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TRANSCRIPT
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GI Block I: Lecture List
01) Esophageal Disorders .......................................................... Nompleggi
02) Gastric Mucosal Injury.......................................................... Houghton
03) Pathology of GI Inflammatory Disorders ............................ Banner
04) Pathology of Upper GI Tumors............................................ Ayata
05) Pathophysiology of Diarrhea & Malabsorption.................. Bhattacharya
06) Pathology of Diarrhea & Malabsorption.............................. Banner
07) Pathophysiology of IBD........................................................ Zawacki
08) Pathology of Intestinal Inflammatory Disease ................... Banner
09) GI Neoplasia............................................................................ Barnard
10) Pathology of Colon Polyps/Cancer.......................................... Ayata
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01: Esophageal Disorders& GERD
Normal EsophagusAnatomy
Histology
Stratified squamous epithelium
Z-line:
stratified squamous ofesophagus change toglandular columnar ofstomach
mucous glands in upper glands & near EGjunction
basal layer of cells is source of new epithelialcells
UES (Upper Esophageal Sphincter)
Anatomy
LES (Lower Esophageal Sphincter)
Anatomy
not a distinct anatomical structure
2-4 cm intraluminal high pressure zone
Physiology
has intrinsic tone
LES relaxation caused by stimulation ofinhibitory neurons
release of NO, VIPagents that LES pressure
possible therapeutics
antacids
cholinergic agonists
metoclopramide
hormones
gastrin
motilin
bombesin
pancreatic polypeptide
agents that LES pressure
possible therapeuticsanticholinergics
theophylline
agonists
agonists
hormones
secretin
CCK
VIP
progesterone
lifestyle interventions
caffeine
fatty meal
smoking
ethanol
chocolate
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01: Esophageal Disorders& GERD
The act of swallowing
higher brain center activates swallowing centerin brainstem
nucleus ambiguous, dorsal motor nucleus inmedulla
pharyngeal contraction and UES relaxationcoordinated
primary peristalsis
food propelled along esophagus, butinsufficient to transport food bolus all theway to stomach
secondary paristalsis
initiated when esophagus is distended byfood bolus or gastric contents
this peristaltic wave complete transport offood bolus into stomach
Esophageal Swallowing DisordersEsophageal Symptoms
Dysphagia= difficulty swallowing
oropharyngeal dysphagia= difficultyinitiating swallow or transferring food frommouth into esophagus. Can also experiencenasopharyngeal regurgitation (comes outnose) or pulmonary aspiration.
esophageal dysphagia= food gets stuck in
esophagus after swallowingsecondary to NM (motility) or obstrutive (structural)disorder
NM disorderdysphagia to both solids andliquids
Structural disorderdysphagia to just solids (butmay progress to liquid dysphagia too)
Causes of dysphagia
obstruction
tumor/abscess of oropharynx
vertebral osteophyte impinging on esophagus
Strictures
Rings (Schatzki) and Webs
Extrinsic compression (neoplasms or bloodvessel)
CNS injury
stroke, MS, ALS
PNS injury
bulbar poliomyelitis
Skeletal muscle disorder
inflammatory myopathy (polymyositis)
muscular dystrophies, etc
NM (neuromuscular) transmission disorder
Myesthenia Gravis
Other
cricopharyngeal dysfunction (myopathy leadsto UES opening)
Motility Disorders
Achalasia(failure to relax)
most often results from post-ganglionicdenervation of smooth muscle of esophagus
absence of inhibitory neural input to LESLESpressure
functional esophageal obstructioncan lead toesophageal dilatation
Similar disorder in Chagas disease (Trypanosomacruzi causes injury to myenteric plexuses ofesophagus)
Diffuse Esophageal Spasm(DES)
periodic chest pain & dysphagia
high amplitude, simultaneous, repetitive SMcontractions
can be spontaneous or initiated by swallow
barium swallowcorkscrew appearance toesophagus
pathogenesis unknown
Scleroderma
systemic disease: endothelial injuryvascular
obliterationsmooth muscle atrophy & fibrosisdistal esophageal peristalsis and LES pressure
Calcinosis
Raynauds
Esophageal symptoms
Sclerodactyly
Telangiectasia
small enlarged blood vessels near thesurface of the skin, usually they measure onlya few millimetres. They can developanywhere on the body but commonly on theface around the nose, cheeks and chin
Non-Specific esophageal motility disorders
Hypertensive LESNutracker esophagus
amplitude, long duration peristalticcontractions
Other esophageal symptoms & definitions
Odynophagia= painful swallowing, impliesesophageal inflammation
Globus= lump in throat
Heartburn= pyrosis= burning painassociated with regurgitation of sour (acidic)or bitter (alkaline) stuff into mouth.
Regurgitation= sudden appearance of
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01: Esophageal Disorders& GERD
small amounts of gastric/esophagealmaterial in mouth
Esophageal chest pain= squeezingretrosternal pressure-like sensation. Unlikecardiac pain, relieved slowly bynitroglycerins and not associated withexercise.
Waterbrash= sudden filling of mouth with
warm salty fluid (saliva), reflexively inducedby GER
Gastroesophageal Reflux (GER)A little bit of GER is normal in all of us
Normally, thoraxic cavity has negative pressureduring inspiration
GER would occur continuously without anti-reflux mechanisms
a portion of esophagus is below the diaphragmintra-abdominal pressure (+5 mm Hg) canreinforce LES pressure (antireflux effect)
Loss of subdiaphragmatic LES correlation
between esophageal hernia and GERDNormal anti-reflux mechanisms
Competent LES (primary barrier to GER)
LES pressures are in GERD patients
but LES pressure alone does NOT account forGER in most GERD patients
Three important LES mechanisms resultingin GER
1) weak basal LES pressure
2) inadequate LES response to abdominalpressuredue to disruption of diaphragmaticsphincter
particularly important w/ hiatus hernias
along w/ LES pressure, is most importantmechanism in patients w/ hiatus hernias
3) transient LES relaxation
this lets you burp
most prevalent mechanism of GER in bothasymptomatic patients and GERD patients
Effective Esophageal Clearance
delayed clearance occurs in up to 50% ofpatients w/ esophagitis
two mechanisms:
1) impaired esophageal peristalsis
2) re-reflux = to and from movement of refluxed
material associated with hiatus herniasmay be especially important in patients withnocturnal GERD
while asleep, salivation and swallowing(primary peristalsis)
Neutralization of refluxed acid by salivary bicarb
decreased during sleep and in cigarettesmokers
Esophageal mucosal resistance
diffusion of H+ can lead to cellularacidification and necrosis
Diagnosis of GERD
Best test: pH probe
checks for existence of acid reflux andassociation between esophageal acid andchest pain
Other tests
Barium swallow
checks for reflux, mucosal damage
esophagoscopy
checks for reflux, mucosal damage
esophagial biopsy
checks for mucosal damage
acid perfusion test (Bernstein): perfuse acidinto esophagus and see what happens
checks association between acid and chest pain
Treatment of GERD
Only clinically useful treatment: antacids andproton pump inhibitors
List of all Medical treatments, by function
LES pressureantacids
bethanechol
metoclopramide
esophageal clearance of gastroduodenalcontents
(none?)
gastric pH
antacids
histamine-H2 receptor blocker
prostaglandins
proton pump inhibitors
gastric emptying and gastric volumemetoclopramide
esophageal mucosal resistance
prostaglandins
sucralfate
Surgical approaches to treatment or GERD
antireflux surgery
Other therapies
endoscopic suturing, etc
Lifestyle modifications
dietary: small meals, no bedtime snacks
mechanical: no tight fitting clothing, elevatehead of bed
Complications of GERD
1) Erosive esophagitis
2) Esophageal ulcer
3) Bleeding
4) Esophageal stricture
5) Intestinal metaplasia (Barretts)
6) Adencarcinoma from Barretts
7) cough, hoarseness, pneumonea, asthma, etc
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02: Peptic Ulcer Disease
Peptic Ulcer (PU) Disease: Range of injurymild inflammation
histology: infiltration of mucosa withinflammatory cells
endoscopy: reddened and sometimes thickenedarea
erosions
denudation of mucosa limited to above themuscular mucosa
ulcer
deeper penetration of injury
Location of injurystomach:
typically in antrum (distal stomach - normallylined by columnar epithelium that does notsecrete acid), specifically @ junction of oxyntic(acid producing) and non-oxynitic mucosa
non-acid secreting mucosa more susceptibleto peptic ulceration
parietal cells located in body/fundus (proximalstomach - ulcers not found as often here)
parietal cells secrete acid and intrinsic factor
long-standing H. pylori infection atrophyof oxyntic mucosa and achlorhydria
patients with ulcers in proximal stomachusually have substantial gastric atrophy andacid output
bacterial overgrowth
duodenum:
within duodenal bulb
can cause outlet obstruction
usually single
multiple/large/more distal ulcersthink ZE
PresentationSymptoms
Symptoms dont correlate with severity ofdisease!
Visceral pain more complicated than simply acidcontact with ulcer
Quality:
wide spectrum of complaints!
can range from asymptomatic (untilcomplications such as
perforation/hemorrhage) to painful
pain can range from burning, gnawing,hunger-like, or vague and cramping
back pain is ATYPICAL unless a DU(duodenal ulcer) has penetrated intopancreas
Classic symptoms of duodenal ulcer (DU):
2-5 hrs after meals
Symptoms also occur at night, between 11 PMand 2 AM
circadian stimulation of acid is maximal
Classic symptoms of gastric ulcer (GU)
more severe pain occuring soon after meals
less frequent relief by antacids or food
Natural history & Duration
symptoms reappear cyclically
residual pain after treatment is a poor indicatorof ulcer healing
Pathogenesis: NSAIDs & HpH. Pylori (Hp)
Epidemiology
In US, Hp responsible for 60% of GU and95% of DU
How does Hp cause ulcers?
host immune response, and pattern ofcytokine secretion
IL-1, TNF-, IL-10 confer greatest risk ofsevere dz and progression to cancer
majority of pts with ulcer disease will have Hpinfection, but converse is not true
many pts with Hp infection areasymptomatic
NSAIDs, Cox-2 antagonists, aspirin, other anti-platelet agents
NSAID Risk
NSAIDs as a group: FDA: clinicallysignificant NSAID-induced GI event (GIbleed, perforation, or pyloric obstruction) =1-4% per year
Aspirin: probably dose dependent, but anydose will risk of ulcer dz
Drug Synergy:
NSAIDs + Corticosteroids: risk compared withNSAIDs
but corticosteroids have no GI risks bythemselves
NSAIDS + anticoags, other NSAIDs, low doseaspirin, alendronate all synergize to risk
Risk factors that GI toxicity with NSAIDS
prior history of clinical ulcer dz
dose, duration of action, duration of therapy,advanced age
Clinical presentation
up to 50% of patients who take chronicNSAIDs have petecheae & erosions, but not
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02: Peptic Ulcer Disease
clinically significant
Its the systemic effect of these drugs thatare important for ulcer pathogenesis!
Clopidogrel (Plaxiv) antiplatelet agent
contraindicated in pts with risk of GIbleeding (history, etc)
COX-2 inhibitors
in risk for clinical peptic ulcers &complications
but they healing of active ulcers
Valdecoxib & refecoxib removed frommarket because of CV complications
risk synergizes () with low-dose aspirin
NSAID Hp synergy is controversial and complex
some patients with Hp and acid secretion maybe protected from effects of NSAIDs
others Hp patients with active ulcers would be atrisk of NSAID complications
bottom line: two known causes of ulcer dz (Hp &
NSAIDs) are worse than oneTrends in prevalence
PU and GU over past several decades
DU and GU
opposite to trends in esophagitis andesophageal/cardiac adenocarcinoma
shift in PU prevalence from M >> F to M = F,less young people getting sick, but more oldpeople getting sick
younger people getting infected with Hp less(better sanitatioon)
NSAID use increases with age
shift in smoking: more women startingsmoking, more men stopping
oh, dont youlook suavenow, baby
Ulcer complicationsMajority of complications associated with:
chronic peptic ulcers (especially in absence ofNSAIDs)
surrounded by fibrosis, smolderingNSAID ulcers sometimes lack fibrosis and arepresumably acute
The complications
heralded by new ulcer symptoms or a change insymptoms
may occur in the absence of typicalsymptoms (silent ulcers)
bleeding, perforation, obstruction, penetratinginto surrounding organs (DU penetrating inpancreas
Presenting symptoms
Penetrating Ulcers
present with shift from vague visceraldiscomfort to localized and intense pain thatradiates to back
not relieved by food or antacids
Perforation
sudden development of severe, diffuseabdominal pain
Pyloric outlet obstruction
Vomiting is cardinal feature
Hemorrhage
nausea, hematemesis (vomiting blood),melena, or dizziness
Many patients underestimate significance ofsymptoms and fail to present in timely fashion
Atypical UlcersGiant u lcers
> 2 cm diameter
Giant DUs
located on posterior wall
present with prolonged typical history, painradiating to back, or can present with fewsymptoms
often complicated by bleeding and posteriorpenetration (pyloric obstruction less common)
more prone to severe hemorrhage andpenetration
risk of malignancy
Etiology: NSAID use, ESRD, Crohns dz
Pyloric channel ulcers
pain after eating, vomiting
due to inflammation & fibrosis of pyloric channel(caused by ulcer)
Postbulbar ulcers
DUs usually located in duodenal bulb within 2-3cm of pylorus
more distal duodenum/proximal jejunum gastrinoma/other hypersecretory states
THINK ZE
Multiple Ulcers
often clustered together
associated with smoking, deformity of duodenalbulb
DiagnosisBottom line
age below 45, without alarm symptoms treated empirically
age over 45 or with alarm symptomsneedinvestigation
risk of cancer
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02: Peptic Ulcer Disease
Alarm Symptomssuspicious of malignancy
weight loss
bleeding
anemia
dysphagia
Blood tests
liver function, [Ca++], etc (to rule out
malignancy)Upper endoscopy (esophagogastroduodenoscopy =EGD)
procedure of choice
differentiation of benign GU from cancer
benign
smooth, regular, rounded edges
flat smooth ulcer base filled with exudate
malignancy
ulcerted mass protrudes into lumen
folds surrounding ulcer crater are nodular,clubbed, or stop short of ulcer margin
margins are overhanging, irregular, or thickened
endoscopic biopsy to rule out malignancy
multipe biopsies of GUs necessary
should even be performed for benignappearing ulcers
may harbor malignancy
You dont need to biopsy DUs
no relationship w/ duodenal cancer
duodenal is very rare
Barium radiographs
definitive radiographic diagnosis of PU requiresevidence of ulcer niche
secondary changes of GU
folds radiating to crater
changes related to edema or scarring
secondary changes of DU
deformity of duodenal bulb
to prevent false positivescheck that craterconfiguration is consistent across multiple X-rayviews
factors effecting sensitivity
single contrast techniques: miss up to 50%of DUs
double contrast, compression, hypotonicduodenography: detect up to 90% of DUs
sensitivity varies with technique of examiner
shallow lesions (
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03: Pathology of Inflammatory Disorders of Esophagus and Stomach
Esophageal Anatomy3 luminal narrowings
cricoid cartilage
left mainstem bronchus
disphragm
No serosa
Esophageal Mechanical & Motility disorders
Achalasiatone of LES
Causes
primary idiopathic
secondary to Chagas dz, diabetes,neurodegenerative, amyloid, sarcoid
Complications
1) squamous carcinoma
2) infections
3) aspiration pneumonia
Hiatal Hernia
protrusion of stomach through diaphragm
reflux
Sliding: most common type (90%)
stomach pulled into thorax by traction fromshort seophagus or scarring
Paraesophageal (rare)
gastric cardia protrudes through defectindiaphragm
can lead to infarction/necrosis
Complications:
ulcerations, bleeding, perforation
Webs and rings
Rings more common than webs
Webs in upper esophagus
Histology
little fold in esophagus, but epithelium is totallynormal
predisposes to carcinomas
F > M (typical: middle-aged woman)
Plummer Vinson syndrome (Paterson-Brown-Kelly)
Web
Iron deficiency anemia
Glossitis (inflammation of tongue)
frequency of carcinoma of esophagus
Schatzkis ring in distal esophagus
Tears
can be due to trauma
Mallory-weiss tear
partial-thickness, linear tear across G-Ejunction
Boerhaaves syndrome
full thickness rupture of esophagus or
stomachZenkers diverticulum
Esophageal Varices
very common
complication of portal HTN
can see veins budding in on endoscopy (darkworm things)
EsophagitisIatrogenic
Alendronate (Foxamax)
can cause esophageal necrosis if pill gets
stuck in esophagustherefore pts instructed to drink a full glassof water and remain standing 30 mins afterthey take pill
Antibiotics doxycycline
NSAIDs
Infections
Herpes Esophagitis
Gross appearance
lots of little erosions
Microscopic
inflammatory exudate, lots of neutrophils
arrow points to edge of mucosal erosion
Multinucleated Giant cells
Ground glass appearance of nuclei
Immunostains for Herpes
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03: Pathology of Inflammatory Disorders of Esophagus and Stomach
Diagnosis
Brushing is effective
CMV Esophagitis
Histology
Virus is in VESSELS (endothelial cells)
Diagnosis
Brushing is NOT effective, since virus is in vessels
Must biopsy
Candida Esophagitis
especially in IC pts
tan granular exudates
silver stain: see hyphae
GERDWhat is GERD?
Reflux of acid-peptic gastric contents into loweresophagus
all agesdysphagia, heartburn, regurgitation
Pathogenesis
damage of esophagus due to reflux of acid andgastric contents
LES incompetence
disordered motility
gastric pressure (i.e. in obesity)
mucosal damage
pH of gastric juice
Hiatal hernia (90%)
Biopsy considerationsmultiple biopsies necessary: histologic s maybe patchy
must biopsy more proximal than 2 cm from GEjunction
distal 2 cm of esophagis may showinflammation and eosinophils inasymptomatic pts
biopsy whole thickness of mucosa
take biopsy to scan for preneoplasia (barretts,dysplasia, metaplasia)
Histologic Features of GERD
1) Squamous hyperplasia
length of subepithelial papillae of laminapropria > 2/3 thickness of mucosa
Basal zone is >20% of total mucosalthickness
Hallmark: elongation of stroma
in left image above, note that cuboidal cellsat top have pushed down
2) Eosinophils! (right image above pink)
Important Complications of Reflux
1) Reflux Stricture
fibrous thickening as a reaction toinflammation
note barium swallow shows gradual narrowing
note very thick white wall of esophagus
NOT achalasia (achalasia is a normal wallthat wont relax)
2) Barretts
acquired condition in which squamousepithelial lining of esophagus is replaced bymetaplastic intestinal-type columnarepithelium
adults & children
pre-existing GERD10% will develop barretts
10% of barretts will develop Adenocarcinoma
Location of intestinal metaplasia:
Z line: squamo-columnar junction (not necessarilyanatomical GEJ)
to a sugeon: GEJ peritoneal reflection
to a radiologist: GEJ end of rugal folds
> 2 cm above Z line barretts
< 2 cm above Z line short-segment barretts
below Z lineunknown significance
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03: Pathology of Inflammatory Disorders of Esophagus and Stomach
Gross Barretts
Criteria for diagnosis of Barretts
1) Intestinal metaplasia: glands with goblet cells
special goblet cell stain
2) Pink mucosa
Watch out for carcinomas!
Magenstrasse: German for stomach street
follows lesser curvature of stomach
is where carcinomas are most likely to befound
3) Bleeding
4) Ulceration
Pathogenesis of Acid Peptic Injury
Body/Fundus of stomach: Gastric OxynticMucosa: H+ secreting cells (Parietal)
Antrum: highest concentration of gastrin-secreting cells (endocrine). Simple glands, Noparietal cells.
Mechanisms of injury
disruption of gastric mucosal barrier
back diffusion of H+
damage to surface epithelium &capillaries
hyperemia, edema, inflammation
surface epiothelium regenerates
NSAIDs, Prostaglands, and Gastric Mucosa
Prostaglandins are cytoprotective
maintian blood flow
mucus secretion
bicarb secretionmaintain cell integrity
NSAIDS prostaglandin secretion
Acute Hemorrhagic GastritisAssociations
stress: cushings ulcer
burns: curlings ulcer
many others (NSAIDs, EtOH, sepsis, smoking,uremia, etc)
Evidence of blood flow, RBCs spilling out of dilatedcapillaries
many tiny red spotscan turn into outrighthemorrhage
can cause fatal GI bleeds
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03: Pathology of Inflammatory Disorders of Esophagus and Stomach
Erosions and UlcersMucosal erosion
loss of epithelium creating defect limited tomucosa
acid peptic injury can also produce
Peptic Ulcer
Definition
loss of tissue creating defect in mucosa thatextends through muscularis mucosa intosubmucosa or deeper layers of gut wall
ulcers which occur in any portion of GI tractexposed to acid/peptic juice
Hp infection in 100% of pts with DU and70% with GU
Sites in descending frequency
duodenum
gastric antrum, lesser curvature
GE junction
gastrojejunostomy (marginal ulcer)
can be casued by Billroth I & II surgeries used totreat gastric cancer
duodenum, stomach, jejunum in ZE
jejunum near Meckels diverticulum
persistence of vitelline duct or yolk stalk
may contain ectopic acid-secreting gastric mucosaand/or pancreatic tissue
most common congenital anomaly of GI tract
can cause bleeding or obstruction near terminalilium
contrast with omphalomesenteric cyst = cysticdilatation of vitelline duct
Acute gastric ulcer
disruption of mucosa
Chronic gastric ulcer
grossly, looks sharp and punched-out
rugal folds run right up to the edge
sharp edges (cancers are irregular & bulky)
Complications of Peptic Ulcer
Hemorrhage (15-20%)
Perforation (5%)
Duodenal obstruction (2%)
Iron deficiency anemia
Carcinoma (rare)
Helicobacter pylori
Clinical features of infection
chronic infection, often asymptomatic
endoscopic appearance: hemorrhages,erosions
complications: GU, DU, gastric carcinoma,MALT lymphoma
Mechanisms of injury
bacteria adhere to surface of epithelial cells
bacteria products injure epithelial cells
urease: buffers acid around bactera, butbreakdown products (ammonia) are toxic toepithelium
bacterial phospholipases, proteases are toxic
VacA (vacuolating toxin) gene regulated by CagA
bacteria induce epithelial cells to procuceinflammatory cytokines
IL8 recruits neutrophils
IL1, IL6, TNF
porins are chemotactic for polys
bacterial proteins are immunogenic for T and Bcells
Biopsy
gold standard for diagnosis
G - , curvilinear rods (Seagulls) present on
surface of gastric epithelium
Inflammation usually involved
Neutrophils indicate activity
lymphoid follicles
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03: Pathology of Inflammatory Disorders of Esophagus and Stomach
Autoimmune Gastritischronic gastritis atrophy predisposing factorfor carcinoma and autoimmune anemias
Histology
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04: Pathology of Upper GI Tumors
Esophageal TumorsClassification
Epithelial Tumors
Squamous cell papilloma
intraepithelial neoplasia - dysplasia
carcinoma
squamous cell carcinoma
adenocarcinomacarcinoid tumor
Non-Epithelial tumors
leiomyoma/sarcoma
rhabdomyosarcoma
lipoma
GIST(gastrointestinal stromal tumor)
kaposi sarcoma
malignant melanoma
Secondary Tumors
Benign tumors of Esophagus
Esophageal squamous papilloma
mature epithelium w/hyperplasia &papillomatosis
core of vascular CT
small, solitary, sessile
assocated w/HPV
Leiomyoma of Esophagus
most common benign tumor of esophagus
bland smooth muscle cells
Squamous cell carcinoma of esophagus
malignant epithelial tumor with squamous celldifferentiation
Epidemiology
M > F
more frequent in eastern countries (Iran,China, S. Africa, Brazil)
Etiology
Pathogenesis
Multistage proccess:
normalbasal cell hyperplasiaintraepithelial neoplasiainvasivecarcinoma
intraepithelial neoplasia (dysplasia) =disorganizatoin of epithelium with loss of normalcell polarity & cytologic atypia
Invasive SCC: penetration of neoplastic squamouscells through basement membrane into laminapropria or deeper
Precursor lesions
dysplasia (intraepithelial neoplasia)
low grade (mild dysplasia)
high grade (severe and carcinoma in situ)carcinoma in situ
Contributing factors
Tobacco and alcohol, nutrition, HPV
Associations:
achalasia, Plummer-Vinson, celiac dz
Gross appearance
Early stage
polypoid
plaque-like
depressed
occult
Advanced stagefungating (exophytic)
ulcerative
infiltrating (stenotic)
Microscopic features
grading based on differentiation
Prognosis: most significant factor is tumor stageAdencarcinoma of Esophagus
malignant epithelial tumor with glandulardifferentiation
Epidemiology
incidence
M > F
average age 65
more common among whites
typically located in distal esophagus
may originate from heterotopic gastric mucosa
Etiology
most important etiologic factor: chronicreflux
tobacco
transition from Barretts (precursor lesion) toadenocarcinoma
normal squamous epithelium
esophagitis
barretts
dysplasia
carcinoma
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04: Pathology of Upper GI Tumors
Dysplasia (intraepithelial neoplasia) in Barrettsesophagus
low grade dysplasia
neoplastic process limited to epitheliummucus secretion
nuclear pseudostratification
mild pleomorphism
mitoses
cytologic abnormalities
high grade dysplasia
glandular crowding, irregular glands, cribriforming
marked pseudostratification
marked atypia
mitoses
Presenting symptoms of adenocarcinoma:
dysphagia, obstruction, weight loss
Adenocarcinoma in Barretts
Histopathology of Adenocarcinoma
typically papillary +/- tubular
rare glandular formations
signet ring cells
mucinous adenocarcinomas also occur
grading based on differentiation
barrets esophagus with dysplasia &adenocarcinoma
Moderately differentiated adenocarcinoma
Poorly differentiated adenocarcinoma
Adencarcinoma of esophagogastric junction
tumors that cross EGH
microscopic features
Prognosis:
advanced tumors spread directly intomediastinum, aorta, stomach
50% metastasize to regional LN
most important factor: stage
Stomach TumorsClassification
Epithelial tumors
Intraepithelial neoplasia Adenoma
Carcinoma (Adenocarcinoma)
Carcinoid tumorNon-Epithelial tumors
GIST
Lymphoma
Secondary Tumors
Gastric adenocarcinoma
malignant epithelial tumor of gastric mucosa withglandular differentiation
Epidemiology
common cancer: 2nd
commonest in the world
incidence and mortality
extremely rare before age 30Etiology: multifactorial
diet
associated with salt, smoked meat, pickledvegetables, chili peppers
bile reflux
Hp infection
H.Pylorichronic gastritis mucosal atrophyintestinal metaplasiaintraepithelial neoplasia
follows atrophic gastritis
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04: Pathology of Upper GI Tumors
macroscopic features of gastric adenocarcinoma
flat or polypoid dysplasia
advanced carcinoma: polypoid, fungating,ulcerated, infiltrative
diffuse (infiltrative) tumors may present aslinitis plastica or leather bottle
mucinous adenocarcinoma appearsgelatinous with glistening cut surface
microscopic features
Gastric Epithelial dysplasia
Low grade intraepithelial neoplasia
slight architectural abnormalities
pseudostratified oval nuclei
mitoses
DDx: reactive/regenerative s
High grade intraepithelial neoplasia
architectural distortion
glandular crowding
prominent cellular atypia
mitoses
Gastric Adenocarcinoma
Histologically variable
Usually one of four patterns predominate
tubular
papillary
mucinous (>50% mucinous pools)
Signet-ring cell (>50 signet-ring cells)
classical signet-ring cell: single cell withnuclei pushed against cell membranedue to expanded, clear cytoplasm
Lauren classification of gastric adenocarcinoma
intestinal type gastric adenocarcinoma
recognizable glands, well differentiated
diffuse type gastric adenocarcinoma
little gland formation, poorlydifferentiated
mixed
indeterminate
Prognosis
overall survival at 1 year after diagnosis is63%
stage is most important prognostic indicator
Gastrointestinal Stromal Tumorsmajority of all mesenchymal tumors involving GItract
Early designations: leiomyoma, cellularleiomyoma, leiomyoblastoma, leiomyosarcoma
most common in stomach, but can involve smallintestine, colorectum, esophagus too
origin: interstitial cells of Cajal (pacemaker cells)
Overexpress CD117 (c-KIT)
receptor kinase
Microscopically:
spindle cell tumorresemble smooth muscle cells
focal nuclear palisading like nerve sheathtumors
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Pathophysiology of Diarrhea & Malabsorption
Diarrhea is both a sign and symptomSymptom
in frequency, in volume, in consistency
Objective Sign
150 200g per 24 hrs
Two mechanisms for diarrhea1) absorption of fluid & electrolytes, could be due
to:a) inhibited/defective absorption:
cholerainhibited fluid absorption
congenital chlorridorheainhibitedelectrolyte absorption
b) osmotically active agents in lumen:
lactase-deficient subjects
sorbitol in sugar free gum
c) propulsive activitycontact time withbrush border
not likely to be a primary cause of diarrhea,
but can augment other mechanisms2) secretion of fluid & electrolytes, caused by:
a) anion secretion
due to stimulation by endogenoussecretagogues
VIP, prostaglandins, histamine
or endogenous toxins
cholera toxin, E. Coli toxins
b) secretion from crypts
Normal GI PhysiologyIntestine has a large surface area for absorption
folds of kekring (3x)villi (10x)microvilli/brush border (20x)
600x multiplication factor of the nakedsurface area
Ion channels/carriers in intestinal cell
Uniport
GLUT2: facilitated glucose transporter
Symport
Na/Glucose cotransporter: important inrehydration of diarrhea pts
Na/K/2Cl cotransporter
Antiport
Cl/HCO3exchanger
Na/H Exchanger
Active Transport
Na/K ATPaseis essential for creating andmaintaining K and Na internalconcentrations that most other transportersrely on
Water Absorption
Give glucose & Na to orally rehydrate a patient
Na absorbed by cotransport with glucose &aas
Water follows Na
Many factors regulate or modulate intestinalwater/electrolyte transport
Primary messengers
paracrine
inflammatory cell products
neurocrine
endocrineSecondary Messengers
cAMP, Ca++, cGMP
mucosal endocrine cells
interspersed among intestinal epithelial cells
secrete active amines and hormonalpeptides to stimulate nearby cells
Enteric neurons
subepithelial myofibroblasts
Immune cells
Classification of Diarrhea
Secretory Diarrhea
General characteristics
electrolyte secretionconcomittent waterflow
isotonic stool
large volume: > IL/day
persists when fasting
Examples:
Cholera:
Disease
intestinal fluid loss due to toxin acting on
small bowel epithelial cellsorganism does not invade mucosal surface
mucosal architecture remains intact
bacteremia is NOT a complication
rice water watery and voluminous diarrhea(origin of fluid is upper small bowel) canquickly dehydrate (fluid losses up to 1 L/hr)
Organism
G-, curved rod
spread: contaminated food and water
uncommon person-person spread
requires a billion organisms to infect
Mechainsm of Toxin
Toxin consits of and subunits:1) binds to GM1-ganglioside luminalmembrane receptor on enterocytes
2) enters cell, translocates throughundetermined mechanism to basal side
3) irreversibly activates basolateraladenylate cyclase
4) conversion of ATP cAMP
5) anion secretion and inhibition of neutralNaCl absorption
luminal accumulation of fluid & diarrhea
Heat-labile and heat-stable E. Coli toxinscause disease similar to Cholera
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Pathophysiology of Diarrhea & Malabsorption
All secretory bacterial enterotoxins share 3major features
1) stimulate net secretion of intestinal fluid andelectrolytes by promoting anion secretion andinhibiting NaCl absorption
2) toxins cause no morphological damage
3) Na-dependent sodium absorption NOT affected
can be treated with oral rehydration
Can be caused by hormone-producingtumors
carcinoidserotonin, prostaglandins, bradykinin,tachykinins
VIPomaVIP
gastrinomaGastrin
medullary carcinoma of thyroid calcitonins,prostaglandins
ganglioneuromaVIP
Osmotic Diarrhea
Lactase deficiency (most common cause ofosmotic diarrhea)
Symptoms
diarrhea, abdominal distension, bloating, cramps,flatulence (due to colonic bacteria fermentationmaking CO2and H2)
Physiology
normally lactose metabolized to glucose +galactose
with lactase deficiency, hydrogen (H2), short chainfatty acids (SCFA), and CO2production isincreased by colonic bacteria
low stool pH due to SCFA
H2exhaled
increased osmotic force leads to luminal H2Ocolonic absorptive capacity overwhelmed
Motility Diarrhea
defective motility can cause diarrhea
normally, motility determines the rate thatliquid chyme is transported through intestine
motilitycontact time with epithelialcells
IBS (Inflammatory Bowel Syndrome)
Characteristics
very common, F > M
due to neurotransmitter imbalance?
psychosocial factors involved
altered motilitydistension/spasm
pain/bloating/urge to defecateSymptoms
diarrhea, constipation, abdominal pain
carcinoid syndrome
postvagotomy/post gastrectomy diarrhea
thyrotoxicosis
Exudative Diarrhea
Clinical
bowel movement frequency
abdominal pain, fever, malaise, enesmus(persistent rectal urgency with fewer BMs)
Mechanism of exudative diarrhea
secretion and absorption
stimulation of enteric nerves causingpropulsive contractions and secretion
mucosal destruction and increasedpermeability
nutrient maldigestion and malabsorption
ExamplesIBD (Inflammatory Bowel Disease)
Crohns disease
Ulcerative colitis
Infectious diarrhea
Shigella
C. diff
Entamoeba histolytica
Antibiotic-associated
Pseudomenbranous colitis
C. diff
any antibiotic can cause, clindamycin istypical
Malabsorptive Diarrhea
physiology
failure of digestion
absorption
transport
theoretical causes
Complex molecules are not boken down inthe lumen i.e. lack of brush border enzymesin lactose intolerance, disaccharidasedeficiency, or diminished bile salt secretion.
Secondary to diminished or damaged
mucosal cells (viral gastroenteritis) ordecreased surface area at in celiac sprue
Lymphatic obstruction
Classification
Mucosal abnormalities
celiac sprue
whipples disease
allergic gastroenteritis
crohns disease
lymphoma
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Pathophysiology of Diarrhea & Malabsorption
Celiac DiseaseCharacteristics
autoimmune disorder
trigger: gluten
malabsorption and villous atrophy
response to gluten free diet
strong association w/ HLA-DQ2 or HLA-DQ8
Clinical manifestationsrange from asymptomatic to severe diarrhea
malabsorption, bloating, flatulence, weight loss
systemic complications:
anemia
hypocalcemia
osteopenia
neurological symptoms
dermatits herpetiformis
intensely pruritic skin eruption with many smallpapules or vesicles
responds to gluten withdrawl
Pathology
affects duodenum first and progresses distally
ultimately causes
villus atrophy
crypt hyperplasiamucosal inflammation
Endoscopy:
mosaic pattern to mucosa after blue dye
scalloping of folds
Mechanisms of Diarrhea
brush border hydrolases resulting inunabsorbed osmols
villous atrophymalabsorption & steatorrhea
fatty acids in lumen further induce colonicfluid & electrolyte secretion
crypt hyperplasiaendogenous secretioninflammation-induced secretion
Whipples diseaseChronic systemic infection
presence of PAS-positive, bacteria-ladenmacrophages
primarily in lamina propria of small intestine
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Pathology of Diarrhea & Malabsorption
Overview of DigestionDigestion
breakdown of complex fats, sugars, proteins
Absorption
molecules move across epithelium into laminapropria
Transport
molecules move from lamina propria intocirculation
Normal functions of small bowel
digestion/absorption
endocrine/regulatory
cell renewal
immune/GALT
Normal structure of small intestine
Brush border (EM)
note light gray haze between microvilliluminal enzymes (sugar breakdown, etc)
Goblet Cells
make mucous & IgA
Crypt endocrine cells
regulatory function, sample contents of
lumenPaneth cells
secrete Lysozyme (bactericidal)
Cell renewal in colon
cell renewal in depths of crypts (same in smallbowel & colon)
cells constantly dividing, migrating upwards,then eventually slough into lumen
small bowel transit time: 2 days
thats why it takes some time to recover fromproliferative diarrhea
Small bowel dome area
T suppressor cells in topmost epithelial layers
B cells in germinal centers
T cells interspersed
GALT: gut-associated lymphoid tissue
immune system of gut
dispersed along entire GI tract
Specialized structure of BM to allow largemolecules through
dome areas can become hyperplastic to fightinfection
Complex cellular migration
M cells absorb antigens (act as APCs) andpresent processed Ags to dome area.
B cells then proliferate, migrate to LN, andsecrete IgA
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Pathology of Diarrhea & Malabsorption
Acute diarrheal syndromesToxic/metabolic effects (non-proliferative)
Characteristics
enterocytes NOT damaged
purely physiological diarrhea, structure notchanged
Toxins (E. Coli)
Bacteria adhering and deforming cellmembrane
brush border disrupted, transport processesdisrupted
pathologically:
villus bluting
inflammation
not TOO much damage
Obstructional diarrhea (Giardia)
Characteristics
Infective cysts in water
trophozoites coat duodenal villi and interfere withbrush border enzymes
they just sit there
Clinical sx: acute diarrheal illness or malabsorption
Dx: cysts in stool, trophozoites in duodenalaspirates/biopsy, or serology
Pathology
L: lots of Giardia sitting on lower part of villus
R: notice large ventral sucker of giardia
giardia just sits there, covering many microvilli disruption of osmotic equilibrium (obstructionalmalabsorption).
Feeds on material in lumen.
Can see giardia on H & E
Damage to enterocytes (proliferative) inflammatory response
Characteristics
enterocytes damaged
Viral infections
Reovirus
See blebs, cell protrusions, denuded villus after afew hours. But quickly recover after 24 hours.
Norwalk agent
Bacterial infections
E. Coli, Salmonella, Shigella, Campylobac,Y. enterocolitica, C. diff
plasma-encoded adhesins allow Bacteria toadhere to microvillus
bacteria produces enterotoxin or invadesmucosa of colon or SI
Pseudomembranous colitis
pseudomembrane plaques of mucus,fibrin, polys, necrotic cells
pseuedomembrane attached at sites ofmucosal injury, mushrooms over intactadjacent mucosa
L: bloody, nasty, exudative bowel
R: eruptive lesions: pseudomembranecomposed of mucus, polys dead cells
L: dead cells, polys, mucous
R: fibrin present, implies damagedcapillaries
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Pathology of Diarrhea & Malabsorption
Chronic diarrheal syndromes malabsorption
Mucosal injury
Celiac sprue= gluten-sensitive enteropathy
malabsorption due to immune-mediateddamage to small bowel mucosa
frequency w/ Class I HLA B8, Class IIHLADR3/DQw2
Mechanism of Injury
abnormal response to gliadin fraction of gluten inwheat, rye, barley
Adenovirus B12
viral protein shares aa sequence with alpha-gliadin
immune response involves both cell-mediated &Ab-mediated injury
Pathology
flattening of microvilli
evidence for intraepithelial lymphocytes (CD3stains for T cells) in celiac dz
Definitive diagnosis1) flat biopsy
2) malabsorption
3) response to gluten free diet should fix it
Complications
vitamin deficiency
Fe-deficiency anemia
growth retardation/osteomalacia
aphthous stomatitis
dermatitis herpetiformis
enteropathy-associated T-cell lymphoma
carcinoma of esophagus, stomach, bowel
Whipples Disease
Systemic infection by Tropheryma whippelii(actinobacterium)
middle-aged white men
Clinical:
malabsorption, weight loss, arthritis,lympadenopathy, neuropsychiatric symptoms
small bowel biopsy diagnostic
treatment: antibiotics
differential diagnose: distinguish between
mycobacterium avium intracellulare (MAI)
compare biopsies to determine
histo
Pathology
extended villimalabsorption
due to bacteria taken up by histiocytes
Damage to crypt cells (not discussed in class)
GVHD
Small bowel biopsy
Colon biopsy
Radiation
HIV
Parvovirus
small bowel transplant rejection
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Pathophysiology of IBD
Inflammatory Bowel Disease (IBD)Definition
group of chronic inflammatory disorders ofunknown cause involving GI tract
Classification
Crohns Disease (CD)
Ulcerative Colitis (UC)
Indeterminant colitis~15% of patients cant be classified as eitherUC or CD
Pathophysiology of IBDThree Key Factors
1) genetic susceptibility
only ~20% of IBD patients have first degreerelative with IBD
CD has greater genetic influence
NOD2(CARD15) gene on chrmosome 16associated w/fibrostenotic ileal Crohns disease
2) environmental/infectious factors: bacterial
and luminal antigens
lack of immune activation and nodevelopment of colitis w/o bacteria
3) GI mucosal immune response
normally, GI system is in state of controlledinflammation to normal colonizing bacteria
tolerance regulated by regulating Tlymphocytes in intestinal mucosa
Pathways of T-cell activation
Nave T cells (TH0) can differentiate into 3 types ofcells under the influence of APCs
APC IL-12TH1produce IFN-, IL-2,
TNFgranulomatous and cell mediatedinflammation
Crohns disease
Celiac disease
TH2produce IL-4, IL-5, IL-10
hypersensitivity rxns (food allergy,helminthic infection) UC
APC IL-10TH3/TR1mediate tolerance
TH3produces TGF
TR1 (regulatory)produces IL-10
normal response to normal flora
Pathogenesis: environmental trigger (infection, drug)
may cause acute GI inflammation:
in most people:
regulatory intestinal mucosal lymphocytes(TH3and TR1) limit response
In susceptible IBD patients:
different mucosal lymphocytes (TH1orTH2)activated
TH1Crohns Disease (CD)
TH1 cells release proinflammatory cytokines(IFN-, IL-2, TNF)
a) tissue damage
b) induce further production ofproinflammatory cytokines
c) stimulate production of adhesionmolecules on walls of intestinal capillarieswhich facilitate migration of PMNs, M0s, andlymphocytes into GI mucosa
TH2Ulcerative Colitis (UC)
cell mediated immune response tointestinal bacteria with associatedinflammatory response and ABSENCE ofmucosal repair
Ulcerative Colitis (UC)characteristics
chronic
diffusemucosal inflammatory process
limited to colon
clinical
bloody diarrhea
evidence of rectal inflammation which extendsproximally in the colon in continuous,symmetrical manner
Crohns Disease (CD)characteristics
patchy
transmural inflammatory processmay affect any part of GI tract
clinical
non-bloody diarrhea
perianal disease
rectal sparing
small intestine involvement
segmental, asymmetric distribution
fistula formation
non-caseating granulomas on biopsy
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Pathophysiology of IBD
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Pathology of Lower GI Inflammatory Disorders
Inflammatory Bowel Diseasechronic relapsing inflammatory disorders of GI tract
abnormal response to normal organisms
pathogenesis involves unregulated and exaggeratedimmune responses to commensal organisms ingenetically susceptible individuals
no specific pathogens identified
abnormal T lymphocyte rxnsCD: Th1
UC: Th2
specific HLA antigens implicated in both CD andUC
Crohns DiseaseEpidemiology/Genetics
westerners
F>M, whites>nonwhites, jews>nonjews
HLA-DR1/DR1/DQw5 in 27%
frameshift mutation in NOD2/CARD15 gene on
chr 16Gross Pathological findings
1) involves all levels of GI tract
small bowel & colon: 30%
small bowel only: 40%
colon only: 30%
upper GI: rare
2) skips areas (jumps around)
3) transmural, sharply delimited inflammationw/fibrosis & strictures
vertical diseasegoes through wall
segmental transmural terminal ileuminvolvement
4) adhesions & mass effect
5) creeping fat
6) fissures, fistulas
7) cobblestoning of mucosa
8) linear ulcers
Microsopic findings
1) aphthous ulcers
very early change
red arrow/line: aphthous ulcer
green arrow: lumen
note pus (PMNs) pouring into base of ulcer
progression
red circle: fissure expanding towards muscularis
early points of breakdown in GALT areas
2) chronic (metaplastic epithelium) and acute(crypt abscesses, ulcers) changes together
3) basal lymphocytosis/plasmacytosis
4) granulomas (50% resections, 35% biopsies)
5) transmural inflammation with lymphoidaggregates and fibrosis
transmural lymphoid aggregates (circled)
TH1pathwaysets up lymphoid-stimulatingcytokines, granuloma formation
6) hypertrophy of nerves & muscle
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Pathology of Lower GI Inflammatory Disorders
Ulcerative ColitisGross
total colectomy
ileo-cecal valve circled
UC not likely to recur after total colectomy
Crohns can occur anywhere in SB socolectomy would be useless
Microscopic
Horizontal Disease
doesnt penetrate wall
early changes
Global process, NOT segmental
doesnt start with aphthous ulcers
starts with conjestion, edema, breakdown of
mucosa
starts inrectum,thenmovesproximally
progression of inflammation
crypt abscess: crypt filled with pus
PMNs damage epithelium
epithelium breaks down in CRYPTS (not onsurface like aphthous ulcers)
breakdown of mucosa (ulcer circled)
hyperemia,extracapillaries,bleeding
inflammatory pseudopolyps
tuft of submucosa left behind on surface ofbroad-based ulcers
epithelium regenerate over surface of ulcer
Chronic UC
Chronic s: Gross
Distal more severely damaged (distalreformed surface circled)
flat mucosa, folds are gone
slightly narrower
everything has been epithelialized with make domucosa
disease is quiescent
but big risk factor for carcinoma
Microscopic clues of past injury (inactive UC)
1) branching crypt (red circle)
2) paneth cell metaplasia (green circle)
Differential DxCD vs UC
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Pathology of Lower GI Inflammatory Disorders
Note: UC can have granulomas near rupturedcrypts, but NOT in lamina propria
left: CD
right: granuloma in UC
DDx of Crohns: Generally infectious or ischemic
Yersinia
can see g- rods
TB
Schistosomiasis
can cause granulomas
can usually see ova in granuloma or in stool
Bowel stricture, due to radiation or ischemia
Ischemic stricture
see regenerative crypts and fibrosis with relativelylittle inflammation
DDx of UC:
Crohns
Infections
Campylobacter, Salmonella
Amebic Colitis
inflammatory exudate w/amebae (circled)
Ischemia
NSAIDs
Complications of IBDLocal
UC: Toxic megacolon
Carcinoma (UC > CD)
dysplasia in UC regeneration
L: distortedepithelium
R: epithelial
atypia
CD: stricture & bowel obstruction
Extraintestinal complications
Involvement of bile ducts: primary sclerosingcholangitis
red: hepatic artery
green: bile duct
blue: vein
fibrous plug where there should be bile duct
ankylosing spondylitis
polyarthritis/sacroiliitis
etc
Ischemic Bowel DiseaseSmall bowel infarct
sharp cutoff
epithelium @ tip of villus susceptible to ischemia
progression of ischemia in SB infarct
earliest s: necrosis & hemorrhage inmucosa
Causes of Infarct
Occlusive mesenteric artery thrombosis
cholesterol embolus
vasculitis
L: vasculitis in pt w/S
fibrinoid necrosis vessel wall
R: CMV colitisCMaffects endothelial cemakes them swell,causes capillaryblockage
intussusception
peristaltic wave causes telescoping
diverticulosis
tends to occur where vessels penetrate walls ofb l