Pathology: GI

Esophageal Pathology ............................................................................................................................................................. 2

Stomach Pathology ................................................................................................................................................................. 9
Small Intestine: Inflammatory & Non-Neoplastic Disorders................................................................................................. 16
Inflammatory & Nonneoplastic Disorders of the Colorectum .............................................................................................. 23
Colorectal Cancer .................................................................................................................................................................. 31
Pediatric GI / Liver Disease ................................................................................................................................................... 37
Normal Liver Anatomy & Injury Patterns .............................................................................................................................. 44
Alcoholic Liver Disease .......................................................................................................................................................... 50

1
 Esophageal Pathology
Normal Anatomy Review
Where can things get stuck?
 Cricoid cartilage, Arch of aorta, Atrium, Diaphragm

Layers of the esophagus

3 parts:
 Nonkeratinizing stratified squamous epithelium
 Lamina propria (loose connective tissue with small
vessels, scattered inflammatory cells)
Mucosa o has lymphatic channels unlike in colon –
different staging of carcinomas
 Muscularis mucosae (thinner than muscularis
propria, thicker than muscularis mucosae in other
areas of GI tract)
Loose connective tissue with
 abundant lymphatics (tumor spread)
Submucosa  scattered inflammatory cells
 nerves, ganglia of Meissner’s plexus
 esophageal submucosal glands (modified salivary
glands; anatomic marker of esophagus)
Thick muscle layer with Auerbach’s plexus ganglia
Muscularis
 Proximal 6-8cm: striated muscle
propria
 smooth muscle distally
Rest of GI tract: has serosal coat
Esophagus: Loose connective tissue / fatty tissue
Adventitia
 Allows tumors, infections that penetrate muscularis
propria to go directly to mediastinum

Note that biopsy samples MUCOSA ONLY!

 but disease can affect any layer!
Tensile strength (surgery) is in submucosa! (weird – loose connective tissue)

Neuromuscular / Anatomic Diseases of the Esophagus

 Agenesis (congenital; don’t develop esophagus)
 Atresia / fistula (congenital; atretic segment of esophagus: thin / non-canalized cord; fistula if connected to trachea)
o Aspiration, inability to feed, pneumonia can result
 Achalasia (see below)
 Webs & rings (mucosal ledges that protrude into esophagus)
o Proximal = webs (e.g. Plummer-Vinson syndrome, iron deficiency anemia + glossitis + cheilosis in middle-aged/older F)
o Distal = Schatzki’s rings

Achalasia
 Degenerative disorder of intra- or extra-esophageal nerves
 Usually primary; can be secondary (Chagas dz, diabetes, amyloid)
 Lack of peristalsis, ↑ tone / incomplete relaxation of LES
o Leads to stricture (narrowing) – lumen gets too small

2
 Esophagitis
Inflammation of esophagus (but some of these conditions, e.g. reflux esophagitis, don’t show much inflammation)
Etiology:
 Medications/Drugs  Allergy  Infections
 Trauma  Radiation  Reflux

Medications / Drugs
 Mostly older patients / multiple meds  stricture
 Injury from direct mechanical effect of pill or
toxicity of medication itself

Directly caustic to esophageal mucosa:

 Iron pills (esp. ferrous sulfate)
 Fosamax (alendronate sodium)
 Potassium chloride
 Aspirin / NSAIDs Iron Pill Esophagitis:
 May or may not see rusty
Ischemic Injury: Kayexalate golden brown pigment
 exchange resin for hyperkalemia in renal failure  causes ulcer
 Ischemic injury from hypertonic sorbitol  can pick up better with
 See big crystals iron stain

Chemotherapeutic agents: inhibit proliferation of basal zone cells (rest of GI tract too)

Others:
 Lye / bleach: direct caustic effect (young children, psychiatric patients)
 Pills that get stuck in esophagus can locally damage too (mechanical / pressure effects or caustic med)

Fosamax & many others: Kayexalate: big crystals Chemical esophagitis (lye):
can’t see actual drug (just ulcer) caustic burns with narrowing

Biopsy of drug related esophagitis:

 Non-specific changes: acute inflammatory cells (PMNs in squamous epithelium), erosions / ulcers
 Iron & Kayexalate are the only two agents you can actually ID on pathology

Ulcer vs. erosion

 Ulcer: damage all the way down to muscularis propria or deeper; can cause perforation
 Erosion: doesn’t extend into submucosa

Course:
 Superficial lesions often heal without scarring
 Deeper lesions can heal with scarring and stricture formation
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Trauma
Etiology:
 Nasogastric tubes (hosp pts)
 Swallowed objects (children, psych pts)
 Burn trauma (hot liquids out of microwave)
 Mallory-Weiss tear: longitudinal laceration in GE junction region
o Usually result of pressure effects of severe vomiting (e.g. alcoholics)

Esophagitis from trauma Top, right: thermal injury (microwave)

(NG tube lesion – note erosion) Note mummified layer, sharp contrast to
intact zones

Allergic Esophagitis
Epidemiology: Unusual
 Usually infants / children with allergies to milk / other dietary components
 Can occur in adults (diet or medication allergies)

Presentation: dysphagia, may have strictures, dysmotility from prolonged injury

 Esophagus alone or part of more generalized eosinophilic gastroenteritis
 Could also be from parasites (not usually in US)

Treatment: May improve with elemental diet, ± steroids (?)

Biopsy: marked infiltration of EOSINOPHILS

 In mucosa, lamina propria, deeper tissues

Esophagitis from Infections

 Bacterial, fungal, or viral: fungal & viral are most clinically relevant
 Especially in immunosuppressed pts (HIV, cancer) – often have concomitant infections with 2+ organisms

Bacterial esophagitis

Primary infection is rare; pretty much everything has been described as causing it
 Really only see in profound neutropenia (e.g. cancer chemo)
 Mycobacteria (MAI / TB)
 Actinomyces (sulfur granules)
 Treponema palladium (2° / 3° syphilis)

Secondary infection of damaged esophagus is more common

 commonly mixed flora

Big crusts of purple-staining bacteria;

usually only in profound neutropenia)

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Fungal esophagitis
Candida albicans CANDIDA ESOPHAGITIS:
 Usually opportunistic IMMUNOSUPPRESSED PATIENTS
 Superinfects ulcers in non-compromised hosts  systemic steroids
 chemotherapy for cancer
 Pathology:  immunosuppresion
o Gray-white plaques (squamous cells, candida, inflamm. cells) post-transplant
 low birth weight babies
o yeast / hyphae / pseudohyphae (“Spaghetti & meatballs”)
 AIDS pts
o Acute inflammatory cells (PMNs) in squamous epithelium
o Best seen with PAS stain

Others:
 Aspergillus
 Histoplasma capsulatum

Candidal esophagitis:
Yeast, pseudohyphae, hyphae
gray-white plaques

Viral Esophagitis
Big two: CMV (cytomegalovirus) & HSV (herpes virus)
 Also varicella zoster virus (VZV), etc

CMV esophagitis
 Usually opportunistic (HIV / transplants)
 Can super-infect pre-existing ulcers
 Usually results in ulcer formation
 Pathology:
o in GRANULATION TISSUE in base of ulcer
o BIG CELLS WITH OWL’S EYE INCLUSION (or binucleated) – Cowdry A inclusion (has a space around it)

Herpes Esophagitis
 Mostly HSV-1, most often opportunistic infection
o Occasionally in non-immunosuppressed
o Neonates: can be acquired intrapartum (HSV-2)

 Multiple, shallow, punched-out ulcers

 Pathology: need to biopsy EDGE of ulcer

o “Smudged” Cowdry B intranuclear eosinophilic

inclusions in SQUAMOUS CELLS at edge of ulcer
HSV: Multiple shallow HSV: cells with inclusions at edge
“punched-out” ulcers of ulcer in squamous epithelium
o IHC stain can help ID

Virus Location Cell size Inclusion “Smudged”

CMV Center Big Owl’s eye (Cowdry A) Cowdry B inclusions
HSV Edge Normal Smudged (Cowdry B)

5
 Esophagitis: Reflux
Gastroesophageal Reflux Disease (GERD)
 Most commonly adult Caucasian males Predisposing factors for GERD
(think FAT WHITE GUYS)  ↓ LES tone (ETOH, scleroderma, etc.)
 NG tubes (interference with LES)
o But can affect M / F / all races / infants
 Hiatal hernia
 Reflux of gastric contents into esophagus  damage
 Achalasia (↓ clearance of refluxed material)
o gastric acid, pepsin
 Diabetes (gastric secretions accumulate)
o duodenal alkaline bile / pancreatic secretions
 Obesity, pregnancy, many more

Pathology of GERD

Epithelial injury
 Balloon cells: cells opened up by damage, emptied out
 Vascular lakes (dilated small blood vessels)
 Erosions / ulcers if severe

Proliferative changes (↑ turnover from damage)

 Widening of basal zone
 Elongation, ↑ # of vascular papillae
o Usually go 1/3 of the way up; now > ½ way

Inflammation
 Usually mild
 SCATTERED eosinophils
(fewer than in allergic esophagitis)
 May be some PMNs too

Complications of GERD
Severe complications are unusual
 Can develop: ulcer, bleeding from ulcer, stricture formation (scarring / deep injury)
 Barrett’s esophagus: develops in ≈ 10% pts with symptomatic reflux

Barrett’s Esophagus
Replacement of normal squamous epithelial lining of tubular esophagus by columnar epithelium
 (metaplasia: replacement of one cell type by another not normally found
in that location)

Can be replaced by either:

 gastric-type mucosa (cardiac or oxyntic-type)
o Cardiac: glands; top (cardia) of stomach
o Oxyntic: parietal, chief cells; middle (fundus) of stomach,part
that makes acid
 “distinctive-type” mucosa (INTESTINAL metaplasia)
o Features found only in small bowel & colon (GOBLET)

Classification of Barrett’s
 In US: need INTESTINAL METAPLASIA to be called “Barrett’s” – don’t know if you got Bx from right place
o Most prone to develop dysplasia & adenocarcinoma
 Other countries: also consider gastric-type metaplasia “Barrett’s” (maybe we should too)

6
Diagnosis
 Pathology: GOBLET CELLS in esophagus (really shouldn’t be there!)

 Endoscopy: tongues, patches of reddish salmon-colored columnar mucosa

o Normal esophagus: grey/pink/pearly squamous epithelium
o Short-segment: < 3 cm, more common
o Long-segment: > 3cm; more likely to progress to esophageal adenoCa

Pathogenesis
 Not clear: associated with chronic reflux; unlikely that it’s direct metaplasia of SSE
 Probably destruction  re-epithelialization by columnar epithelium;
 Cell of origin unknown: pluripotent stem cell?

Presentation:
 NO SX caused by Barrett mucosa itself
 Sx of GE REFLUX only

Importance: pre-neoplastic condition!

 Can lead to esophageal adenocarcinoma
 Metaplasia  dysplasia  adenoCa

Risk of progression to adenoCa

 10% of all pts presenting with Barrett’s have or will develop adenoCa
(incl. pts w/ adenoCa on presentation)
 about 0.5% / yr will progress from BE  adenoCa

Esophageal Adenocarcinoma
Adenocarcinoma = tries to recapitulate glands

Epidemiology:
 50% esophageal cancer in USA, ↑ in past 20 yrs (obesity)
 White males in high socioeconomic groups (same guys who get Barrett’s)
 Risk factors: Barrett’s, males, whites, obesity, smoking, alcohol

Gross pathology: adenocarcinoma in background of velvety columnar Barrett’s mucosa

 Usually lower 1/3 of esophagus (begins at GE junction)
Dysplasia: precancerous cytologic changes following metaplasia
 high grade = close to cancer (big nuclei, complex gland structure)

Dysplasia in Barrett’s Mucosa: Esophageal adenoCa: shouldn’t see glands

↑ grade with more atypia, bigger nuclei, down at bottom (invading!)
more disorganized glands
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 Esophageal Squamous Carcinoma
Epidemiology: ↓ in comparison to adenoCA in USA
 high incidence in “developing” countries (China, Iran, southern Africa)

Risk factors: (know these)

 Males  Smoking  Lye strictures
 African-Americans  Diet: nitrosamines, nitrates  Achalasia
 Alcohol* (fish products)
* ALDH1 polymorphism in SE Asians: Japanese, Chinese, Korean; also causes “flushing” with EtOH consumption

DRINKING & SMOKING have a SYNERGISTIC effect (multiplicative: potentiate one another)

Site of esophageal squamous CA: mostly middle 1/3 (50%)

 Vs. lower 1/3 for adenoCA
 Site determines which mediastinal structures would be invaded (upper 1/3 is worst!)
Precursor lesion: squamous epithelial dysplasia
 “carcinoma in situ” frequent at periphery – high grade dysplasia / intraepithelial neoplasia

Pathology:
 Enlarged cells, not maturing
 Eventually undergo paradoxical maturation (abnormal keratinization)
o Form keratin whorls (“SQUAMOUS PEARLS”) – common in squamous CA

NORMAL lower esophagus mucosa / Esophageal squamous dysplasia: Squamous pearl: Eso Squamous CA (here
squamous epithelium enlarged cells, not maturing abnormal keratinization upper 1/3 – bad Pgx)

Prognosis TNM Staging of esophageal CA

T1: invades lamina propria or submucosa
5-year survival (with Tx) T2: invades muscularis propria
T3: invades adventitial fat
Overall < 15%
T4: invades adjacent structures
Superficial (T1) CA 75-80% N: Nodal involvement
M: Distant metastases
Bad survival!
 Most pts present at T3-4 – takes a long time for them to come in!
 Esophageal obstruction, extension into mediastinal / intrathoracic structures, etc. (not distant mets so much)
 Earlier detection  better survival!

Treatment:
 Radiotherapy, chemotherapy (palliative, not really curative)

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 Stomach Pathology
Normal Anatomy Review

 Esophagus  LES 
 Cardia, fundus, body  transitional zone
 (Pyloric) Antrum 
 Pyloric sphincter 
 Duodenum

Normal Histology Review

Oxyntic (= “acid secreting”) mucosa

 Parietal cells (secrete HCl) – “fried egg”

 Chief cells (secrete pepsinogens) - pinkish
Fundus &  Surface, foveolar epithelium PAS (+)
Body o mucus secreting

FOV = foveolae (small pits)

PC = parietal cells
CC = chief cells

(cardia by GE junction similar– but no endocrine cells)

 Mucus and/or pepsinogen secreting cells

 Lots of PAS (+) – mucus secreting
o glandular epithelium too!
Antrum
 Endocrine-secreting cells (see below

LUM = gastric lumen

FOV = foveolae (small pits)
AG = antral glands

Endocrine Cell Types

 Can see all via chromogranin immunostaining
Cell type Location Secretes Function
G cells Antrum Gastrin  Stimulates ECL cells  ↑ histamine release (↑ acid from PCs)
 Trophic factors: stimulates parietal cell growth
D Cells Antrum Somatostatin  Puts brakes on parietal cells (suppresses G cells’ gastrin release)
ECL Cells Body Histamine  Stimulates parietal cells (↑ acid production by parietal cells)

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 Gastritis
Classification of gastritis
Acute gastritis Chronic gastritis
 “Chemical gastritis” – Aspirin / NSAIDs, bile reflux, others?
 Acute hemorrhagic gastritis  H. pylori gastritis
 Acute infectious gastritis (chiefly bacterial, e.g. HP, & viral)  Autoimmune gastritis
 Other uncommon forms

Acute hemorrhagic & erosive gastritis (AHG) INITIATING FACTORS

 A.k.a. “acute gastritis” / “gastropathy” (minimal inflammation)  Ischemia (2° to hypoperfusion: stress, shock)
 Think: frat boy who drank too much  Chemicals (Aspirin, NSAIDs, bile salts, EtOH)
 NOT H. pylori
Pathological Features
 Multiple, often punctuate hemorrhages (gross)
 Damage to subepithelium:
o erosions, edema, hemorrhage
 Minimal inflammation (gastropathy)

Pathogenesis
 All causes: damage to surface epithelium  breakdown of
+ +
barrier to H ions  injurious substances enter (H ,
proteases, bile acids)  underlying capillaries / other
structures damaged  edema, hemorrhage,
+
inflammation, ↑ H secretion
 NSAIDS: initial injury may be related to COX inhibition Endoscopy: multiple punctuate & confluent superficial
 ↓ prostaglandins  ↓ mucosal protection hemorrhages; H&E: localized hemorrhages, epithelial
detachment, erosions

Chronic chemical gastropathy (NSAIDs, other drugs)

A.k.a. “reflux gastritis, reactive gastritis, NSAIDs gastropathy (minimal inflammation again)

Clinical Findings / Associations

 No Sx or nonspecific upper GI Sx  Bile reflux (mainly with gastroenteropathy: post antral gastrectomy)
 CHRONIC NSAID EXPOSURE COMMON  Others (?) hypersecretion, EtOH, other irritants?

Pathological Features:
 ANTRUM ≫ BODY (corpus) for gross changes

 Gross: Highly variable, not characteristic / diagnostic

o erythema, thickened folds
o hyperplastic polyps less common

 Micro: Repeated injury / repair (REGENERATIVE)

(NO prominent inflammation)
o ↑ SMOOTH MUSCLE
o Foveolar hyperplasia with CORKSCREW PITS
o Vascular dilation & congestion

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Gastric Ulcers
 Can be seen in acute or chronic gastritis

Pathogenesis: ↑ acid secretion & ↓ mucosal defenses

Etiologies: MANY
 Aspirin or other NSAIDs (very common)
 H. pylori
 Acid hypersecretion (esp. duodenal ulcer pts)
 Reflux of duodenal contents (bile acids, pancreatic enzymes)  stomach (?)

Complications of ulcer disease

 Bleeding (rupture underlying vessels)
 Perforation (communicate w/ peritoneal cavity)
 Penetration (extension into adjacent organ
 Stricture (healing  scarring)

Pic: gastric ulcer (could be from whatever etiology)

Erosion vs Ulcer
Erosion  Ulcer
Shallow Full-thickness
break in mucosa break in mucosa
Can reach muscularis
Penetrates muscularis
mucosae, but doesn’t
mucosae, may go even deeper
penetrate

Gastric Ulcer: in H. Pylori (see below for more on H. pylori)

 H. pylori predisposes: metaplastic epithelium more vulnerable(acid, proteases, etc.)
 ANTRUM at TRANSITIONAL ZONE (junction with body), usually single
 Normo or hypochlorhydric
 MUST RULE OUT GASTRIC CANCER
o similar presentation, appearance, association w/ EMAG

Gastric Ulcer: with NSAIDs

 Chronic NSAID use predisposes
(not fully understood: breakdown of protection?)
 DISTAL ANTRUM (“PRE-PYLORIC”)
 can also cause ulcers throughout GI tract
(duodenum, small intestine, colon)
 NO HP infection
 Single or multiple ulcers
 Associated chemical gastritis on microscopy

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 Helicobacter pylori gastritis
Epidemiology
 Found throughout the world
o USA: ↑ > 40 yo, uncommon in children
 (30-50% USA adults @ Bx, 20% by serology)
o Developing world: ↑ in all ages
 Importance 1st demonstrated in 80s

Microscopic appearance
(Diff-Kwik (modified Giemsa), or immunostaining)
 Curved organisms with flagellae  Look coccoid after treatment
 Adhere to gastric epithelium / in mucus  Lympho-plasmacytic chronic inflammation
o Don’t colonize other GI epithelial types (e.g. o ± active (acute) inflammation
intestine) o Lymphoid follicles present (MALT tissue)

Presentation / Consequences:
 Many asymptomatic, some have dyspepsia
 Peptic ulcer (duodenum / antrum)
 Long term – damages mucosa  atrophy and intestinal metaplasia (damage / repair cycles)
o ↑ risk intestinal type adenocarcinoma
o ↑ risk MALT lymphoma
 Link to autoimmune gastritis (?)

H. Pylori Consequences: Peptic Ulcers

Why peptic ulcers?
 Helicobacter preferentially infects D cells
 Lose D cells → ↓ somatostatin  G cells unopposed  ↑ acid

Gross Path: duodenal / antral ulcers

 often in duodenal bulb (right past pyloric junction)
 ± pre-pyloric ulcers (distal stomach, just before pyloric sphincter)
 Rugal hypertrophy (big folds)

Histology:
 Duodenal ulcer with Brunner Gland (BG) hyperplasia
o Response to persistent acidity
 Penetrating muscularis mucosae  damaged artery  bleed!
o Also penetrated pancreas?

Eradicate H. Pylori: helps prevent recurrence

See fewer duodenal ulcers these days (everybody gets abx for one thing or another  treat HP inadvertently)

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Environmental Metaplastic Atrophic Gastritis (EMAG)
 Damage  atrophy  repair, metaplasia
Causes:
 H. pylori infection
 Diet (high salt, smoked foods, pickled foods, nitrosamines: Japan, ↓ antioxidants / green veggies)
 smoking

Major clinical correlations

 No pernicious anemia (only with autoimmune)
 Hypochlorhydria sometimes (achlorhydria rarely)
 Serum gastrin: low or normal levels
 Gastric ulcers / cancers are important associated findings

Pathology:
 Intestinal metaplasia in ANTRUM
o PAS: see RED = mucins of normal gastric epithelium
o Alcian BLUE = goblet cells (intestinal metaplasia!)
 1st appears in transition zone, lesser curve (H. pylori)
 Chronic inflammation ± acute inflammation

Stemmerman’s technique:
 Alkaline phosphatase stain
 Technique makes anything with goblet cells turn RED!
 More red = more metaplasia

H. pylori: doesn’t like to live where there’s intestinal metaplasia

 Intestinal metaplasia – like a type of defense mechanism?

H. pylori & Gastric Cancer

Intestinal type adenocarcinoma
 Intestinal-type metaplasia  dysplasia  adenocarcinoma
 ↑ risk with H. pylori infection; eradicate ↓ risk of H. pylori
 Pic: carcinoma (luminal mass) in setting of EMAG

Malt lymphoma
 Years of responding to helicobacter 
low grade lymphomas
 Mess up lymphoid tissue here
 Pic: normal MALT area
(physiologic)

H. pylori: Overview of Consequences

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 Autoimmune Metaplastic Atrophic Gastritis (AMAG)

Gastritis by etiology & location (KNOW THIS)

Autoimmune BODY messed up Antrum OK
H. Pylori ANTRUM messed up Body OK

Patient
think little old ladies (autoimmune: F>M)
 AA / latina / white affected about the same; inherited predisposition

Pathogenesis
 Ab against intrinsic factor or parietal cells  damage to oxyntic mucosa (body)
o Parietal cells lost, metaplasia appears  achlorhydria
o loss of IF  B12 malabsorption  deficiency  pernicious anemia
 H. pylori normally absent

Pathology
Body / fundus only (where parietal cells are)
 DIFFUSE METAPLASIA, thin mucosa

 Loss of oxyntic glands (atrophy)

o FLAT (loss of good rugae) (left pic)

 Thinning, intense chronic inflammation (bottom pics)

 Intestinal & pyloric metaplasia (right pic)

Antrum: no metaplasia, hyperplasia

Endocrine: G-cell, ECL cell hyperplasia

Pathology
approach to
Autoimmune
Gastritis

1. Supposed to be the body: 2. Double check: from body? 3. ECL hyperplasia (↑↑ gastrin
but no parietal cells! Gastrin (-) – not antrum! from antrum b/c ↓ acid!)

Clinical correlations
 Achlorhydria, marked hypochlorhydria
 B-12 malabsorption (can  pernicious anemia / neuro problems)
 Serum gastrin: high levels (↑ because no acid made)
 Gastric cancer: ?? risk increased
 Gastric ulcer: not a problem (no acid)

ECL hyperplasia  carcinoids (neuroendocrine tumors)

 hypochlorhydria  antrum puts out more gastrin 
↑↑ ECLs – trophic effect (L. pic)
 Years of ↑↑ ECLs  can progress to carcinoids! (R. pic)
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 Gastric Cancer
Overview (gastric cancer overall)
 3% all US cancers (↑ in males, non-whites, lower SES)
o ↓ since 1930s overall
 ↑ in Japan, Iceland, Scandinavia, Andean So. America, many developing countries
 Most adenocarcinomas arising from antral region

Risk factors for Gastric Cancer

 Metaplastic atrophic gastritis (e.g. H. pylori infection / autoimmune)
 Dietary: smoked foods (nitrites), high salt intake, poor intake of fresh vegetables / fruits / antioxidants
 Adenomatous polyps

Classification: Intestinal vs. Diffuse types

Intestinal Diffuse
 Relatively well differentiated;
recognizable glandular architecture  Poorly differentiated, e.g. “Signet ring” type
 Protruding masses  Infiltrative form: Linitis plastica (leather bottle)
 Associated with H. pylori Really hard on gross!
(chronic inflammation, atrophy, metaplasia)  Histological precursor unclear
 Low grade dysplasia high grade  adenocarcinoma  No marked decline in frequency
 Commonest type in most areas (no H. pylori association to be improved on)
 Declining frequency, western countries

L: intestinal-type carcinoma in setting of EMAG (H. pylori)

R: microscopy: can recognize cancer in certain areas L: macro view of diffuse cancer
R: signet ring cells (mucus droplet, pushes nucleus out to side)

An aside: hereditary diffuse gastric cancer

 Autosomal dominant, pts get gastric cancer in youth
o Germ line mutations  2nd hit generates problem
o E-cadherin is mutated (cells don’t stick together)
 ↑ risk for mammillary lobular cancer too in F (another cancer where cells don’t stick together)

15
 Small Intestine: Inflammatory & Non-Neoplastic Disorders
Normal Small Bowel

Brunner’s glands: submucosal glands; only in duodenum (good landmark) – secrete bicarb-rich fluid to counteract acid

Mucosa: where a lot of pathology takes place; Villi:crypt should be about 4:1 ratio in size
Villous Epithelium Crypt Epithelium

 Goblet cells: sole function is to secrete mucus  Paneth cells (pink granules) – contain lysozyme
o secrete contents into lumen
 Brush border: lots of digestive enzymes, etc.
 Endocrine cells: smaller cells (also pink granules)
 Enterocytes: do the absorbing
o secrete contents into surrounding vasculature
Disorders:
 Peptic diseases  Malabsorptive disorders  Stasis syndromes  Infections

Peptic Disease
Peptic duodenitis & peptic ulcer disease (PUD) – continuum of the same process
 Western countries, > 40 yo, M > F
• Caused by toxic effects on the duodenal mucosa by excess gastric acid
• Vs. gastric ulcers (due to altered mucosal defenses, NOT excess gastric acid)
• Helicobactor pylori infection found in 80% of patients with PUD
• Other associations: smoking, chronic NSAID use, decreased motility

Peptic Duodenitis
 Damage to the mucosa

Gross pathology:
 Most common: in DUODENAL BULB (where acid hits first)
 Looks nodular on endoscopy (Brunner gland hyperplasia): trying to respond to ↑ acid with ↑ bicarb

16
Microscopy: epithelial damage and reactive changes
 Gastric mucin-cell metaplasia
o adaptive response to chronic acid exposure
o Note that this is intestinal  gastric metaplasia!
 Brunner gland hyperplasia (nodularity)
 Villous blunting
 Acute inflammatory cells (PMNs) in the lamina propria or epithelium
o mostly seen when co-existent Helicobactor Pylori infection
 Ulcerations (indicates severe disease)

Gastric mucin cell metaplasia & villous Mucin cell metaplasia (mucin is PAS Brunner Gland hyperplasia – note ↑ number,
blunting (almost looks like colon!) positive – see enhancement, r.) extension into mucosa (normally submucosal)

(Bleeding) Peptic Ulcers

 Duodenitis  gets worse  ulcer
 Causes up to 50% of upper GI bleeds
o 5%: hematochezia (bright red bloody stools - normally lower GI)
 Bleeding most common when occurs in posterior bulb
o close to pancreatoduodenal & gastroduodenal aa.
 Intraperitoneal hemorrhage can result (life-threatening)

Gross findings:
remember: continuum with
duodenitis

 Most in duodenal bulb

 Tend to be small & circular,

rarely > 3cm

 Surrounding mucosa Duodenal bulb ulcer, Peptic ulcer in duodenum (note BG

nodular on endoscopy with pre-pyloric ulcers, rugal hypertrophy hypertrophy, proximity to pancreas,
(Brunner gland penetration into artery– bad!
hyperplasia)

Gastric (mucin-cell) metaplasia of duodenal bulb:

 correlates with ACID EXPOSURE of ANY TYPE, not H. pylori infection!
 But if you see PMNs (“active peptic duodenitis”)  H. pylori usually involved!

17
“Active” peptic duodenitis
 When you see PMNs as a component of peptic duodenitis
think H. pylori / “active” (o/w “chronic”)

Pathology:
 Gastric metaplasia, BG hyperplasia, villus blunting (chronic too)
 PMNs & H. pylori in mucosa (active only)

H. pylori & pathogenesis of duodenal ulcer

 Inhibits D-cells  releases “break” on G-cells / Gastrin 
↑ acid secretion (parietal cells)  peptic ulcer

 Multifactorial too: gender, genetics, smoking, etc.

o but if you eradicate H. pylori,
other causes aren’t sufficient to cause ulcer recurrence!

Non-peptic causes of duodenitis

 Crohn’s Disease
 Celiac Disease
 Zollinger Ellison Syndrome (gastrin-producing neuroendocrine tumor)
 Infections (Giardiasis, MAI, Crytosporidiosis, Microsporidiosis, CMV,
Whipple’s Disease)

Crohn’s disease
 Same changes of duodenitis: intramucosal BGs, ulcer, etc.
 Can see PMNs too (unusual in peptic disease)

Zollinger-Ellison Syndrome
 MULTIPLE duodenal ulcers
 Pathogenesis: gastrin hypersecretion by neuroendocrine tumor of
pancreas, duodenum  ↑↑ acid, many ulcers!
 Think ZES:
o multiple duodenal and/or jejunal ulcers
o uncommon locations
o no risk factors for PUD

Refractory ulcers w/o ZE found in smokers, site of prior duodenal perforation, gastric outlet obstruction

Malabsorptive Disorders
Malabsorbtion: impaired uptake of any substance(s) by small intestine
Malabsorbtion Syndrome: constellation of findings including
 Diarrhea  Weight loss
 Steatorrhea  Deficiency states (protein, vitamins, etc)

Lactase Deficiency
Forms:
 Infantile (rare)
 Adult onset (most common)
o Otherwise healthy adults, esp. dark-skinned races
o Brush border enzyme reduced post-childhood
 Acquired forms: due to intestinal damage (e.g. celiac dz, sprue)
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Chief symptom: milk intolerance

Lactose tolerance test: give lactose & measure blood glucose

 No blood glucose spike after lactose feeding if no lactase!

Path: mucosa completely normal (above)

 Special stain for lactase: ↓↓ lactase (right)

Osmotic diarrhea can result

 No lactase  can’t break down to glucose / galactose & absorb
 ↑ lactase in lumen, ↑ acid  ↑ luminal osmolality  suck out water

Celiac disease
 Multisystem autoimmune disorder Epidemiology
Risk factor Prevalence
st
Extraintestinal manifestations: 1 degree relative 1:22
nd
 Type I diabetes  Autoimmune hepatitis 2 degree relative 1:39
 Epilepsy  Many more Extraintestinal disorder
1:56
 Autoimmune myocarditis assoc. w/ CD
None 1:133
Pathogenesis
Environmental triggers Genetic risk factors Immunologic factors
 Gliadins (wheat)  HLA class II genes
 CD4+ T-cells that recognize dz-activating peptides
 Hordeins (barley) (HLA-DQ2, HLA-DQ8)
(↑ cytokines like IFN-γ  inflammation, injury)
 Secalins (rye)  70-80% MZ concordance

Active celiac disease (Prior to gluten-free diet)

 Clinically: malabsorption Syndrome
 Histopathology:
o FLAT Mucosa (NO VILLI)
o Epithelial lymphocytosis
o SURFACE epithelium damaged
o ↑ Crypt mitosis
o Chronic inflammation

L: normal, R: active celiac dz Intraepithelial lymphocytosis Crypts: see chronic inflammation in

Villous blunting, ↑ crypt size (arrows) lamina propria & lots of mitoses

19
After gluten free diet (1wk – 3mo)
 Marked clinical improvement (↑ wt, etc)
 Histopathology
o SURFACE EPITHELIUM RESTORED
o Slight return of villi
o Other findings unchanged

Long term gluten free diet

 Continued clinical improvement
 Histopathology
o Further return of villi
o Mitotic activity subsides
o Chronic inflammation subsides
o Some residual ↑ intraepithelial lymphocytes

Histopathology: If you add gluten back to diet

 Changes come back!
 Epithelial damage- upper villi, ↑ lymphs
 Rest of changes follow (later)

Diagnosis of Celiac disease

 Only by demonstrating resolution of mucosal damage after gluten-free diet
(need path!)
 Best in post-bulbar duodenal or jejunal biopsies
o bulbar Bx can give false negative results (see case 2: bulb looks nL!)
 Can’t diagnose with serology only

Monitoring Celiac Disease

 Can use serology: Anti-transglutaminase II, anti-gliadin ab to follow dz!

Prognosis:
 Should have complete resolution of pathology with strict gluten-free diet
 If refractory:
o Strict diet not being followed (might think they are)
o 80% have clonal T-cell population (a little more progressed)
 high risk for enteropathy-associated T-cell lymphoma (EATL)

Tropical Sprue
A.k.a. Post-infectious Tropical Malabsorbtion
 Cause unknown (no single etiologic agent identified)
 Residents of / visitors to tropics (West Indies, Indian subcontinent)

Clinical features
• Chronic diarrhea and malabsorption after infectious diarrhea
• Bacterial overgrowth (aerobic, ?toxin-producing)
• Associated deficiency states, esp. B-12, folate (ILEAL INVOLVEMENT – not CD)
• Glossitis, for instance (B12) – think tropical sprue; fix w/ B12
• Can respond to antibiotics + vitamin supplementation (B-12,folate)

20
Histology of Tropical Sprue
• Highly variable, “Non-specific” inflammatory changes

• Epithelial injury (resembles celiac disease)

• Villous blunting, crypt hyperplasia, chronic inflammation
• ILEAL involvement (vs CD: only proximal small bowel)
• Can see bacterial organisms (EM) – not in CD

• Resolves with abx & B12 Rx

Tropical Sprue (looks like CD: villous blunting,
crypt hyperplasia, chronic inflammation;
resolves with B12 + abx)

Stasis syndrome
 Malabsorption due to stasis / Causes of Stasis Syndromes
immotility of small bowel Disease-related Acquired (surgery, etc.)
 “Blind” loop or pouch
 Crohns disease, IBD
 Overgrowth of anaerobic bacteria  Entero-enterostomy
 Diverticular Disease
(balance disturbed with ↓ peristalsis)  Afferent loop
 Scleroderma of small intestine
o Deconjugate bile salts  Gastro-jejuno-colic fistula
 Pseudo-obstruction
o ↓ vitamin B12  Adhesions and partial obstructions
o Damage surface
epithelium

 Looks like partially

developed / treated CD

Scleroderma (pics to left):

preferentially destroys inner circular
layer of muscularis propria (↓
peristalsis) Scleroderma: bowel Thinning, scarring with Mucosa looks normal
markedly distended, loss of muscularis propria in SCL in scleroderma!
loss of muscle tone

Pathogenesis: Stasis  Bacterial overgrowth 

 B12 depletion (anemia)
 Bile salt deconjugation, epithelial injury (malabsorption)

Treatment: antibiotics (↑ weight gain, ↑ ability to absorb fat!)

Whipple’s Disease
 Hopkins guy (Dr. George Whipple, 1907) discovered it, so we emphasize it (even though uptodate puts the
overall prevalence at 30 cases / year); bacterial etiology confirmed in 1961

Clinical features
 Men (8-10:1); 30s – 50s
 Diarrhea, low grade fever, wt loss, abd pain, anemia, arthralgias
 Lymphadenopathy in 50% pts

21
Histology:
 Post-bulbar duodenum, jejunum
 Yellow patches / plaques on mucosa
 Characteristic finding: BLUNTED / ROUNDED VILLI full of foamy pink Mϕ
o Mϕ contain PAS-positive rod-shaped bacterial inclusions

PAS stain of jejuna Bx: Anti-T. whippelii immunostain:

Rounded villi with expansion of Normal epithelium, PAS+ foamy Mϕ positive!
lamina propria lamina propria full of
foamy pink Mϕ
Bacterial Agent: Tropheryma whippelii
 Small gram positive rods
 Extra- and intracellular (IC=mainly macrophages)
 Identification/Speciation: (related to Actinomycetes)
 Antibody reagents now available (allow for rapid diagnosis in tissue biopsies)

Treatment: abx (resolves!)

22
 Inflammatory & Nonneoplastic Disorders of the Colorectum
Endoscopyic biopsy: basic goals to distinguishL

 Normal vs abnormal:
o histology of normal colon varies by site
o endoscopy prep can cause artifacts that resemble disease (enema effects)

 Acute colitis vs chronic inflammatory disease

Normal Histology

 Lamina propria with inflammatory cells

between crypts
 Muscularis mucosae below it
 Crypts parallel; bottoms touch muscularis
mucosae

Basic terminology / concepts

Active inflammatory changes
Reflect acute injury to colorectal mucosa
• Cryptitis (PMN infiltrate in crypt epithelium)
• Crypt Abscesses (intraluminal PMNs)
Features
Chronic inflammatory changes
Reflect chronic injury to colorectal mucosa
• Crypt distortion (loss of parallelism / shortening  forked crypts)
• Crypt loss/atrophy
• Basal plasmacytosis (inflammation fills up bottom of lamina

• Erosions (breakdown of superficial
epithelium)
• Ulcers (breakdown penetrates entire mucosa)
• Acute fibrinoinflammatory exudates
• Neutrophils are the key!!!!
Not specific, found in variety of conditions
 bacterial infections
Etiology
propria so that crypts become separated from muscularis mucosa)
 Pyloric metaplasia (gastric glands replace normal intestinal crypts)
o Parietal, chief cells, etc.
 Paneth cell metaplasia: paneth cells in left colon (normally
have paneth cells in right colon, but stop by splenic flexure)
o Pink, granular cytoplasm

Can accompany any condition with repeated bouts of active

 idiopathic IBD
inflammation or other injury
 iatrogenic colitis – NSAIDs
 ischemic diseases
Active chronic inflammatory disease: when active & chronic changes occur in combo with one another
(Metaplasia – presence of fully differentiated epithelial cell not native to the site)
KEY FEATURES to distinguish acute colitis from chronic inflammatory bowel disease:
 No crypt distortion  No basal plasmacytosis

Histopathology: ACUTE changes

23
Histopathology: CHRONIC changes

Active (“Acute”) Colitis

 Forms of colitis characterized by predominantly acute inflammation
 The histologic changes are not specific for any one disease

Differential diagnosis of active colitis in a mucosal biopsy:

 Infection (Bacterial, viral, fungi)  Emerging Crohn’s disease
 Ischemia (atherosclerosis, infectious)  Bowel preparation (“enema effect”)

Histopathology
 Cryptitis, crypt abscesses and/or erosions/ulcers.
 No crypt distortion or loss!!
 No basal plasmacytosis!!
 For some forms of active colitis, specific histologic changes may also be seen to help classify the disease
o Salmonella- mucosal ulcerations over hyperplastic Peyers patches
o CMV-viral inclusions and patchy ischemic changes

Early acute self-limited

colitis (ASLC):
cryptitis (right), crypt
abcesses (center) without
crypt distortion or basal
plasmacytosis (crypts still
parallel to each other,
perpendicular to surface)
Late ASLC 
Now focal cryptitis;
regenerative changes
(healing epithelium): blue
crypts (↑ mitotic figures)

Acute infectious-type colitis

 Acute onset diarrhea ± blood (can have fevers, myalgias, etc)
 Resolves without residual inflammation or recurrent Sx (w/in 2 wks)
Etiology: variety of infectious agents (Salmonella, Shigella, Campylobacter, E. coli, C. difficile, CMV, fungi, amebiasis, etc.)
 Exact cause not usually found

Focal Active Colitis (Enema effect)

 Microscopic foci of active inflammation only (cryptitis / crypt abscesses) in o/w normal bx
 Commonly seen in followup biopsies at site of polypectomy (insignificant finding)
24
 Idiopathic Inflammatory Bowel Disease (IBD)
Relapsing bouts of active bowel inflammation lasting weeks to months!
 If you see CHRONIC CHANGES on path, think IBD
 Idiopathic etiology (lots of mechanisms), genetics involved

Ulcerative Colitis and Crohn’s Disease are the big two kinds (divergent but overlapping cliniopathologic profiles)
 Fulminant colitis: severe cases, majority of mucosa is ulcerated
o ↑ risk of toxic megacolon: dilation  ischemic necrosis, perforation (40% mortality)

Epidemiology of IBD (UC/CD)

 Most common in Westernized countries
 Usually initially present 15-25 or 55-65 yo (bimodal distribution)
Ulcerative colitis
Histopathologic Criteria
 Diffuse mucosal inflammatory infiltrate
(lots of PMNs, cryptitis, crypt abcesses)
 Basal plasmacytosis
 Crypt distortion
 Goblet cell depletion
 Paneth cell metaplasia

Distorted crypts with forking, lots of inflammation in lamina propria,

Distribution of inflammatory changes
basal plasmacytosis. Can see crypt abcesses (R pic) (PMNs in lumen)
 Left-sided colitis
 involves RECTUM (100% of time) and varying amounts of colon

Pseudopolyposis:
 confluent ulcerations with mucosa in between
 END STAGE UC
 “pseudopolyps” are really just retained mucosa with lots of
ulcers between
 Compare to FAP: actual polyps

Crohn’s Disease
 Patchy mucosal infiltrate with skip areas (part of bowel affected, then part is normal – sharp demarcations)
 Transmural inflammation (only seen on surgical resection)
 Granulomas (50% cases, can be extraintestinal too)
 Histiocytes may be very prominent
 Paneth cell metaplasia
 Creeping fat (omentum covering small bowel; since serositis can occur – transmural!)

Distribution:
 Patchy distribution, Right-sided
 Can involve small bowel! (rest of GI tract too)
25
Crohn’s Disease: Histopathology (continued)

CD: terminal ileal involvement, Basal plasmacytosis (diffuse, vs.

↑ risk stricture (transmural) structured peyer’s patches), villous Granulomas & giant cells
Patchy distribution (cecum nL!) blunting

Apthous ulcers (ulcers with intense

lymphoid infiltrate at base)
Perianal strictures & fistulas: present in >25% CD pts; can be initial manifestation

Extraintestinal manifestations of IBD

 Arthritis  Sclerosing cholangitis*
 Uveitis  Ankylosing spondylitis*
 Dermatitis (pyoderma gangrenosum, erythema nodosum)
* don’t resolve with colectomy! (others do)

Cancer risk in IBD

 ↑ risk for development of
colorectal cancer in IBD

 UC pts have 3-5% lifetime risk

(greater than Crohn’s – more
mucosa involved)

 Cancer risk ↑ with time (often

post-20 yrs of IBD)

 Surveillance Bx for DYSPLASIA

(DALM = dysplasia-associated
lesion or mass)

DALM: polyploid type: dark, dysplastic DALM: flat dysplasia (harder to recognize & manage
cells. Easier to manage (remove)

26
 Collagenous / Lymphocytic Colitis (“microscopic colitis”)
 Chronic watery diarrhea (mo  yrs), waxes and wanes
 Females>males (8:1), middle aged or older
 NORMAL ENDOSCOPY (“microscopic colitis” – need to use microscope to dx)
 NO dysplasia  carcinoma sequence! No ↑ cancer risk!

Etiologies:
 NSAID use  Autoimmune diseases (RA, autoimmune thyroiditis, scleroderma, etc)
 Celiac disease  Luminal antigen? (CC goes away if colon diverted, recurs when hooked back up!)

Histopatology: Collagenous colitis Histopathology: Lymphocytic colitis

 Irregular subepithelial collagen layer  Patchy distribution, etc.
o Normally type IV collagen, now made of  Similar to collagenous colitis:
types I/II collagen & fibronectin o but no thickened BM
 ↑ intraepithelial lymphocytes
 Surface epithelial damage
 Superficial plasmacytosis of lamina propria
 No crypt distortion
 Rare neutrophils

Collagenous colitis: thickened basement membrane (esp on trichrome stain Lymphocitic colitis: like collagenous colitis
where ECM = blue, middle); also ↑ CD3 lymphocytes (IHC stain, right) but no thickened basement membrane

Ischemic Colitis
 Insufficient blood flow
 Can effect small mucosal segment or all of colorectum
o Colon more vulnerable than small intestine (esp. splenic flexure: SMA/IMA watershed area!)

Etiologies:
Occlusive vascular diseases Infections Systemic hypotension Mechanical Factors
 atherosclerosis,  CMV
 Septic shock
thromboemboli, vasculitis  Enterohemorrhagic volvulus, intussusceptions *
 hypovolemic shock
 Most common cause of E. coli 0157:H7 (bowel twisted on itself)
ischemic colitis in US
* intusseception: most common in pediatric ileum (hypertrophied peyer’s patches form leading edge)
Histology: depends on severity & duration of injury
• Mucosal necrosis • In chronic phase, progresses to mucosal
• Hemorrhage atrophy, fibrosis of lamina propria
• Heme-laden macrophages in lamina propria • Microcrypts (trying to regenerate)
• Fibrin thrombi • Unaffected areas: acute colitis signs

27
 Histopathology of ischemic colitis

Fat in atherosclerotic plaque – can

Dilated, red bowel embolize, cause ischemic bowel

Note sharp demarcation, From infection: boggy, ischemic Lamina propria: necrosis, hemorrhage;
focal injury mucosa no inflammation, fibrotic changes.
Crypts: trying to regenerate

Microcrypts 
(top , smaller crypts:
 big-time
attempt to regenerate,
hemorrhage
lined by regenerative
epithelium)

Treatment: need to excise surgically if transmural necrosis (gangrene) before perforation!

 Sepsis is big complication

Causes of Ischemic Colitis

E. coli O157:H7
 non-invasive organism, produces shiga-like toxins
 lives in intestine of healthy cattle; meat can become contaminated in slaughter
o bacteria can go udders / equipment  milk

Routine stool cx: can’t distinguish O157:H7 & other strains

 but most labs use Cx medium to screen (based on sorbitol fermentation)

CMV infection
 “Owl’s Eye” Inclusions

28
Pseudomembranous Colitis
 Description, not an entity itself
o Most cases: from C. difficile toxin following abx therapy
o CMV, for instance, is less common cause
 Presentation: diarrhea (often bloody), fever, pain

Gross: Plaques of adherent pseudomembrane with normal-appearing intervening mucosa

Microscopy:

 Necrosis of surface, upper crypt

 Inflammatory pseudomembrane fills dilated crypts, covers

surface (“exploding out”)

Approach to Mucosal ischemia

 Age, presentation, Abx history, stool cultures, toxin assays

Diverticular disease
 Disease of western civilization (lack of fiber  colonic contraction rings, divide bowel into segmented closed chambers,
uneven contraction  ↑ intraluminal pressures  blow out through wall)
 Typically in L. colon (sigmoid)
 Herniation of mucosa through muscularis propria in regions of penetrating vessels (area of weakness)
o Muscular hypertrophy results around herniated zones

Poking right out Extend into vessel 

through muscularis mucosa bleed
Complications (acute diverticulitis)
 Perforation  Bleeding (right near vessel)
 Inflammation / abscess formation (can simulate mass-like lesion)

Diverticular disease-associated colitis (chronic)

 Looks just like IBD but ONLY near diverticula
 Diffuse or patchy colitis in area of diverticula (usually sigmoid)
 Presentation: like IBD
(rectal bleeding, crampy lower abd. pain, constipation, intermittent diarrhea)
o No hx of IBD

29
  Gross: looks like Crohn’s
 Histopath: can have granulomas & sinus tracts
o CLUE: find ACTIVE CHRONIC INFLAMMATORY CHANGES in distribution of diverticular disease
 Treatment: simple resection (don’t need to give antiinflammatories like for IBD)
Involved segment: active chronic colitis

Hypercellular lamina propria

Crypt distortion Cryptitis
(plasma cells, eosinophils)

Appendicitis
 Most common cause of acute abdomen in US (5% may develop)
o Commonly presents at 10-25 yrs
o Rarely fatal (even after perforation & sepsis: < 1%)
Etiology:
 Obstruction of appendiceal lumen (fecalith, lymphoid hyperplasia, neoplasm – rare)
 Overgrowth of normal fecal flora
 ↑ luminal pressure, compromise of intraluminal vessels  ischemia

Normal appendix; looks like less- Sections of appendix; note huge abscess Periappendiceal abscess with PMNs
well developed colon, surrounded (arrow) extending into fat (label) and foreign body giant cells
by peri-appendiceal fat responding to stool (arrows)

Possible etiologies

Fecalith (hardens, calcifies, obstructs)

Lymphoid Hyperplasia
(viral infection, etc.)

30
 Colorectal Cancer
Major Points
 Colorectal cancer is completely preventable with optimal screening, but most don’t get screened
o Precursor lesion (=adenoma) present in patient for a long time before progressing to carcinoma
 Third most common cancer in US (both M/F)
 State @ Dx determines survival
 Big-time environmental & genetic predispositions: ID families with CRC for aggressive surveillance
 70% of large bowel adecarcinoma is in the colon and 30% in rectum
o Sigmoid most frequently, transverse colon is increasing
o Location influences detectability (sigmoidoscopy vs colonoscopy ± barium enema)
 Usual histology: moderately differentiated adenocarcinoma (gland-forming)

Epidemiology
 3rd most common malignancy (M/F) – 148k/yr, #2 cause of cancer death (CFR 37%, 10% all cancer deaths)
o Men: prostate / lung, women: breast/lung
o Women: incidence ↓ since 1940s, men since 80s
 Cancer: currently #2 cause of death in US; will soon be #1 (heart disease dropping)

Basic Terminology
GROSS definitions
 Polyp: any mass projecting into the lumen (bad: doesn’t say benign/malignant, etc.)
Colorectal Polyps
 Adenoma: a benign tumor with dysplastic features; Non-neoplastic Neoplastic
clearly a pre-malignant lesion  Hyperplastic polyps  Tubular adenoma
o Sessile adenoma: attached by broad base  Hamartomatous polyps  Tubulovillous adenoma
o Pedunculated adenoma: attached by stalk  Inflammatory polyps  Villous adenoma

MICROSCOPIC definitions
 Villous: adenoma with finger-like progression
 Tubular: adenoma with tube-like glands; like a balloon with fingers inserted
 Tubulovillous: adenoma with mixed features
 Flat / Depressed lesions: CRC in setting of ulcerative colitis; no polyp phase

Natural History of CRC

Multistep progression:

Dysplastic Adenoma
Normal Field Low-risk High-risk Primary Metastatic
aberrant crypt containing
Epithelium defect adenoma adenoma AdenoCa AdenoCa
focus AdenoCa

Inside the dotted line: can potentially detect the lesion & treat (before it gets metastatic!)

Adenoma  Colorectal Cancer

 Incidence of adenomas / CA track together, except that adenoma curve is left shifted (side)
 Lesions inside lesions: see CAs inside adenomas, residual adenomas inside CA
 Natural history (in cases when adenomas not removed)
 Colorectal cancer incidence ↓ by resection of adenomas
 DNA mutations overlap

Untreated polyps
 Pts LTF, refuse surgery, not surgical candidates
 Studies: lots of cancers arise at site of previous polyps (but broad range)
31
 Normal Colon Histology: Review

 Normal crypts

(nuclei at base,
don’t extend more
than 1/6 of way up
cell towards lumen)

Crypts: Nuclei should be at BASE, extend NO MORE THAN 1/6 of the way up the cell towards the lumen
Adenoma Histology
Adenomatous epithelia
 Blue at low power (↑ N/C)
 By definition: colonic adenoma shows low grade dysplasia

Tubular adenoma Villous adenoma Tubulovillous adenoma

“Balloon with fingers inserted” Dysplastic nuclei; Pedunculated polyp here; see
 Note some crypts cut in cross-section,  Not confined to bottom 1/6 of cells fibrovascular core, mix of tubular &
others longitudinal (disarray) villous features

Probability of carcinoma in an adenoma increases with

 Size of adenoma (predominant)
 Proportion of villous component (villous ≈ “villain”, worse type)
 Presence of high grade dysplasia

↑ incidence with ↑ age

Even adenomas are late in disease process

 Aberrant crypt foci may be earliest morphological change; Kras, APC mutations found in them
Non-Genetic Risk Factors for CRC
Environmental Component
 Incidence varies dramatically across the world (10-fold) – genetics, environment, both?
 Immigrant studies: Japanese immigrants that migrate to USA
o ↑ CRC incidence with successive generations  environmental factors!

Diet & pathogenesis: Very complex process: calcium, carcinogens in cooked meat, fat, stool bulk, transit time

32
Non-genetic risk factors
 Ulcerative colitis  Smoking (esp. with certain SNPs: CYP450,
 Crohn’s disease (if long-standing) glutathione S-transferase)
 Dietary factors (vary between studies)

Genetics of CRC (overview)

Oncogenes Tumor Suppressor genes
Mutations restricted Mutations widespread
Mutations activating Mutations are deleterious
Rarely associated with LOH LOH is common
Cyto: nothing or translocations Cyto: deletions, whole chromosome losses
Not methylated Can be methylated
Function: accelerates growth, permits multilayering Function: slows growth

Key distinction: Sporadic or familial? Need for ↑ screening in families!

Colon cancer is a disease of the elderly!
 If someone in family has colon cancer < age 50 – think familial (FAP / HNPCC)
 Would be really rare for sporadic forms to present < age 50

Genetics: Inherited Colon Cancer

Familial Adenomatous Polyposis (FAP
 Rare condition
 Colon studded with innumerable polyps (100s1000s)
 Patients present at young age

APC: tumor suppressor gene, chromosome 5q (good for 2-hit hypothesis)

Plays a role in BOTH FAP and sporadic CRC!
 FAP families:
o affected members have one allele mutated in germline
o 2nd hit happens in tumor
 Sporadic: both alleles inactivated somatically
 Mutations occur very early in CRC carcinogenesis (both FAP & sporadic)
o Normal function: binds, promotes degradation of β-cateinin (growth factor) in cytoplasm
o With mutation: β-catenin is unchecked, migrates to nucleus, activates transcription, ↑ growth, etc.

Treatment: surgical resection of entire colon (total colectomy – each polyp could progress to cancer!)

Hereditary Non-Polyposis Colon Cancer (HNPCC / Lynch syndrome)

 “Family G” – described by Alfred Warthin – young onset R-sided CRC
 Site: HPNCC generally right sided; sporadic left sided
o First approximation ONLY! Not always true
 Still pass through polyp phase: just don’t see innumerable polyps like FAP

Onset / inheritance: Autosomal dominant; Mean age 44 yo, 90% penetrance

Site: 70% proximal to splenic flexure, though 30% distal!
Histology: more likely poorly differentiated, mucinous, signet ring cells, intense lymphoid infiltrates
Associated CAs: (take a FHx for CA): endometrium, stomach, ovary, small bowel, renal pelvis and ureter

33
Microsatellite Instability
 Novel length alleles in tumor as compared to patient’s germline
oSerendipitously discovered when mapping for HNPCC:
small repetitive genome elements (microsatellites) were unstable
 Lymphoid infiltrates correlate with MSI

Mismatch repair (MMR) is the culprit in HNPCC

 DNA repair system for rapid repair of DNApol errors
 MMR function genes mutated (can’t repair  MSI / cancer!)
o hMSH2, hMLH1 are best documented

Autosomal Dominant inheritance

 1st “hit” inherited in germline (one MMR gene defective)
o Germline cells are therefore still MMR competent –1 functional copy
 nd
2 hit in tumor (LOH, etc)  MSI / cancer!

Lynch syndrome: term when defined MMR defect is identified in HNPCC family

APCAshkenazi mutation
 6% of Ashkenazi jews
 Gene not “mutated” (not a dysfunctional protein) but at risk for mutation
o Changes A to T to make 8As in a row: AAATAAAA  (A)8
o (A)8 is hypermutable  (A)9
o End up with dysfunctional APC from frameshift mutation
 2-5x ↑ lifetime CRC risk

Peutz-Jehgers Syndrome: “Spots & Polyps”

 Buccal mucosa spots & hamartomas (↑ CRC risk)
 1/25-30k births
 Aka “hereditary intestinal polyposis syndrome”

Overall: remember that

 Sporadic colon cancer is more common
 FCC (familial colorectal cancer) is “basket term” for unidentified inheritable forms
 For FCC: HNPCC > FAP > others

Genetics of Sporadic Colon Cancer

Multistep Progression (chart): basic idea, but not every tumor needs to go through this exact sequence of steps

Genomic instability is big feature of colon cancer

 Lots of microsatellite instability
 Either MSI or chromosome-instability

Average CRC has 80 mutations, but only ~ 15 are

“driver mutations” – rest are “passengers”

34
K-Ras
 K-ras (Kirsten ras, 12p) most commonly mutated in CRC (of 3 viral “Ras” homologs)
 Involved in cell-cycle regulation, G protein, active and in-active conformations
 Commonly mutated in sporadic CRC to constitutively active form
 Mutations in this oncogene are highly restricted to a couple codons (12 and 13) and are activating.

Long Arm of Chromosome 18 (18q)

 Often deleted in sporadic CRC (not in MSI-associated CRC)
 Entire long arm often deleted
 Contains 3 tumor suppressor genes (DCC – colon cancer, DPC4/Smad4 – pancreatic cancer)
o DCC = “deleted in colon cancer”, DPC4 = “deleted in pancreatic cancer” – nice names!

p53 tumor suppressor gene

 Tumor suppressor gene on 17p
 Most commonly mutated in all of cancer cells
 Transcription regulatory activity (cell cycle G1, mitotic spindle checkpoint controls)
o Mutations may cause genomic instability
o p53-mutated cells resistant to ionizing radiation & chemo-induced apoptosis
o Interacts with other oncogenes / tumor suppressor genes

Goal: know how genotype should impact treatment (chemosensitivity, etc.)

Staging of CRC
Duke’s staging (info?)
 Duke’s A – Mucosa / submucosa with no muscularis propria / nodal involvement; good prognosis (95% @ 5yrs)
 Duke’s B – Into / past muscularis propria but no nodes (80% @ 5 yrs)
 Duke’s C – Local mets to regional lymph nodes (60% @ 5 yrs) Stages of CRC
 Duke’s D – widely metastatic, probably will die (5% @ 5 yrs) Stage I: T1-2 N0 M0
Stage II: T3-4 N0 M0
TNM staging Stage III: Any T N1-2 M0
 T1 confined to submucosa Stage IV: Any T Any N M1
 T2 invades into muscle layer
 T3 invades through muscle layer
 T4 invades other organs / structions / perforates visceral peritoneum
 M for distant mets
 N for nodes (N1 = 0-3 nodes; N2 = 4+ nodes)

Spread / Metastasis of CRC

 Direct extension (contiguous structures / peritoneal cavity)
 Lymphatic vessel invasion (LN metastases)
o Unlike stomach, lymphatics in colon LP/MM are inaccessible – need to invade into submucosa to have mets
 Venous invasion (hepatic metastases via portal vein)

Cancer invading muscularis propria serosa CRC invading CRC metliver: total replacement
blood vessel of liver parenchyma 35
 Screening for CRC
EARLY DETECTION is KEY: resect if stage I/II w/o LN involvement - much much better prognosis
 People aren’t getting screening: only 20% getting fecal occult blood; only 34% getting colonoscopy

Assay Sensitivity Cost Invasiveness

Occult Blood 70-80% $1-8 “None”
Barium Enema 80% $180-230 Somewhat
Sigmoidoscopy 60% $205 Highly
Colonoscopy 90% $2,000 Highly

Colonoscopy is best (although $$) Virtual colonoscopy: pretty good but not gold standard
 Bowel prep needed (not great fun for patient)
 Still need bowel prep, still some (but lower)risk of perforation
 Invasive; need general anesthesia
 Sensitivity only about 90%
 Risk of perforation (1/1000) and death (1/5000)
 High false positive rate
 Gold standard; miss rate < 6% for polyps ≥ 1 cm

nd
Need to do 2 (real) colonoscopy to remove any lesions
 Superior to barium enema for followup

Fecal Occult Blood: inexpensive, really low risk, but low diagnostic sensitivity (81-92%)
 Low positive predictive value too (only 20%: high false positive rate)

Guidelines for screening

 Start at age 50
 FOB – test annually
 Colonoscopy – every 10 years
 If positive for adenoma or if FHx + , colonoscopy performed more frequently

Flat/Depressed neoplasms: especially important in CRC in setting of ULCERATIVE COLITIS

 36% of adenomas in UC – need to use spray dye technique; often missed

Molecular screening for CRC

 Proof of principle only now – maybe in the future
 Targets K-ras, p53, APC, Bat26, highly amplifiable DNA

Treatment of CRC
Adjuvant 5-FU (after surgery) is mainstay of therapy Other chemo options
 ↑ dz-free survival 20% @ 4 yrs; only about 1/3 pts benefit from it Oxaliplatin
rd
(3 generation Pt compound)
 Multiple actions: Irinotecan (topo I inhibitor)
o Incorporated into RNA, prevents processing Erbitux (anti-EGFR Ab)
o Inhibits thymidylate synthesase (de novo nucleotide synthesis enzyme)

Patient Specific Chemotherapy (Example: anti-EGFR Ab)

 Goal: only give expensive / dangerous chemo to pts who will benefit (based on genetics)
 FDA-approved for CRC; EGFR-expressing metastatic CRC resistant to irinotecan
 Sensitivity: correlates with presence of EGFR amplification and lack of Kras/braf mutations
o Do Kras test beforehand!
o Check: EGFR by FISH for amplification (also do IHC before use to document)

Post-genomic era cancer treatment / research: If we know all mutations…

 Probably not too much impact on prevention
 Potentially very high impact on early detection
 If therapeutics are available, we can tailor them (↑ efficacy, ↓ relapse?)

36
 Pediatric GI / Liver Disease
Most common: infections, IBD, etc. (in adults too) – these are congenital conditions (specific to peds)

Amniotic Fluid: About 1000 cc at term, always being turned over

Depleted by fetal swallowing if you obstruct fetal GI tract in utero, end up with polyhydraminos (too much fluid)
Repleted by fetal urination (micturation) Renal dysfunction in utero causes oligohydramnios (too little fluid)

Meconium:
 Composed of: mucinous GI tract seretions, bile, shed intestinal epithelial cells, desquamated fetal skin
 Normally passed within 24h of birth
o Meconium passage in utero: implies that fetus is distressed
o FAILURE to pass meconium w/in 24h: implies GI tract obstruction

Hirschprung’s disease
In utero arrest of the normal cranial to caudal migration of ganglion cell precursors,
resulting in non-innervated, aperistaltic bowel

Epidemiology: 1/5k births, 4:1 males, 10% familial, 3-10% of Down’s syndrome pts

Normally: neurons migrate down; form two plexuses around GI tract Hirschprung’s: aganglionic segment from rectum  up with
no ganglion cells (right); proximal to that the colon is dilated
(and would have normal ganglia)

Normally: ganglion cells migrate cranialcaudal

 submucosal (Meissner’s, between inner circular/ outer longitudinal mm layers) & myenteric (Auerbach’s) plexuses
 Functions: RELAX SPHINCTERS & ↑ MOTILITY

Hirschprung’s: don’t migrate

 Distal bowel: cells don’t make it down, ends up aperistaltic; dilation occurs proximally
 Extent depends on how early arrest occurs (more with early arrest); rectum always involved
o 75% cases: confined to distal bowel (only 8% total bowel)

Clinical Presentation:
 Failure to pass meconium within 1st 24 hrs
 Chronic constipation, abdominal distention
 Rectal exam: BLAST SIGN: insert finger, manually relax sphincter  poop shoots across the room (built up pressure)
 Complications: intestinal perforation, enterocolitis

37
Diagnosis: would need laparotomy to get down to myenteric layers (not ideal) – see pic

Endoscopic biopsy: looks at mucosa only, but can still use

 Absence of ganglion cells (both myenteric & submucosal plexuses) if you get a piece
 Acetylcholinesterase stain: ↑ pre-sympathetic parasympathetic fibers, with abnormal extension into mucosa
o Abnormal localization of cholinergic nerve fibers (not being directed by ganglia)

Drawing H&E Acetylcholinesterase

Normal

Ganglia in submucosa; few cholinergic fibers in mucosa Ganglia in submucosa No staining in mucosa
Hirschprung’s

No ganglia;↑ cholinergic fibers in mucosa No ganglia Intramucosal nerve fibers (+)

Treatment: Surgical resection of aganglonic segment, with excellent prognosis

Meckel’s Diverticulum
Persistent remnant of the vitelline (omphalomesenteric) duct

Vitilline duct: connection between midgut & yolk sac (embryology)

 Midgut: herniates into umbilical cord at week 6, rotates, then returns to
abdomen at 10 weeks gestation; connection to yolk sack obliterated normally
 Can have vitelline ligament too (just thin connection to umbilicus)

Clinical Presentation
 COMMON: 2% of general population has one, most asx
 Usually at terminal ilieum with small bowel mucosa lining
o 2 cm, 2 feet from ileocecal valve, 2% of population

Pathogenesis:50-70% have gastric mucosa  ectopic acid production

 Gastrin secretion  acid made by parietal cells  dumped out on small
bowel, which lacks protective mechanisms of stomach (Brunner glands,
pancreatic/biliary secretions, etc.)
 Leads to mucosal ulceration & lower GI bleeding (often painless)
99
Diagnosis: TC-pertechnetate scan (“Meckel scan”)
 picks up ectopic gastric mucosa; can see diverticulum
38
 Meckel’s Normal mucosa to left, ectopic gastric mucosa Ulceration of Meckel’s diverticulum (bleeding)
Diverticulum to the right (parietal cells, make acid, etc)

Pathology: Small, 1-5cm outpouching of ileum, characteristically on anti-mesenteric border

 contains all layers of bowel (true diverticulum)

Treatment: Resect if symptomatic

Gastrointestinal Atresia, Stenosis, Web

In utero ischemic damage to formed bowel causing variable degrees of luminal obstruction

Epidemiology: 1/1300-1/2000 live births

 Duodenum (50%) > jejunum / ileum (40%) > colon (10%)

Atresia: Complete obliteration of / failure to form the lumen of a hollow viscus

Stenosis: Gradual narrowing of gut lumen
Web: Discrete mucosal / submucosal band partially obstructing the lumen

Clinical presentation
 Polyhydramnios in utero (not eliminating amniotic fluid)
 Bilious vomiting, failure to pass meconium, abdominal distension

Treatment: Surgical resection

Duodenal atresia is distinctive:

 Associated with Down syndrome (1/3 Down pts)
 “Double bubble” sign on radiology
(gas distention of the stomach & proximal duodenum;
separated by pyloric constriction)

Tracheoesophageal Fistula / Atresias

Incomplete separation of lung bud from foregut

Normal development:
 trachea / esophagus develop from single tube (foregut)
 larynx/trachea/lung pinch off as lung bud

Epidemiology: 1/2000 – 1/35000 births

 30% have other malformations (cardiac, anorectal; determine prognosis)

Fistula: abnormal communication between hollow viscus & another organ

Atresia: complete obliteration of or a failure to form the lumen of a hollow viscus

39
Clinical Presentation
 Polyhydramnios in utero
 Choking on secretions, respiratory distress worse on feedings
 Can’t place gastric tube

 Often get esophageal atresia & tracheoesophageal fistula together

 Can also have one or another; symptoms are slightly different
o Esophageal atresia (blind pouch): mucousy babies, can’t swallow, no air in abdomen
o Tracheoesophageal fistula: baby feeds  cyanotic (food goes into lungs)

Treatment: immediate surgical reconstruction

Meconium Ileus
Obstruction of distal ileum by thick, viscid meconium of a child with CYSTIC FIBROSIS
 Important to make diagnosis: essentially making CF Dx too (15% CF pts)
 Meconium too thick; ileum is narrowest portion of small bowel (blocks!)

Clinical presentation
 Failure to pass meconium w/in 1st 48 hrs; abdominal distention
 X-ray: dilated small bowel proximally with microcolon distally
 Complications: perforation & meconium peritonitis (sterile b/c meconium sterile)

Treatment
 Uncomplicated: hypertonic enema (wash out)
 Complicated: surgery

Thick meconium  block ileum Histology: thick, viscid meconium Meconium peritonitis: multinucleated
obstructs ileum, sticks to mucosa giant cells eating meconium (brown)

Meconium peritonitis:
 Multinucleated giant cells react to foreign material (meconium)
 See brown pigment inside
 Don’t see many neutrophils like diverticulitis (sterile, irritant type reaction)

Meconium plug syndrome

 Often confused with meconium ileus
 Meconium impacted in colon, not ileum
 Not associated with CF

40
 Neonatal Hypertrophic Pyloric Stenosis
Progressive hypertrophy of the pyloric sphincter, causing obstruction
Epidemiology: 1/400 live births, Males > F (5:1), first born = ↑ risk, ↑ among 1st degree relatives
 Etiology unknown

Clinical presentation:
 Non-bilious projectile vomiting develops between 2-6wks
 Vigorous gastric peristaltic waves (can actually see) – trying to push food through pylorus
 Olive-shaped mass in upper abdomen can sometimes be palpated (Hypertrophic pyloric sphincter!)

Pathology: inner circular smooth muscle layer up to 4x thicker than normal; often disorganized muscle fibers
Complications: dehydration, metabolic acidosis, hematemesis (ulceration 2° to distention)

Treatment:
 Myotomy of pyloric sphincter with excellent prognosis: Just cut pyloric sphincter longitudinally!

Thickened pyloric sphincter Barium swallow: barely Giant peristaltic waves

(cross-section) passes through pylorus (seen just post-feeding)

Neonatal Necrotizing Enterocolitis (NEC)

An acquired, multifactorial process resulting in segmental necrosis of bowel

Epidemiology: Bane of NICU: mostly in premature, LBW babies (2.5% of NICU)

Pathology: simple bowel ischemia / infarction (but etiology not so simple)

Clinical presentation: classic triad

 Abdominal distension
 Bilious vomiting
 Bloody stools

Radiological findings: “double contour” of bowel wall (gas between layers)

Etiology: multifactorial
 Vascular: excessive blood shunting away from gut (stressed!)
 Direct mucosal injury: initiation of enteral feedings damages mucosa
 Infectious: epidemic NEC – multiple babies in NICU

Pathology:
 Ischemic necrosis of bowel wall (Ileum is 1st site involved)
o Mucosa dies first (L pic, most metabolically active & farthest from blood supply)  Transmural eventually

 Overgrowing bacteria (feeding on transmural necrosis) produce H2 gas in dead bowel wall
o Pneumatosis cystoides intestinalis (gas cysts in the intestine, R pic)  “double contour sign” on radiology
41
 Prolonged Neonatal Cholestasis / Jaundice

Key question: Is it extrahepatic or intrahepatic? (treatment different!)

DDx of prolonged neonatal jaundice (↑ conjugated bilirubin)
Extrahepatic Intrahepatic
Etiology Biliary atresia (40%) Neonatal hepatitis (50%)
Others: choledochal cyst, tumors Others: idiopathic bile duct paucity, bile acid metabolism errors, etc
Treatment Surgery Medical (surgery makes it WORSE)

Extrahepatic Biliary Atresia

Idiopathic inflammatory & fibrous obliteration of the extrahepatic bile ducts
 Liver choking on all the extra bile!

Presentation: normal at birth, jaundice (2-3 wks)  cirrhosis (3 mo)

Diagnosis: Disida scan: inject isotope, see normal pick-up, no excretion into duodenum (blocked)

Pathology
Gross Bile Ducts Liver
 Bile ductule proliferation
 Inflammation
 Periportal fibrosis
Findings Shrunken, hardened biliary tree  Injury
 Sparing of zone 3
 Progressive fibrosis
(centrilobular area)
Biopsy? Avoid! (would have to do laparotomy) Yes (no laparotomy needed)

Treatment:
 Kasai procedure: resect all the bile ducts; paste jejunum right to the liver
o Problem: putting bowel (bacteria) in direct contact with liver
o Buy time until transplant
 Liver transplant: best, if available
Bile duct Liver
Normal

Open lumen
Extrahepatic biliary
atresia

Shrunken, basically no lumen Bile duct plugs, bile ductile proliferation

42
Neonatal Hepatitis
Inflammation primarily of hepatocytes
 wastebasket term (any disorder that presents with cholestasis w/o structural cause)

Etiology: variety of causes

 Infection (TORCH, hep B/C)
 Metabolic: α-1-antitrypsin deficiency, CF
 Idiopathic

Diagnosis:
 Disida scan: poor uptake by liver, but do get excretion into duodenum
o Liver injured, but no obstruction of biliary tree

Pathology:
 uniform hepatocellular disarray (portal and centrilobular)
 giant cell transformation
 minimal bile duct proliferation
 liver biopsy isn’t specific for the different etiologies!

Treatment: medical treatment for underlying disorder

43
 Normal Liver Anatomy & Injury Patterns
Objectives to the lecture (will be exam questions)
1. Definition of cirrhosis
a. bridging fibrosis + nodules of hepatocytes
2. Which hepatitis virus has the highest rate of chronic infection?
a. “C” is for “Chronic!” - HCV
3. What are the histologic features of acute & chronic hepatitis?
a. Acute: parenchymal collapse, lobular disarray, inflammation, ballooning degeneration, cholestasis
b. Chronic:fibrosis, apoptosis, lymphocytes, necroinflammatory necrosis

Basic Anatomy

Hilum: Portal vein, hepatic artery, common bile

duct in vascular sheath

Outflow: hepatic vein

Zones: defined better metabolically than

anatomically

 zZone 1 near portal triad

 one 3 near central vein,

Histology: always start with bile duct

 Looks like beaded necklace
 Zone 1 is right around it

Recovery after injury

The liver can recover after injury!
Partial hepatectomy: can totally regrow the rest of the liver!

Acute injury  if not fatal, can get full restoration

Chronic injury  scarring  very slowly reversible

Below, left: mouse liver regenerating;

Below, right: human liver regenerating (CT)

44
 Basic Patterns of Liver Cell Injury
Ballooning Feathery degeneration Coagulative necrosis Apoptosis Necroinflammatory injury
Cell swelling Foamy cytoplasm Groups of ghost cells Individual “mummified” Inflammation + hepatocytes
Description Clumping organelles, hepatocyte, red, nucleus
cytoskeleton starting to fragment
Etiology Fatty liver disease Biliary obstruction Hepatic artery thrombosis Viral hepatitis Chronic viral hepatitis
Pathogenesis Loss of osmotic control Toxic effect of bile salt Ischemic injury Programmed cell death Immune mediated necrosis

Picture

Chronic Injury
Repeated acute injury  chronic injury
Chronic injury: Gross Chronic injury: Trichrome

Fibrosis (scarring), hepatocyte nodules (regeneration)

fibrotic areas are white, nodules of hepatocytes are brown
 Blue = collagen, red = hepatocyte nodules
Caused by any chronic liver injury Caused by any chronic hepatitis

Cirrhosis
CIRRHOSIS = BRIDGING FIBROSIS + NODULES OF HEPATOCYTES (know this!)

Bridging fibrosis: from portal tract to portal tract or central vein

 Molecular model (no need to know): injury  inflammation  cytokines / growth factors / chemokines 
fibroblast activation  + TGFβ  collagen production  fibrosis

45
 Hepatitis
Hepatitis = inflammation associated with hepatocyte death / injury
 Causes: viral hepatitis, autoimmune hepatitis, drug-induced hepatitis
Acute hepatitis Chronic hepatitis
Timing Days to weeks At least 6 months
 Toxins
 Viral hepatitis (A, B/D, non-hepatitis-virus)
Causes Acute, recurrent hepatitis / injury
 Alcoholic liver disease
 Genetic / metabolic
 Parenchymal collapse  Ballooning degradation
 Fibrosis  Lymphocytes
Histology  Lobular disarray  Mϕ infiltrates
 Apoptosis  Necroinflammatory necrosis
 Inflammatory infiltrate  Cholestasis

Cartoon

Acute Hepatitis

Lobular disarray (no architecture; can’t tell Parenchymal collapse: see wrinkled
where you are); also inflammation & Gibson’s capsule (hepatocytes↓ 
ballooning degradation parenchyma shrinks!  saggy)

Complications of cirrhosis
What’s bad about viral hepatitis?
 Hepatic encephalopathy
 Could resolve, or develop fulminant or chronic hepatitis
 Varices
 Chronic hepatitis  stable, or…  Ascites
o Hepatocellular carcinoma  Splenomegaly
o Other complications: see text box

46
 Chronic Hepatitis
Major questions:
Is injury occurring? Has recovery occurred?
 Are hepatocytes dying?
 Does the patient have fibrosis?
 What types of injury are occurring?
 Are there hepatocyte nodules?
Necroinflammatory / ballooning / coagulative necrosis
Necroinflammatory Injury (below) Fibrosis
Top: cartoon with varying degrees Top: cartoon with fibrosis, ± scarring
Bottom: see lymphocytes pouring out Bottom: fibrosis (↑ collagen in trichrome, lower pic)

Specific Diseases: Viral Hepatitis

Hepatitis A
 RNA virus
 Fecal-oral transmission
 NO CHRONIC INFECTION
 Rarely fulminant
 Anti-HAV

Pathology: inflammatory changes, mostly unremarkable

Hepatitis B
 Many don’t know that they’re infected

 DNA virus
 Blood, etc. transmission
 Acute & chronic forms
 Diagnosis:
o HBsAg = infection acute / chronic
o Anti-HBc+ HBsAg = chronic infection

47
Pathology:
 Ground glass hepatocytes, grayish in middle
 IHC for surface antigen

Ground glass hepatocytes IHC: HBsAg + More ground glass hepatocytes (arrows)

Hepatitis C
 Most patients develop chronic hepatitis (85%)
o Remain stable or progress to cirrhosis

 RNA virus
 Blood-blood transmission
 “C” MEANS CHRONIC
 Anti-HCV can detect
 Viral RNA: very low fidelity RNApol (↑ diversity)
Pathology:
Nodular portal inflammation Intracellular fat
(Dense lymphocytic infiltrate into portal tract)

Specific Diseases: Autoimmune Hepatitis

Pathology Features Type 1 Type 2
 Chronic but can look acute Age (10-20 / 45-70 yo) (2-14 yo)
 Bridging necrosis Women (%) 78 89
 Lymphocyte infiltrate Concurrent immune disease (%) 41 34
Autoantibodies ANA Anti-LKM
 Prominent IgG positive plasma cells
Gamma globulin elevation +++ +
Histology Plasma cells Plasma cells
PCs: vaguely triangular; have eccentric nucleus Progression to cirrhosis (%) 45 82
with white tuft next to it

Bridging necrosis, lymphocytes + PCs Lots of plasma cells (arrows & lymphocytes Dense lymphocytic infiltrate

48
 Specific Diseases: Drug-induced Hepatitis
Intrinsic Idiosyncratic
 Predictable  Unpredictable
 Sufficient dose induces injury in everyone  Depends on metabolic rate
 Immune system stimulation involved
Example: Tylenol – give enough and everybody gets liver damage Example: reaction to PCN
 Drug-induced hepatitis may be histologically indistinguishable from other types of liver injury

Acetaminophen Isoniazid Procainamide Methotrexate

 Coagulative necrosis
 Minimal inflammation  Diffuse necrosis  Enhanced SER
Change?  Periportal lymphocytic  Ground-glass Portal fibrosis
Mushrooms, α-methyl inflammation appearance
dopa can do this too
 Periportal (inflammation)
Where? Zone 3 (near central vein) Portal triad
 Diffuse (necrosis)

 ischemic injury
Mimics: Viral hepatitis Viral hepatitis B Chronic viral hepatitis
 hepatitis

Picture

49
 Alcoholic Liver Disease
Alcoholic Fatty Liver
Fat accumulation
a regular, reversible accompaniment of heavy alcohol consumption
 Nutritional & toxic effects (e.g. acetaldehyde)

 Holes: accumulation of lipids / TGs dissolved out during tissue formation

 Know it’s fat because it’s a droplet (liquid at body temperature
 Patients can present with fatty liver as only abnormality
o Hepatocytes can work just fine even if they look like this
o abnormal LFTs result from hepatocyte injury (acetaldehyde production, etc)

Mitochondrial damage (GIANT mitochondria)

Mitochondrial damage from acetaldehyde exposure EM: can see remnants of cristae in giant mitochondria

Alcoholic Hepatitis
 Active hepatocellular injury + inflammation seen in some alcoholics after many years of abuse

Clinical manifestations:
 ± jaundice
 ↑↑ AST, ↑ ALT (but lowish: defect in production of ALT). AST > ALT
o Most severe acute alcoholic hepatitis may have “normal” ALT (impaired production!)

Histology: combo of focal hepatocellular injury, active inflammatory response, active intralobular pericellular fibrosis

Category Histological findings Notes

Focal hepatocellular injury
Acute inflammation
Hydropic degeneration
“alcoholic” / “Mallory’s” hyaline
Focal cell necrosis / drop-out
Mostly PMNs
Irregular hyaline cytoplasmic inclusions
 accumulation of keratin-like filamentous proteins
 related to IFs
 represents disruption of cytoskeleton
PMNs‼ (vs lymphocytes in viral hepatitis)

Active intralobular Often seen with Greater degree of fibrosis than in comparable
pericellular fibrosis sclerosis of hepatic veins* degrees of other liver dz
Alcoholic hepatitis: most severe in centrilobular regions
 ± fat accumulation, cholestasis (not needed for Dx)

*Veno-occlusive disease: primarily centrilobular; affects small draining hepatic veins

50
 Veno-occlusive disease
Swollen hepatocytes (arrow)
Mallory’s hyaline Pericellular fibrosis (more severe: centrolobular region);
Mallory’s hyaline (open arrowheads),
(EM) (trichrome) small vein here half obliterated by
PMN –rich response (closed arrowheads)
fibrosis / cellular reaction

Non-Alcoholic Steatohepatitis (NASH)

Same histologic / clinical picture as alcoholic hepatitis, but not in alcoholics!

Risk factors: metabolic syndrome, ↑TGs, DM, obesity, HTN, etc.

 Anything that causes endoplasmic reticulum stress can lead to this
o Portal endotoxemia, for example
o Fat itself doesn’t play a huge role NASH Severe NASH
(post-jejunal-ileal bypass)
Example: pts who got early jejunal-ileal bypass
 endotoxemia from infection of blind pouch
 Obesity + ER stress (endotoxins)
 Produced non-alcoholic steatohepatitis!

NASH = (“steato”)hepatitis in context of NAFLD

 fatty liver background
 inflammatory changes like alcoholic hepatitis

Can progress to cirrhosis!

Cirrhosis
A disease in its own right!
 Can come from alcoholic or non-alcoholic hepatitis or variety of other etiologies

↑ intrahepatic resistance to blood flow is key problem

 Obliteration of small intrahepatic veins is the big problem

Complications: Hepatic encephalopathy, ascites, esophageal Varices (can rupture!)

 from portal hypertension / shunting of blood away from hepatocytes and
 reduced functional hepatocyte mass

Oten considered irreversible: but in early stages, can see reduction of fibrosis / architectural distortion / portal HTN
 if you can stop the active injury!

51
Cirrhosis: Pathology
Histologic definition: interconnecting bands of fibrosis and nodules of “regenerated” hepatic parenchyma

Esophageal varices big, dilated vein just under epithelium Ruptured varix with Rupturing varix: dissected
(gross) (varix) – more to right, but this one = bad “blood blister” through epithelium

Cirrhosis (trichrome): nodular distortion Cirrhosis: see lots of fibrosis! Veno-occlusive disease (same
& tons of fibrosis as above: cirrhosis destroys
small intra-hepatic veins)

Hepatic Veinograms: Recovery from cirrhosis

normal (left): note fine branching; Left: active alcoholic cirrhosis (bands / nodules)
alcoholic cirrhosis (right) – bigger / truncated veins, Right: same pt after 20 yrs of abstinence (structure restored!)
simplified structure – obliteration of small veins!
↑ resistance in alcoholic cirrhosis!

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 More Fun Facts About Cirrhosis
 in France, ↓ cirrhosis during WWI/WWII (↓ EtOH availability!)

The Study (histologic features of alcoholic liver disease)

Looking at heavy drinkers to see what histological changes correlate with disease
 Bigger fat droplets = more fat in samples
 Hepatocellular injury is associated with presence of acute fibrosis, not fat accumulation!
 After 1 month of abstinence: ↓ fat accumulation, ↓ hepatocellular injury, fibrosis was mixed response
o Presence of alcoholic hyaline seemed to be important

Prognostication of how much portal HTN @ 1 mo:

What predicts what CWHVP will be in 1 mo?
 Prothrombin time (good)
 CWHVP (really good) at baseline
 HISTOLOGY (super good)

Take home point: biopsy every alcoholic with possible

cirrhosis (just kidding)

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 Primary Liver Tumors
Overview of Neoplasm
By cell type
Cell type Benign Malignant
Focal nodular Hyperplasia*
Hepatocyte Hepatocellular carcinoma
Hepatic adenoma
Von Meyenburg Complex*
Cystadenocarcinoma
Bile duct Bile duct adenoma
Cholangiocarcinoma
Cystadenoma
Hemangioma Angiosarcoma
Vascular
Infantile Hemangioendothelioma Hemangioendothelioma
Mesenchymal/mixed Mesenchymal Hamartoma Hepatoblastoma
*Note: Von Meyenburg complexes and focal nodular hyperplasias form mass lesions, but are not truly clonal processes .

By age
Age Tumor
Hepatoblastoma
Infant
Infantile Hemangioendothelioma
Hepatocellular Carcinoma
Children/young adults Fibrolamellar Carcinoma
Hepatic Adenoma
Hemangioma
Bile duct adenoma
Adults Focal nodular Hyperplasia
Hepatocellular Carcinoma
Cholangiocarcinoma
Hepatocellular carcinoma
Older Adults
Angiosarcoma

Vascular tumors
Hemangiomas (benign)
 Most are cavernous hemangiomas
 Most common primary tumor of the liver
 Benign, composed of dilated blood vessels
 Usually small, incidental findings

Gross:
 Single, dark, red-colored
 Spongy consistency (blood vessels)

Histology:
 Thin-walled vessels, dilated, ± thrombi
 Scarring / hyalinization / obliteration of blood vessels can replace
center
 ± large “feeder vessels” at periphery

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Infantile Hemangioendotheliomas (benign)
 Rare overall but still #1 liver lesion in 1st yr of life

Presentation:
 Can present with high-output cardiac failure
o (AV shunting / thrombocytopenia from platelet sequestration)
 May present only with hepatomegaly / diffuse abd. enlargement
 PE: palpable hepatic mass / diffuse enlargement
 ½ have cutaneous hemangiomas Multiple red spongy nodules

Prognosis: tend to spontaneously regress at 6-8 mo

Gross: multiple lesions, spongy  fleshy in appearance

 Vs. hemangioma: frequently multiple, not subcapsular

Histology: irregularly-shaped small vessels in sparse fibrous stroma

Irregular vessels in sparse fibrous stroma
Angiosarcoma (malignant)
 Extremely rare that arise from blood vessels of liver
 Risk factor: chemical exposure
o thorotrast, vinyl chloride (dry cleaning), arsenic

Gross: tan-white or hemorrhagic, can be spongy

 Small nodules scattered throughout liver
o Occasionally: single mass
Distorted blood vessel + atypia More sheet-like pattern

Histology: pleomorphic endothelial cells

 Form small channels, can contain blood
 Have atypia (as opposed to benign lesions)
 Multiple possible histologies:
o poorly formed vascular channels
o solid sheets
o growing along sinusoids (hardest to Dx)
Normal liver Angiosarcoma growing
along sinusoids

Hepatocellular Tumors
Focal nodular hyperplasia (benign)
 70% pts are female, usually 30-50 yo (OCP  trophic or ↑ risk rupture?)
 Not always a neoplasm (may not be clonal) but in DDx for liver masses
o Thought to arise from vascular malformation (A-V shunting)
o Can be single or multiple
o No risk for malignancy; NOT in cirrhotic livers
Gross:
 Well circumscribed, most (< 5cm) with central fibrotic scar (1/3 to ½)
 On non-cirrhotic background

Histology:
 Focal lesion: looks like “focal cirrhosis”
 Bands of fibrosis, bland hepatocyte nodules
 Abnormally thick-walled vessels (AV-shunt) often in tumor center
 Central scar (not always present)

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Hepatic adenomas (benign with risk of malignant differentiation)
 Typically women of reproductive age, most with OCP use (85-90%) with estrogen
o OCP use may be remote – need good history
 Can be seen in several other rare conditions (androgen use, glycogen storage dz type I,III)
 NOT in cirrhotic livers

Possible complications:
 Risk of progression: 10% can progress to cancer
 Rupture → intraperitoneal hemorrhage (#1 risk)
 Can recur if not completely excised

Gross:
 Well circumscribed, 75% encapsulated
 Frequently have areas of hemorrhage
 Non-cirrhotic background

Histology:
 Uniform, bland hepatocytes
 Often partially encapsulated
 Can show ↑ steatosis vs. non-neoplastic liver (right)
 Thin-walled vessels (left, arrowhead) can be at ↑ risk rupture

Hepatic adenomas can progress to cancer

A. Gross: see area of hepatic adenoma (arrow), uninvolved liver
B. Junction of hepatic adenoma (left) and HCC (right)
C. Adenoma (left), hepatocellular carcinoma (right)
D. Reticulin stain of (C); shows ↓ reticulin along sinusoids in HCC

Hepatoblastoma (malignant)
 Malignant neoplasms
 Infants / young children (almost always < age 3); 2:1 Male:F
 Mutations in wnt-signalling pathways strongly linked to hepatoblastomas (β-catenin)
 ↑ AFP (α-fetoprotein) in 90% cases (USEFUL!)
o Infant with liver mass and ↑ AFP = hepatoblastoma in almost all cases
o Monitor AFP after surgery to check for recurrence

Gross:
 Non-cirrhotic livers (babies)
 Solitary, usually well-circumscribed in right lobe of liver
 Hemorrhage, necrosis, calcifications

Histology:
 Predominantly of primitive epithelial cells (left)
 With admixture of immature mesenchymal cells (right)
 Unusual pattern of growth
o in liver, unique to hepatoblastoma

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Hepatocellular carcinoma (malignant)
 HCC is one of most common cancers worldwide (4/10k in USA, ↑ in SE Asia)
 In USA: HCC is 80% of primary liver carcinomas

Risk factors:
 Chronic HBV hepatitis (most important world-wide)
 Chemical carcinogens:
o Aflatoxin B1 (toxic metabolite of Aspergillus flavus: contaminant of grains / legumes in Asia / Africa)
o HBV + Aflatoxin B1: synergistic effect
o Thorotrast, vinyl chloride, arsenic too (now more rare exposure)
 Cirrhosis from chronic HCV is most common risk factor in USA (more chronic HCV)

Epidemiology of HCC in USA

 Average 61 yo; rare before age 40 (get hepatitis C in 25-35 yo age range; takes time to develop)
 70% men; ↑ incidence in USA

Prognosis:
 Generally bad (≈ 6 mo)
 Worse with: Age (> 5), male, tumor stage / grade, presence of cirrhosis
 Often not detected until late stage
o Screen for HCC in high risk groups (serum AFP, CT scans)
o Can resect if you see it early

Gross
 Can be in both cirrhotic (80%) or non-cirrhotic liver
 Well circumscribed ± capsule
 Can be greenish (bile) or yellowish (fatty)
 Can be multifocal or one large nodule + “satellite nodules”
 Fed by abnormal hepatic artery growth (upper right in pic)
o Good for radiology (vascularized)

Histology:
 ↑ mitotic figures, ↑ cellularity
o Thickened hepatocellular plates (> 3 cells)
o ↓ reticulin staining
 NO portal tracts
 Abnormal arterioles
 AFP-expressing (1/3 patients) HCC: No portal tracts ↑ N/C ratio, no portal tracts
 Can have lots of different patterns too!
Standard cancer changes too: ↑ N/C ratio, hyperchromatic, etc.

Vascular invasion: ↑ risk recurrence

Abnormal arterioles: found in L: Normal, R: HCC ↑ proliferation AFP + with IHC

lobules too, not just portal tract Note ↓ reticulin stain in HCC (↑ mitotic figures)
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More HCC Pathology
More Possible HCC Patterns

Pseudoacinar structures ↑ fat ↑ glucose ↑ proteins (inclusions) ↑ Lymphocytes

Vascular invasion: ↑ risk recurrence
 HCC invading small
vessel (big tumor
thrombus)

HCC invading portal v.

Produced thrombus (see
thrombin, etc.)

Fibrolamellar carcinomas (malignant)

 Subtype of HCC (5%)
 Younger patients (≈ 25), no gender predilection
 Just as aggressive as usual HCC
o No cirrhosis in background (↑ survival rate)
o More likely to go to lymph nodes vs typical HCC

Gross: Background non-cirrhotic

Histology:
 Bands of dense fibrosis (fibro-) that tend to run parallel to each other (-lamellar)
 Abundant pink cytoplasm, big nucleoli

Bile duct tumors

Bile duct adenoma (benign)
 Small, solitary, sub-capsular benign neoplasms of bile ducts
 No malignant potentially
 Usually incidental finding
o (while pt undergoing abd. surgery for another cause)
 Can mimic metastatic disease: small firm white nodules

Cholangiocarcinomas(malignant)
 Arise from bile ducts anywhere w/in biliary tree
o If in hilum of liver = Klatskin tumor
 Risk factors for EXTRA-hepatic cholangiocarcioma are different than intra-hepatic
Extrahepatic cholangiocarcinoma Intrahepatic cholangiocarcinoma
 Cirrhosis from any cause
Diseases that cause chronic biliary tree inflammation
 HCV
 PSC, Caroli’s disease, parasites
 EtOH
Extrahepatic cholangiocarcinomas are ↓ in frequency: we’re getting better at treating PSC, etc.
Intrahepatic cholangiocarcinomas are ↑ in frequency: ↑ HCV, ↑ cirrhosis in USA

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Gross:
 White, firm, well-circumscribed
o Elicit lots of desmoplasia
o Never encapsulated
 ± background cirrhosis (risk factor)

Histologically:
 Malignant proliferation of poorly formed infiltrating
small glands that form duct-like structures
 Desmoplastic response (firm on gross exam)
 Perineural invasion

Dysplasia is precursor to cholangiocarcinoma

Metastatic disease
Metastatic lesions to the liver are 16x more common than primary liver neoplasms in autopsy
 90% show MORE THAN ONE NODULE
 Pancreas, colon, breast, stomach, lung

Colon carcinoma (met to liver) Neuroendocrine carcinoma (met to liver)

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