondary to edema or scarring Approx. 2% of patients Most often associated with pyloric channel ulcers Incapacitating, crampy abdominal pain Rarely cause total obstruction and intractable vomiting

Acute Gastric Ulceration Treatment: Prophylactic H2 histamine receptor antagonist or proton pump inhibitors Blood transfusion for severe bleeding Correction of underlying cause

Chronic Gastritis Symptoms less severe but more persistent Nausea and abdominal discomfort Hematemes is uncommon Most common cause: Helicobacter pylori infection Other causes: Chronic irritants – psychologic stress, caffeine, alcohol, tobacco use Autoimmune – most common cause of atrophic gastritis; < 10% of cases Less common causes – radiation, chronic bile reflux, mechanical injury, systemic disease (Crohn’s, amyloidosis, graft-versus-host disease)

Chronic Gastritis: Helicobacter pylori H. pylori present in gastric biopsy specimens of almost all patients with duodenal ulcers, gastric ulcers or chronic gastritis Present in 90% of patients with chronic gastritis affecting the antrum Most common cause of duodenal ulcer 2 nd most common cause of gastric ulcer Increased risk of gastric CA and gastric lymphoma

Chronic Gastritis: Helicobacter pylori Most common cause of chronic gastritis Most often presents as predominantly antral gastritis with high acid production Some progress to involve the gastric body and fundus  associated with multifocal mucosal atrophy, reduced acid secretion, intestinal metaplasia, and increased risk of gastric adenoCA

Chronic Gastritis: Helicobacter pylori Four important virulence factors: Flagella  rapid motility  easily penetrate mucus layer Urease  generates ammonia  increase local gastric pH Adhesins  enhance bacterial adherence to surface foveolar cells Toxins (cytotoxin-associated gene A or CagA )  poorly-defined mechanisms

Chronic Gastritis: Helicobacter pylori Morphology: Organism typically found in the antrum Antral mucosa usually erythematous with coarse or nodular appearance Neutrophilic infiltrates within lamina propria  accumulate in lumen of gastric pits  create pit abscesses Intra-epithelial neutrophils & subepithelial plasma cells characteristic (+) lymphoid aggregates with germinal centers  induced MALT  may transform to lymphoma

H. pylori bacteria (red arrow) imbedded in stomach lining. Courtesy of wikimedia commons.

Active chronic H. pylori gastritis. The gastric mucosa contains large numbers of lymphocytes and plasma cells while polymorphs infiltrate the foveolar epithelium. The surface epithelium shows marked degenerative changes. Hematoxylin and eosin; magnification, ×100.

Chronic H. pylori gastritis. This low-power view shows marked glandular atrophy, lymphoid follicles, and centrally a focus of intestinal metaplasia. H&E ×25.

Chronic Gastritis: Autoimmune Gastritis < 10% of cases of chronic gastritis Typically spares the antrum & includes hypergastrinemia Characterized by: Antibodies to parietal cells & intrinsic factor – detected in serum and gastric secretions Reduced serum pepsinogen I concentration Antral endocrine cell hyperplasia Vitamin B12 deficiency Defective gastric acid secretion

Autoimmune gastritis Pathogenesis: Loss of parietal cells  absent gastric acid production  stimulation of gastrin release  hypergastrinemia and hyperplasia of antral gastrin-producing G cells Lack of intrinsic factor  disables ileal vitamin B12 absorption  B12 deficiency  slow-onset megaloblastic anemia (pernicious anemia)

Chronic Gastritis Complications: PUD Most often associated with H. pylori- induced hyperchlorhydric chronic gastritis May occur in any portion of the GIT exposed to acidic gastric juices  most common in the gastric antrum & first portion of duodenum Risk of development higher in males; females affected during or after menopause Gastric ulcers generally develop on a background of chronic gastritis

Chronic Gastritis Complications: PUD Gastric Ulcers Primary underlying causes: H. pylori infection (>70%) and NSAID use Other contributory factors: Zollinger-Ellison syndrome Multiple peptic ulcerations in the stomach, duodenum, and even jejunum due to uncontrolled gastrin release by a tumor Cigarette smoking Impair mucosal blood flow & healing High-dose corticosteroids Suppress PG synthesis & impair healing

Chronic Gastritis Complications: PUD Duodenal Ulcers More frequent in individuals with: Alcoholic cirrhosis COPD Chronic renal failure  (+) hypercalcemia  stimulate gastrin release Hyperparathyroidism – similar mechanism as CRF NEVER malignant!

Chronic Gastritis Complications: PUD Morphology: 4x more common in proximal duodenum Duodenal ulcers usually within a few centimeters of pyloric valve & involve anterior duodenal wall Gastric ulcers predominantly located along the lesser curvature near the interface of the body and antrum Solitary in > 80% Lesions < 0.3 cm in diameter usually shallow; those > 0.6 cm usually deeper ulcers

Chronic Gastritis Complications: PUD Morphology: Classic ulcer: four layers in sequence noted in histologic sections Necrotic debris Inflammation with predominance of neutrophils Granulation tissue (repair tissue) Fibrosis

The inner lining of the stomach consists of a very thick mucosal layer consisting of tall rows of glandular cells running parallel to each other. The thick mucosa has a deep narrow gap extending to the bottom of the mucosa. This gap is the ulcer. Normal stomach mucosa (40X2.8) Stomach mucosa with ulcer (40X2.0)

Chronic Gastritis Complications: PUD Feature Gastric Ulcers Duodenal Ulcers % of ulcer cases 25% 75% Epidemiology Male:female ratio 1:1 Smoking does not cause PUD but delays healing Male:female ratio 2:1 Risk increased with MEN I, cirrhosis, COPD, renal failure, hyperparathyroidism H. pylori ~ 80% of cases 90 – 95% of cases Pathogenesis Defective mucosal barrier due to H. pylori Mucosal ischemia (reduced PGE), bile reflux, delayed gastric emptying BAO & MAO normal to decreased Defective mucosal barrier due to H. pylori Increased acid prod’n (inc. parietal cell mass) BAO & MAO both increased

Chronic Gastritis Complications: PUD Feature Gastric Ulcers Duodenal Ulcers Location Single ulcer in lesser curvature of antrum (same location for cancer) Single ulcer on anterior portion of 1 st part of duodenum ffed by single ulcer on posterior portion (danger for perforation into pancreas) Complications Bleeding (most commonly in left gastric artery) Perforation Bleeding (most commonly in gastro - duodenal artery) Perforation (air under the diaphragm, pain radiates to left shoulder) Gastric outlet obstruction, pancreatitis Clinical findings Burning epigastric pain soon after eating Burning epigastric pain 1 – 3 hours after eating

Chronic Gastritis Complications: Mucosal Atrophy and Intestinal Metaplasia Long-standing chronic gastritis  loss of parietal cell mass  intestinal metaplasia Presence of goblet cells Increased risk of gastric adenocarcinoma  greatest in autoimmune gastritis Due to overgrowth of bacteria  produce carcinogenic nitrosamines

Chronic Gastritis Complications: Dysplasia Chronic gastritis Epithelium exposed to Free radical damage Proliferative stimuli Genetic alterations DYSPLASIA CARCINOMA

Chronic Gastritis Complications: Dysplasia Morphologic hallmarks: Variations in epithelial size, shape and orientation Coarse chromatin texture Hyperchromasia Nuclear enlargement

Chronic Gastritis Complications: Gastritis Cystica Exuberant reactive epithelial proliferation Associated with entrapment of epithelial-lined cysts May be found in: Submucosa  gastritis cystica polyposa Deeper layers of gastric wall  gastritis cystica profunda May mimic invasive adenocarcinoma

Hypertrophic Gastropathies Uncommon Giant cerebriform enlargement of the rugal folds due to epithelial hyperplasia without inflammation Associated with excessive growth factor release

Hypertrophic Gastropathies: Menetrier’s Disease Rare; due to excessive secretion of TGF- α Diffuse hyperplasia of foveolar epithelium of the body and fundus Protein-losing enteropathy  hypo-proteinemia Increased risk of gastric adenoCA in adults Characteristic feature: hyperplasia of foveolar mucous cells

Hypertrophic Gastropathies: Menetrier’s Disease Microscopic appearance of Menétrier's disease. There is marked hyperplasia of the crypts accompanied by mild atrophy of the underlying secretory mucosa.

Hypertrophic Gastropathies: Zollinger-Ellison Syndrome Cause: gastrin-secreting tumors (gastrinomas)  most commonly found in SI and pancreas 60% - 90% of gastrinomas malignant 25% of patients with MEN I Clinical: duodenal ulcers or chronic diarrhea Morphology: 5x increase in number of parietal cells  doubling of oxyntic mucosal thickness Hyperplasia of mucous neck cells Mucin hyperproduction Proliferation of endocrine cells within oxyntic mucosa

Hypertrophic Gastropathies: Zollinger-Ellison Syndrome

Gastric Polyps: Inflammatory & Hyperplastic Polyps ~75% of all gastric polyps are inflammatory or hyperplasic polyps Most common in 50 – 60 yrs old individuals Develop in association with chronic gastritis Risk of dysplasia correlates with size

Gastric Polyps: Inflammatory & Hyperplastic Polyps Gross appearance of gastric polyps of hyperplastic type. Many of the lesions show central umbilication. Low-power microscopic view of gastric polyps of hyperplastic type. The cystic dilatation of the glands is more evident on the left side.

Gastric Polyps: Fundic Gland Polyps Occur sporadically in patients with familial adenomatous polyposis (FAP) Increased incidence in patients undergoing proton pump inhibitor therapy Reduced gastric acidity  increased gastrin secretion  glandular hyperplasia 5x more common in women; ave. age 50 y/o Well-circumscribed lesions with a smooth surface

Gastric Polyps: Fundic Gland Polyps Endoscopic image of fundic gland polyposis taken on retroflexion of gastroscope. This patient was chronically taking proton pump inhibitors. H&E stain of fundic gland polyp showing shortening of the gastric pits with cystic dilatation.

Gastric Tumors: Gastric Adenoma 10% of all gastric polyps  progressive increase in incidence with age 50 – 60 yrs old; males > females (3:1) Increased incidence in patients with FAP Almost always occur on a background of chronic gastritis with atrophy & intestinal metaplasia Risk of adenocarcinoma related to size of lesion (> 2 cm in diameter)

Gastric Tumors: Gastric Adenoma Usually solitary; antrum Majority with intestinal type of epithelium All GI adenomas have epithelial dysplasia that can be classified as low grade or high grade.

Gastric Tumors: Gastric Adenoma Gross appearance of gastric adenomatous polyps. The larger lesion is a tangle of fingerlike projections. Adenomatous polyp. (From Oota K, Sobin LH: Histological typing of gastric and oesophageal tumours, Geneva, World Health Organization, 1977)

Gastric Tumors: Gastric Adenocarcinoma Most common malignancy of the stomach Risk factors: Intestinal metaplasia due to H. pylori - most important Nitrosamines, smoked foods (Japan), diets lacking fruits/vegetables Type A chronic atrophic gastritis Menetrier’s disease

Gastric Tumors: Gastric Adenocarcinoma Pathogenesis: Diffuse gastric cancer Germline mutations in CDH1 (encodes E-cadherin) BRCA2 mutations p53 mutations Intestinal type gastric cancer Individuals with FAP Mutations in β catenin Microsatellite instability Mutations in p53, TGF β RII, BAX, IGFRII & p16/INK4 α

Gastric Tumors: Gastric Adenocarcinoma Morphology: Classified according to location in the stomach, gross & histologic morphology Most involve gastric antrum; lesser curvature > greater curvature If with intestinal morphology  bulky and composed of glandular structures; exophytic or ulcerated If with diffuse morphology  infiltrative pattern; composed of signet ring cells that do not form glands

Gastric Tumors: Gastric Adenocarcinoma Morphology: Diffuse type not associated with H. pylori May infiltrate stomach wall  desmoplastic reaction that stiffens the gastric wall  called linitis plastica (leather bottle appearance) Produce Krukernberg tumors of the ovaries

Gastric Tumors: Gastric Adenocarcinoma Gross appearance of gastric adenocarcinoma of polypoid type. Gross appearance of gastric adenocarcinoma of ulcerative type showing marked resemblance to chronic peptic ulcer.

Gastric Tumors: Gastric Adenocarcinoma Typical gross appearance of diffuse carcinoma of linitis plastica type. Practically the entire wall of the stomach is involved by tumor. Note the prominence of rugal folds.

Gastric Tumors: Gastric Adenocarcinoma Gastric adenocarcinoma of intestinal type. Diffuse type of gastric adenocarcinoma. An Indian file pattern of infiltration of the muscularis externa can be appreciated.

Gastric Tumors: Gastric Adenocarcinoma Clinical: Weight loss (most common), epigastric pain with vomiting Metastasis to left supraclavicular node ( Virchow’s node ) Paraneoplastic skin lesions Acanthosis nigricans Multiple outcroppings of seborrheic keratoses Metastasis to umbilicus ( Sister Mary Joseph sign ) Common metastatic sites: liver, lung, ovaries

Gastric Tumors: Gastric Adenocarcinoma

Gastric Tumors: Lymphoma Most common extra-nodal site is GIT, particularly the stomach Nearly 5% of all gastric malignancies Often referred to as lymphomas of mucosa-associated lymphoid tissue (MALTomas) Usually arises at sites of chronic inflammation Most common cause: chronic H. pylori infection

Gastric Tumors: Lymphoma Dense lymphocytic infiltrate in the lamina propria Infiltrate the gastric glands focally  create lymphoepithelial lesions  diagnostic Express the B cell markers CD19 and CD20 Most common presenting symptoms are dyspepsia and epigastric pain

Gastric Tumors: Lymphoma EXTRANODAL MARGINAL ZONE B-CELL (MALT) LYMPHOMA — This tumor, previously called MALT-type lymphoma or MALT lymphoma is now called extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in the WHO classification system.

Gastric Tumors: Lymphoma MALT-type malignant lymphoma of stomach involving mucosa and submucosa.

Gastric Tumors: Carcinoid Tumor Arise from diffuse components of endocrine system – majority found in the GIT; > 40% in the small intestines Associated with: endocrine cell hyperplasia, chronic atrophic gastritis, & Zollinger-Ellison syndrome Best considered as well-differentiated neuro-endocrine carcinomas

Gastric Tumors: Carcinoid Tumor Gross: Intramural or submucosal masses Yellow or tan in color Very firm due to intense desmoplastic reaction  cause bowel kinking and obstruction Microscopic: islands, trabeculae, strands, glands, or sheets of uniform cells with scant, pink, granular cytoplasm and round to oval stippled nucleus Positive for endocrine granule markers (synaptophysin and chromogranin A)

Gastric Tumors: Carcinoid Tumor Clinical: Tumors that produce gastrin  cause Zollinger-Ellison syndrome Ileal tumors  cause carcinoid syndrome Cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, and right-sided cardiac valvular fibrosis Strongly associated with metastatic disease

Gastric Tumors: Carcinoid Tumor Most important prognostic factor is location Foregut tumors Found within the stomach, duodenum proximal to ligament of Treitz, and esophagus Rarely metastasize & cured by resection Midgut tumors Jejunum and ileum Multiple and aggressive Hindgut tumors Appendix (at the tip) and colorectum Discovered incidentally Rarely > 2 cm in diameter except if proximal colon

Gastric Tumors: Carcinoid Tumor Small carcinoid tumor of the stomach composed of enterochromaffin-like cells.

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