Bod Giblock1

8/11/2019 Bod Giblock1

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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

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