Pathology: GIEsophageal 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

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Esophageal PathologyNormal Anatomy ReviewWhere 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 Meissners plexus esophageal submucosal glands (modified salivary glands; anatomic marker of esophagus) Thick muscle layer with Auerbachs 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; dont 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 = Schatzkis 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

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EsophagitisInflammation of esophagus (but some of these conditions, e.g. reflux esophagitis, dont 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 Ischemic Injury: Kayexalate exchange resin for hyperkalemia in renal failure Ischemic injury from hypertonic sorbitol See big crystals

Iron Pill Esophagitis: May or may not see rustygolden brown pigment

causes ulcer can pick up better withiron 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: cant see actual drug (just ulcer)

Kayexalate: big crystals

Chemical esophagitis (lye): 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: doesnt extend into submucosa Course: Superficial lesions often heal without scarring Deeper lesions can heal with scarring and stricture formation 3

TraumaEtiology: 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 (NG tube lesion note erosion)

Top, right: thermal injury (microwave) Note mummified layer, sharp contrast to intact zones

Allergic EsophagitisEpidemiology: 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 esophagitisPrimary 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 floraBig crusts of purple-staining bacteria; usually only in profound neutropenia)

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

Others: Aspergillus Histoplasma capsulatum

Candidal esophagitis: gray-white plaques

Yeast, pseudohyphae, hyphae

Viral EsophagitisBig 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 OWLS EYE INCLUSION (or binucleated) Cowdry A inclusion (has a space around it) Herpes Esophagitis Mostly HSV-1, most often opportunistic infectiono o Occasionally in non-immunosuppressed 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 IHC stain can help ID Cell size Big Normal Inclusion Owls eye (Cowdry A) Smudged (Cowdry B)

o Virus CMV HSV

HSV: Multiple shallow HSV: cells with inclusions at edge punched-out ulcers of ulcer in squamous epithelium

Location Center Edge

Smudged Cowdry B inclusions

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

Pathology of GERDEpithelial 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 papillaeo Usually go 1/3 of the way up; now > way

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

Complications of GERDSevere complications are unusual Can develop: ulcer, bleeding from ulcer, stricture formation (scarring / deep injury) Barretts esophagus: develops in 10% pts with symptomatic reflux

Barretts EsophagusReplacement 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 o Cardiac: glands; top (cardia) of stomach 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 Barretts In US: need INTESTINAL METAPLASIA to be called Barretts dont know if you got Bx from right place o Most prone to develop dysplasia & adenocarcinoma Other countries: also consider gastric-type metaplasia Barretts (maybe we should too)

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Diagnosis Pathology: GOBLET CELLS in esophagus (really shouldnt be there!) Endoscopy: tongues, patches of reddish salmon-colored columnar mucosao o o Normal esophagus: grey/pink/pearly squamous epithelium Short-segment: < 3 cm, more common Long-segment: > 3cm; more likely to progress to esophageal adenoCa

Pathogenesis Not clear: associated with chronic reflux; unlikely that its 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 Barretts have or will develop adenoCa (incl. pts w/ adenoCa on presentation) about 0.5% / yr will progress from BE adenoCa

Esophageal AdenocarcinomaAdenocarcinoma = 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 Barretts) Risk factors: Barretts, males, whites, obesity, smoking, alcohol Gross pathology: adenocarcinoma in background of velvety columnar Barretts 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 Barretts Mucosa: grade with more atypia, bigger nuclei, more disorganized glands

Esophageal adenoCa: shouldnt see glands down at bottom (invading!)

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Esophageal Squamous CarcinomaEpidemiology: in comparison to adenoCA in USA high incidence in developing countries (China, Iran, southern Africa) Risk factors: (know these) Males African-Americans Alcohol* Smoking Diet: nitrosamines, nitrates Lye strictures Achalasia

(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 / squamous epithelium

Esophageal squamous dysplasia: Squamous pearl: enlarged cells, not maturing abnormal keratinization

Eso Squamous CA (here upper 1/3 bad Pgx)

Prognosis 5-year survival (with Tx) Overall < 15% Superficial (T1) CA 75-80%T1: T2: T3: T4: N: M:

TNM Staging of esophageal CAinvades lamina propria or submucosa invades muscularis propria invades adventitial fat invades adjacent structures Nodal involvement 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) 8

Stomach PathologyNormal Anatomy Review Esophagus LES Cardia, fundus, body transitional zone (Pyloric) Antrum Pyloric sphincter Duodenum

Normal Histology ReviewOxyntic (= acid secreting) mucosa Parietal cells (secrete HCl) fried egg Chief cells (secrete pepsinogens) - pinkish Surface, foveolar epithelium PAS (+) o mucus secreting

Fundus & Body

FOV = foveolae (small pits) PC = parietal cells CC = chief cells (cardia by GE junction similar but no endocrine cells)

Antrum

Mucus and/or pepsinogen secreting cells Lots of PAS (+) mucus secreting o glandular epithelium too! 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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GastritisClassification of gastritisAcute gastritis Acute hemorrhagic gastritis Acute infectious gastritis (chiefly bacterial, e.g. HP, & viral)

Chronic gastritisChemical gastritis Aspirin / NSAIDs, bile reflux, others? H. pylori gastritis Autoimmune gastritis Other uncommon forms

Acute hemorrhagic & erosive gastritis (AHG)

INITIATING FACTORS Ischemia (2 to hypoperfusion: stress, shock) Chemicals (Aspirin, NSAIDs, bile salts, EtOH) NOT H. pylori

A.k.a. acute gastritis / gastropathy (minimal inflammation)

Think: frat boy who drank too much

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 prostaglandins mucosal protection

Endoscopy: multiple punctuate & confluent superficial 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 CHRONIC NSAID EXPOSURE COMMON Pathological Features: ANTRUM BODY (corpus) for gross changes Gross: Highly variable, not characteristic / diagnostico o erythema, thickened folds hyperplastic polyps less common

Bile reflux (mainly with gastroenteropathy: post antral gastrectomy) Others (?) hypersecretion, EtOH, other irritants?

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 Shallow break in mucosa Can reach muscularis mucosae, but doesnt penetrate

UlcerFull-thickness break in mucosa Penetrates muscularis mucosae, may go even deeper

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 CANCERo 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 gastritisEpidemiology 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 Adhere to gastric epithelium / in mucus o Dont colonize other GI epithelial types (e.g. intestine) Look coccoid after treatment Lympho-plasmacytic chronic inflammation o active (acute) inflammation 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 lymphomaLink to autoimmune gastritis (?)

H. Pylori Consequences: Peptic UlcersWhy 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) 12

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 Stemmermans technique: Alkaline phosphatase stain Technique makes anything with goblet cells turn RED! More red = more metaplasia H. pylori: doesnt like to live where theres intestinal metaplasia Intestinal metaplasia like a type of defense mechanism?

H. pylori & Gastric CancerIntestinal 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 Consequences13

Autoimmune Metaplastic Atrophic Gastritis (AMAG)Gastritis by etiology & location (KNOW THIS) Autoimmune BODY messed up Antrum OK H. Pylori ANTRUM messed up Body OK

Patientthink 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 o Parietal cells lost, metaplasia appears achlorhydria loss of IF B12 malabsorption deficiency pernicious anemia

H. pylori normally absent

PathologyBody / 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: but no parietal cells!

2. Double check: from body? Gastrin (-) not antrum!

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

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 dont stick together) risk for mammillary lobular cancer too in F (another cancer where cells dont stick together)

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Small Intestine: Inflammatory & Non-Neoplastic DisordersNormal Small Bowel

Brunners 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 Brush border: lots of digestive enzymes, etc. Enterocytes: do the absorbing Disorders: Peptic diseases Malabsorptive disorders

Paneth cells (pink granules) contain lysozymeo secrete contents into lumen

Endocrine cells: smaller cells (also pink granules)o secrete contents into surrounding vasculature

Stasis syndromes

Infections

Peptic DiseasePeptic 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

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Microscopy: epithelial damage and reactive changes Gastric mucin-cell metaplasiao o

adaptive response to chronic acid exposure 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 blunting (almost looks like colon!)

Mucin cell metaplasia (mucin is PAS positive see enhancement, r.)

Brunner Gland hyperplasia note number, 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 nodular on endoscopy (Brunner gland hyperplasia)Duodenal bulb ulcer, with pre-pyloric ulcers, rugal hypertrophy Peptic ulcer in duodenum (note BG hypertrophy, proximity to pancreas, penetration into artery bad!

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!

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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 arent sufficient to cause ulcer recurrence!

Non-peptic causes of duodenitis Crohns Disease Celiac Disease Zollinger Ellison Syndrome (gastrin-producing neuroendocrine tumor) Infections (Giardiasis, MAI, Crytosporidiosis, Microsporidiosis, CMV, Whipples Disease)

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

Lactase DeficiencyForms: Infantile (rare) Adult onset (most common)o o Otherwise healthy adults, esp. dark-skinned races Brush border enzyme reduced post-childhood

Acquired forms: due to intestinal damage (e.g. celiac dz, sprue) 18

Chief symptom: milk intoleranceLactose 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 cant break down to glucose / galactose & absorb lactase in lumen, acid luminal osmolality suck out water

Celiac disease Multisystem autoimmune disorder Autoimmune hepatitis Many more

Extraintestinal manifestations: Type I diabetes Epilepsy Autoimmune myocarditis

Epidemiology Risk factor st 1 degree relative nd 2 degree relative Extraintestinal disorder assoc. w/ CD None

Prevalence 1:22 1:39 1:56 1:133

Pathogenesis Environmental triggers Gliadins (wheat) Hordeins (barley) Secalins (rye)

Genetic risk factors HLA class II genes (HLA-DQ2, HLA-DQ8) 70-80% MZ concordance

Immunologic factors CD4+ T-cells that recognize dz-activating peptides( cytokines like IFN- inflammation, injury)

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 Villous blunting, crypt size

Intraepithelial lymphocytosis (arrows)

Crypts: see chronic inflammation in lamina propria & lots of mitoses

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

Long term gluten free diet Continued clinical improvement Histopathology o Further return of villio o o Mitotic activity subsides Chronic inflammation subsides 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 biopsieso bulbar Bx can give false negative results (see case 2: bulb looks nL!)

Cant 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 SprueA.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)

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

Stasis syndrome Malabsorption due to stasis / immotility of small bowel Overgrowth of anaerobic bacteria (balance disturbed with peristalsis)o o o Deconjugate bile salts vitamin B12 Damage surface epithelium

Causes of Stasis Syndromes Disease-related Acquired (surgery, etc.)Crohns disease, IBD Diverticular Disease Scleroderma of small intestine Pseudo-obstruction Blind loop or pouch Entero-enterostomy Afferent loop Gastro-jejuno-colic fistula Adhesions and partial obstructions

Looks like partially developed / treated CD

Scleroderma (pics to left): preferentially destroys inner circular layer of muscularis propria ( peristalsis)

Scleroderma: bowel markedly distended, loss of muscle tone

Thinning, scarring with loss of muscularis propria in SCL

Mucosa looks normal in scleroderma!

Pathogenesis: Stasis Bacterial overgrowth B12 depletion (anemia) Bile salt deconjugation, epithelial injury (malabsorption) Treatment: antibiotics ( weight gain, ability to absorb fat!)

Whipples 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

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

Rounded villi with expansion of lamina propria

Normal epithelium, lamina propria full of foamy pink M

PAS stain of jejuna Bx: PAS+ foamy M

Anti-T. whippelii immunostain: positive!

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!)

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Inflammatory & Nonneoplastic Disorders of the ColorectumEndoscopyic biopsy: basic goals to distinguishL Normal vs abnormal:o o histology of normal colon varies by site 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 / conceptsActive inflammatory changes Reflect acute injury to colorectal mucosa Cryptitis (PMN infiltrate in crypt epithelium) Crypt Abscesses (intraluminal PMNs) Erosions (breakdown of superficial epithelium) Ulcers (breakdown penetrates entire mucosa)

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 laminapropria 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

Features Etiology

Acute fibrinoinflammatory exudates Neutrophils are the key!!!! Not specific, found in variety of conditions bacterial infections idiopathic IBD iatrogenic colitis NSAIDs ischemic diseases

Can accompany any condition with repeated bouts of active inflammation or other injury

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

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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) Ischemia (atherosclerosis, infectious) Emerging Crohns disease 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 diseaseo o Salmonella- mucosal ulcerations over hyperplastic Peyers patches 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 Crohns 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 colitisHistopathologic Criteria Diffuse mucosal inflammatory infiltrate (lots of PMNs, cryptitis, crypt abcesses) Basal plasmacytosis Crypt distortion Goblet cell depletion Paneth cell metaplasiaDistorted 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

Crohns 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

Crohns Disease: Histopathology (continued)

CD: terminal ileal involvement, risk stricture (transmural) Patchy distribution (cecum nL!)

Basal plasmacytosis (diffuse, vs. structured peyers patches), villous blunting

Granulomas & giant cells

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 Uveitis Dermatitis (pyoderma gangrenosum, erythema nodosum) Sclerosing cholangitis* Ankylosing spondylitis* * dont 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 Crohns 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)

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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 Celiac disease

Autoimmune diseases (RA, autoimmune thyroiditis, scleroderma, etc) Luminal antigen? (CC goes away if colon diverted, recurs when hooked back up!) Histopathology: Lymphocytic colitis Patchy distribution, etc. Similar to collagenous colitis: o but no thickened BM

Histopatology: Collagenous colitis Irregular subepithelial collagen layero Normally type IV collagen, now made of types I/II collagen & fibronectin

intraepithelial lymphocytes Surface epithelial damage Superficial plasmacytosis of lamina propria No crypt distortion Rare neutrophils

Collagenous colitis: thickened basement membrane (esp on trichrome stain where ECM = blue, middle); also CD3 lymphocytes (IHC stain, right)

Lymphocitic colitis: like collagenous colitis 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 (bowel twisted on itself) E. coli 0157:H7 Most common cause of ischemic colitis in US * intusseception: most common in pediatric ileum (hypertrophied peyers patches form leading edge)

Histology: depends on severity & duration of injury Mucosal necrosis Hemorrhage Heme-laden macrophages in lamina propria Fibrin thrombi

In chronic phase, progresses to mucosal atrophy, fibrosis of lamina propria Microcrypts (trying to regenerate) Unaffected areas: acute colitis signs 27

Histopathology of ischemic colitis

Dilated, red bowel

Fat in atherosclerotic plaque can embolize, cause ischemic bowel

Note sharp demarcation, focal injury

From infection: boggy, ischemic mucosa

Lamina propria: necrosis, hemorrhage; no inflammation, fibrotic changes. Crypts: trying to regenerate

big-time hemorrhage

Microcrypts (top , smaller crypts: attempt to regenerate, lined by regenerative epithelium)

Treatment: need to excise surgically if transmural necrosis (gangrene) before perforation! Sepsis is big complication

Causes of Ischemic ColitisE. 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: cant distinguish O157:H7 & other strains but most labs use Cx medium to screen (based on sorbitol fermentation)

CMV infection Owls Eye Inclusions

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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 through muscularis mucosa

Extend into vessel bleed

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

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 Crohns Histopath: can have granulomas & sinus tracts o CLUE: find ACTIVE CHRONIC INFLAMMATORY CHANGES in distribution of diverticular disease Treatment: simple resection (dont need to give antiinflammatories like for IBD) Involved segment: active chronic colitis

Hypercellular lamina propria (plasma cells, eosinophils)

Crypt distortion

Cryptitis

AppendicitisMost 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 lesswell developed colon, surrounded by peri-appendiceal fat

Sections of appendix; note huge abscess (arrow) extending into fat

Periappendiceal abscess with PMNs (label) and foreign body giant cells responding to stool (arrows)

Possible etiologies Fecalith (hardens, calcifies, obstructs) Lymphoid Hyperplasia (viral infection, etc.)

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Colorectal CancerMajor Points

Colorectal cancer is completely preventable with optimal screening, but most dont get screenedo 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 rectumo o Sigmoid most frequently, transverse colon is increasing 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 TerminologyGROSS definitions Polyp: any mass projecting into the lumen (bad: doesnt say benign/malignant, etc.) Colorectal Polyps Adenoma: a benign tumor with dysplastic features; Non-neoplastic Neoplastic clearly a pre-malignant lesion Hyperplastic polyps Tubular adenomao o Sessile adenoma: attached by broad base Pedunculated adenoma: attached by stalk Hamartomatous polyps Inflammatory polyps Tubulovillous adenoma 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 CRCMultistep progression:Normal Epithelium Field defect Dysplastic aberrant crypt focus Low-risk adenoma High-risk adenoma Adenoma containing AdenoCa Primary AdenoCa Metastatic 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, dont 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 HistologyAdenomatous 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 Note some crypts cut in cross-section, others longitudinal (disarray)

Dysplastic nuclei; Not confined to bottom 1/6 of cells

Pedunculated polyp here; see fibrovascular core, mix of tubular & 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 CRCEnvironmental 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

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

Genetics of CRC (overview)OncogenesMutations restricted Mutations activating Rarely associated with LOH Cyto: nothing or translocations Not methylated Function: accelerates growth, permits multilayering

Tumor Suppressor genesMutations widespread Mutations are deleterious LOH is common Cyto: deletions, whole chromosome losses Can be methylated 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 CancerFamilial Adenomatous Polyposis (FAP Rare condition Colon studded with innumerable polyps (100s1000s) 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 -cateinin (growth factor) in cytoplasmo With mutation: -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 sidedo First approximation ONLY! Not always true Still pass through polyp phase: just dont see innumerable polyps like FAP

Onset / inheritance: Site: Histology: Associated CAs:

Autosomal dominant; Mean age 44 yo, 90% penetrance 70% proximal to splenic flexure, though 30% distal! more likely poorly differentiated, mucinous, signet ring cells, intense lymphoid infiltrates (take a FHx for CA): endometrium, stomach, ovary, small bowel, renal pelvis and ureter

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Microsatellite Instability Novel length alleles in tumor as compared to patients germline Serendipitously discovered when mapping for HNPCC: small repetitive genome elements (microsatellites) were unstable Lymphoid infiltrates correlate with MSI o

Mismatch repair (MMR) is the culprit in HNPCC DNA repair system for rapid repair of DNApol errors MMR function genes mutated (cant 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

2 hit in tumor (LOH, etc) MSI / cancer!

nd

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 mutationo o o Changes A to T to make 8As in a row: AAATAAAA (A)8 (A)8 is hypermutable (A)9 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 CancerMultistep 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

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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 o

o

Mutations may cause genomic instability p53-mutated cells resistant to ionizing radiation & chemo-induced apoptosis Interacts with other oncogenes / tumor suppressor genes

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

Staging of CRCDukes staging (info?) Dukes A Mucosa / submucosa with no muscularis propria / nodal involvement; good prognosis (95% @ 5yrs) Dukes B Into / past muscularis propria but no nodes (80% @ 5 yrs) Stages of CRC Dukes C Local mets to regional lymph nodes (60% @ 5 yrs) Stage I: T1-2 N0 M0 Dukes D widely metastatic, probably will die (5% @ 5 yrs)

TNM staging T1 confined to submucosa 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)

Stage II: Stage III: Stage IV:

T3-4 Any T Any T

N0 N1-2 Any N

M0 M0 M1

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 blood vessel

CRC metliver: total replacement of liver parenchyma

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Screening for CRCEARLY DETECTION is KEY: resect if stage I/II w/o LN involvement - much much better prognosis People arent getting screening: only 20% getting fecal occult blood; only 34% getting colonoscopy Assay Occult Blood Barium Enema Sigmoidoscopy Colonoscopy Colonoscopy is best (although $$) Bowel prep needed (not great fun for patient) Invasive; need general anesthesia Risk of perforation (1/1000) and death (1/5000) Gold standard; miss rate < 6% for polyps 1 cm Superior to barium enema for followup

Sensitivity 70-80% 80% 60% 90%

Cost $1-8 $180-230 $205 $2,000

Invasiveness None Somewhat Highly Highly

Virtual colonoscopy: pretty good but not gold standard Still need bowel prep, still some (but lower)risk of perforation Sensitivity only about 90% High false positive rate nd Need to do 2 (real) colonoscopy to remove any lesions

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

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 DiseaseMost common: infections, IBD, etc. (in adults too) these are congenital conditions (specific to peds) Amniotic Fluid: About 1000 cc at term, always being turned overDepleted by fetal swallowing Repleted by fetal urination (micturation) if you obstruct fetal GI tract in utero, end up with polyhydraminos (too much fluid) 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 birtho o Meconium passage in utero: FAILURE to pass meconium w/in 24h: implies that fetus is distressed implies GI tract obstruction

Hirschprungs diseaseIn 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 Downs syndrome pts

Normally: neurons migrate down; form two plexuses around GI tract

Hirschprungs: 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 cranialcaudal submucosal (Meissners, between inner circular/ outer longitudinal mm layers) & myenteric (Auerbachs) plexuses Functions: RELAX SPHINCTERS & MOTILITY Hirschprungs: dont migrate Distal bowel: cells dont make it down, ends up aperistaltic; dilation occurs proximally Extent depends on how early arrest occurs (more with early arrest); rectum always involvedo 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

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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 mucosao Abnormal localization of cholinergic nerve fibers (not being directed by ganglia)

Drawing

H&E

Acetylcholinesterase

NormalGanglia in submucosa; few cholinergic fibers in mucosa

Ganglia in submucosa

No staining in mucosa

Hirschprungs

No ganglia; cholinergic fibers in mucosa

No ganglia

Intramucosal nerve fibers (+)

Treatment: Surgical resection of aganglonic segment, with excellent prognosis

Meckels DiverticulumPersistent 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) 38

picks up ectopic gastric mucosa; can see diverticulum

Meckels Diverticulum

Normal mucosa to left, ectopic gastric mucosa to the right (parietal cells, make acid, etc)

Ulceration of Meckels diverticulum (bleeding)

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, WebIn 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 / AtresiasIncomplete separation of lung bud from foregutNormal 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

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Clinical Presentation Polyhydramnios in utero Choking on secretions, respiratory distress worse on feedings Cant 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, cant swallow, no air in abdomen o Tracheoesophageal fistula: baby feeds cyanotic (food goes into lungs)

Treatment: immediate surgical reconstruction

Meconium IleusObstruction 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 obstructs ileum, sticks to mucosa

Meconium peritonitis: multinucleated giant cells eating meconium (brown)

Meconium peritonitis: Multinucleated giant cells react to foreign material (meconium) See brown pigment inside Dont 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

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Neonatal Hypertrophic Pyloric StenosisProgressive 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 (cross-section)

Barium swallow: barely passes through pylorus

Giant peristaltic waves (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 / JaundiceKey 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 AtresiaIdiopathic 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 Bile Ducts Inflammation Injury Progressive fibrosisAvoid! (would have to do laparotomy)

Gross Findings Biopsy? Shrunken, hardened biliary tree

Liver Bile ductule proliferation Periportal fibrosis Sparing of zone 3 (centrilobular area) Yes (no laparotomy needed)

Treatment: Kasai procedure: resect all the bile ducts; paste jejunum right to the livero o Problem: putting bowel (bacteria) in direct contact with liver Buy time until transplant

Liver transplant: best, if available Bile duct

Liver

NormalOpen lumen

Extrahepatic biliary atresia

Shrunken, basically no lumen

Bile duct plugs, bile ductile proliferation

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Neonatal HepatitisInflammation 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: -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 isnt specific for the different etiologies! Treatment: medical treatment for underlying disorder

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Normal Liver Anatomy & Injury PatternsObjectives 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 AnatomyHilum: 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 injuryThe 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)

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Basic Patterns of Liver Cell InjuryBallooning Description Etiology PathogenesisCell swelling Clumping organelles, cytoskeleton Fatty liver disease Loss of osmotic control

Feathery degenerationFoamy cytoplasm

Coagulative necrosisGroups of ghost cells

ApoptosisIndividual mummified hepatocyte, red, nucleus starting to fragment Viral hepatitis Programmed cell death

Necroinflammatory injuryInflammation + hepatocytes

Biliary obstruction Toxic effect of bile salt

Hepatic artery thrombosis Ischemic injury

Chronic viral hepatitis Immune mediated necrosis

Picture

Chronic InjuryRepeated acute injury chronic injury Chronic injury: Gross Chronic injury: Trichrome

fibrotic areas are white, nodules of hepatocytes are brown Caused by any chronic liver injury

Fibrosis (scarring), hepatocyte nodules (regeneration) Blue = collagen, red = hepatocyte nodules Caused by any chronic hepatitis

CirrhosisCIRRHOSIS = 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 + TGF collagen production fibrosis

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HepatitisHepatitis = 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 M infiltrates Apoptosis Necroinflammatory necrosis Inflammatory infiltrate Cholestasis

Cartoon

Acute Hepatitis

Lobular disarray (no architecture; cant tell Parenchymal collapse: see wrinkled where you are); also inflammation & Gibsons capsule (hepatocytes ballooning degradation parenchyma shrinks! saggy)

Whats bad about viral hepatitis? Could resolve, or develop fulminant or chronic hepatitis Chronic hepatitis stable, or o Hepatocellular carcinoma o Other complications: see text box

Complications of cirrhosis Hepatic encephalopathy Varices Ascites Splenomegaly

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Chronic HepatitisMajor questions: Is injury occurring? Are hepatocytes dying? What types of injury are occurring? Necroinflammatory / ballooning / coagulative necrosis

Has recovery occurred? Does the patient have fibrosis? Are there hepatocyte nodules?

Necroinflammatory Injury (below)Top: cartoon with varying degrees Bottom: see lymphocytes pouring out

FibrosisTop: cartoon with fibrosis, scarring Bottom: fibrosis ( collagen in trichrome, lower pic)

Specific Diseases: Viral HepatitisHepatitis A RNA virus Fecal-oral transmission NO CHRONIC INFECTION Rarely fulminant Anti-HAV

Pathology: inflammatory changes, mostly unremarkable

Hepatitis B Many dont know that theyre infected DNA virus Blood, etc. transmission Acute & chronic forms Diagnosis: o HBsAg = infection acute / chronic o Anti-HBc+ HBsAg = chronic infection

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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(Dense lymphocytic infiltrate into portal tract)

Intracellular fat

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

Bridging necrosis, lymphocytes + PCs

Lots of plasma cells (arrows & lymphocytes

Dense lymphocytic infiltrate

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Specific Diseases: Drug-induced HepatitisIntrinsic Predictable Sufficient dose induces injury in everyoneExample: Tylenol give enough and everybody gets liver damage

Idiosyncratic Unpredictable Depends on metabolic rate Immune system stimulation involvedExample: reaction to PCN

Drug-induced hepatitis may be histologically indistinguishable from other types of liver injury

Acetaminophen Coagulative necrosis Minimal inflammation Change?Mushrooms, -methyl dopa can do this too

Isoniazid Diffuse necrosis Periportal lymphocytic inflammation Periportal (inflammation) Diffuse (necrosis)

Procainamide Enhanced SER Ground-glass appearance

MethotrexatePortal fibrosis

Where? Mimics:

Zone 3 (near central vein) ischemic injury hepatitis

Portal triad Viral hepatitis B Chronic viral hepatitis

Viral hepatitis

Picture

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Alcoholic Liver DiseaseAlcoholic Fatty LiverFat 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 its fat because its 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 > ALTo 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 Hydropic degeneration Focal hepatocellular injury alcoholic / Mallorys hyaline Focal cell necrosis / drop-out Acute inflammation Active intralobular pericellular fibrosis Irregular hyaline cytoplasmic inclusions accumulation of keratin-like filamentous proteins related to IFs represents disruption of cytoskeleton

Notes

Mostly PMNs Often seen with sclerosis of hepatic veins*

PMNs (vs lymphocytes in viral hepatitis) Greater degree of fibrosis than in comparable 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

Swollen hepatocytes (arrow) Mallorys hyaline (open arrowheads), PMN rich response (closed arrowheads)

Mallorys hyaline (EM)

Pericellular fibrosis (trichrome)

Veno-occlusive disease (more severe: centrolobular region); small vein here half obliterated by 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 doesnt play a huge role NASHExample: pts who got early jejunal-ileal bypass endotoxemia from infection of blind pouch Obesity + ER stress (endotoxins) Produced non-alcoholic steatohepatitis!

Severe NASH (post-jejunal-ileal bypass)

NASH = (steato)hepatitis in context of NAFLD fatty liver background inflammatory changes like alcoholic hepatitis Can progress to cirrhosis!

CirrhosisA 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!

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Cirrhosis: PathologyHistologic definition: interconnecting bands of fibrosis and nodules of regenerated hepatic parenchyma

Esophageal varices (gross)

big, dilated vein just under epithelium (varix) more to right, but this one = bad

Ruptured varix with blood blister

Rupturing varix: dissected through epithelium

Cirrhosis (trichrome): nodular distortion & tons of fibrosis

Cirrhosis: see lots of fibrosis!

Veno-occlusive disease (same as above: cirrhosis destroys small intra-hepatic veins)

Hepatic Veinograms: normal (left): note fine branching; alcoholic cirrhosis (right) bigger / truncated veins, simplified structure obliteration of small veins! resistance in alcoholic cirrhosis!

Recovery from cirrhosis Left: active alcoholic cirrhosis (bands / nodules) Right: same pt after 20 yrs of abstinence (structure restored!)

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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 TumorsOverview of NeoplasmBy cell type

Cell typeHepatocyte Bile duct Vascular Mesenchymal/mixed

BenignFocal nodular Hyperplasia* Hepatic adenoma Von Meyenburg Complex* Bile duct adenoma Cystadenoma Hemangioma Infantile Hemangioendothelioma Mesenchymal Hamartoma

MalignantHepatocellular carcinoma Cystadenocarcinoma Cholangiocarcinoma Angiosarcoma Hemangioendothelioma Hepatoblastoma

*Note: Von Meyenburg complexes and focal nodular hyperplasias form mass lesions, but are not truly clonal processes .

By age

AgeInfant Children/young adults

TumorHepatoblastoma Infantile Hemangioendothelioma Hepatocellular Carcinoma Fibrolamellar Carcinoma Hepatic Adenoma Hemangioma Bile duct adenoma Focal nodular Hyperplasia Hepatocellular Carcinoma Cholangiocarcinoma Hepatocellular carcinoma Angiosarcoma

Adults

Older Adults

Vascular tumorsHemangiomas (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 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 stromaIrregular vessels in sparse fibrous stroma

Angiosarcoma (malignant) Extremely rare that arise from blood vessels of liver Risk factor: chemical exposureo thorotrast, vinyl chloride (dry cleaning), arsenic

Gross: tan-white or hemorrhagic, can be spongy Small nodules scattered throughout liver o Occasionally: single mass Histology: pleomorphic endothelial cells Form small channels, can contain blood Have atypia (as opposed to benign lesions) Multiple possible histologies:o o o poorly formed vascular channels solid sheets growing along sinusoids (hardest to Dx)

Distorted blood vessel + atypia

More sheet-like pattern

Normal liver

Angiosarcoma growing along sinusoids

Hepatocellular TumorsFocal 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 masseso o Thought to arise from vascular malformation (A-V shunting) 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 ) 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) 55

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 (-catenin) AFP (-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 effecto 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 stageo o Screen for HCC in high risk groups (serum AFP, CT scans) 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, cellularityo o

Thickened hepatocellular plates (> 3 cells) reticulin staining

NO portal tracts Abnormal arterioles AFP-expressing (1/3 patients) Can have lots of different patterns too!

HCC: No portal tracts

N/C ratio, no portal tracts

Standard cancer changes too: N/C ratio, hyperchromatic, etc.

Vascular invasion: risk recurrence

Abnormal arterioles: found in lobules too, not just portal tract

L: Normal, R: HCC Note reticulin stain in HCC

proliferation ( mitotic figures)

AFP + with IHC

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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,