GI Final Pathology

Normal Colon.

top to bottom: mucosa, muscularis mucosa, submucosa, muscularis propria

Normal Colon

top to bottom

eipthelial crypts
lamina propria
muscularis mucosa

Active Colitis (neutrophils present)

Left box = cryptitis
Right = crypt abscess

Features = cryptitis(neutrophils within crypt epithelium)

crypt abscess(neutrophils within crypt lumen)
ulceration(disruption of mucosa)

Box = crypt branching. Seen in chronic colitis, other features of which are

Altered crypt architecture

crypt disarray, dropout, and branching

Increased lamina propria chronic inflammation

Loss of regular spacing

Lamina Propria inflammation

Normal: modest numbers of inflammatory cells with lowest density at crypt bases(lymphocytes, plasma cells, some eosinophils)
In chronic colitis, more inflammation. Might see Basal plasmacytosis(increased numbers of plasma cells between crypt bases and muscularis mucosa)

Box = basal plasmacytosis. Seen in chronic colitis

Pseudopolyps(islands of hyperplastic/regenerative mucosa) and box on right = surrounding ulcerated mucosa

gross features of UC

hemorrhagic, granular mucosa
pseudopolyps

Microscopic features of UC

Key: you won't see lymphoid aggregates within deep submucosa and muscularis propria

will see lymphoplasmacytic infiltrate expanding the lamina propria, often with conspicuous basal plasmacytosis
crypt abnormalities characteristics of chronic colitis
neutrophils present or absent depending on active dz

top left = linear ulcer, bottom left = fat wrapping, and right = cobblestoning
Crohn's Disease: gross features

segmental, skip lesions
cobblestoning, linear ulcers, fissures fistulas, and fat wrapping

Top = surface ulceration bottom = transmural inflammation
Microscopic features of Crohn's

same as in UC +
inflammation is transmural(cannot be observed on superficial endoscopic biopsies)
granulomas

Predictable sites for pathologic processes in digestive tract

Epithelium: neoplastic

squamous ca in squamous layer, adeno ca in columnar/glandular epith and intestinal epith

Mucosa/epithelium: infectious/inflammatory processes
Muscularis mucosa and submucosa: bleeding
Muscularis propria, Auerbach's plexus: motility disorders and MALT = lymphoma

Esophageal Erosion

necrosis of epithelium
arrow points to area remnant of epithelial basal layer

Erosions only involve mucosa. Heal by regeneration(i.e. without fibrosis/scar)

Stomach Ulcer

at top see normal mucosa
Ulcer extends into deep layers; scar

Ulcers involve mucosa + deeper layers. Heals with granulation tissue becoming fibrosis/scar

GI stenosis

Etiologies: congenital, fibrosis/scar(any necrosis of the wall which causes substantial repair with fibrosis/scar bc circumferential scar contracts leading to stricture). Or neoplasms
Presentation: obstructs so if in esophagus get dysphagia, in stomach through anus get obstruction

Normal Esophagus

epithelium
lamina propria
muscularis mucosa
Submucosa(has glands)
Muscularis propria(sandwiches Auerbach's plexus which you can't see)
Adventitia(very bottom)

Hiatal hernia

Protrusion of stomach into the thorax through an enlarged diaphragmatic hiatus

Common. Usually acquired(not congenital). Can arise secondary to weakening of hiatal opening or conditions/dzs that push stomach cephalad
May cause incompetent LES leading to GERD

Esophagitis

Esophageal inflammation. The etiology leads to mucosal necrosis.

Infectious(Candida, CMV, HSV), drug/pill, corrosive/chemical, eosinophilic, GERD

I'm not giving histo examples of CMV or HSV. We've seen them before
HSV = epithelial. nuclear inclusions(ground glass, margination, molding, multinucleated
CMV = infects lamina propria(deep epithelium) like endo cells/fibroblasts. Nuclear inclusions

Esophageal Candidiasis

psuedomembranes composed of candida pseudohyphae, PMNs, necrotic debris
Grossly: superficial white plaques(these are the pseudomembranes)

Pill Esophagitis

Ingested pills get caught mid-distal esophagus. Causes injury of mucosa

often secondary to esophageal dysmotility/stricture, nature of medicine, or little food/recumbent position
Histo: localized inflammation +/- erosion/ulceration

Chemical(corrosive) esophagitis

Adults(suicide) and children(accidental)

alklaline solutions the worst (liquefactive necrosis)
Acids(leads to coagulative necrosis that leaves a protective eschar) worse than alkaline solids

1st degree = mucosa/submucosa, 2nd = maybe to muscularis propria leading to ulcerations/granulation tissue, and possible stricture 3rd degree = full thickness necrosis(through the muscularis propria)

Eosinophilic Esophagitis

unknown cause, seen in all ages
Can look normal, have erosions or strictures
Histo: intraepithelial inflammation with eosiniphils(pink/neon red, bi-lobed

GERD(with eosinophilic infiltrate)

Gross: distal esophagus, erythema and may see erosions or ulcers
Histo: intraepithelial inflammation (PMN, eos)

Barrett esophagus/metaplasia

metaplasia of normal esophageal stratified squamous epithelium to intestinal columnar epithelium
The intestinal simple columnar has both columnar cells and goblet cells, big clue
10% of pts with Barretts go on to get adenocarcinoma. Risk related to length of metaplastic segment and the presence and degree of dysplasia

Adenocarcinoma

Composed of glands
Arises from either...

normal simple columnar glandular epithelium
exocrine glands
metaplastic glandular epithelium

Squamous cell carcinoma

Arises from squamous epithelium

composed of solid nests/cords of squamous cells +/- keratin pearls

Gross morphology of malignancies in GI tract

Far left: fungating. Polypoid and exophytic
Middle = Infiltrating (grows into wall)

if infiltrates entire stomach it can become linitis plastica

Ulcerating = see deep excavations

Malignancies usually a combo of some of these

Barrett Dysplasia

Histo: typified by nuclear changes(nuclei are large, pleomorphic, hyperchromatic, prominent nucleoli, at multiple levels in cell, and more mitotic figures)
Pathogenesis: the metaplastic epithelium regenerates more and with all the mitosis, more chance for genetic alterations which lead to dysplasia

Esophageal Adenocarcinoma

At top of pic there is some dysplastic Barrett's epithelium, but at bottom you see the malignant glands invading underlying layers of esophageal wall

Esophageal squamous cell carcinoma

Histopath: nests/cords of atypical squamous epithelial cells in desmoplastic(fibrotic) stroma
Infiltrating nests/cords
In this pic, has invaded at least into muscularis propria

Nodes Esophageal cancers go to

Nodal mets: rich lymphatics in wall

upper 1/3 go to cervical and supraclavicular nodes
middle 1/3 go to hilar and tracheal nodes
Lower 1/3 go to gastric and celiac nodes

Local infiltration and visceral mets in esophageal cancer

Local infiltration: no serosa so lots of infiltrates into neighboring structures

recurrent laryngeal nerve = hoarseness
trachea = couch
aorta, pericardium and pleura = hemorrhage

Visceral mets to liver, lung, etc

Normal gastric mucosa histo

Gastric lumen and pits/foveola all lined by columnar mucous cells and same in all stomach regions
Gastric glands(deep to foveola): vary by regions

Normal histo: body-fundus

superficial = foveolar compartment(lined by columnar mucous cells)
Deep compartment = glandular compartment

Upper part = pink and has Parietal Cells(HCL, IF)
Lower = Blue and has Chief Cells(pepsinogen)

Normal histo: cardia, antrum, pyloris

Superficial compartment = foveolar. Lined by columnar mucous cells
Deep compartment = glandular

has Mucous cells(plus G cells in antrum, and they make gastrin)

H. pylori(silver stain)

Gram-neg rod that lives in layer of mucus adherent to gastric foveolar cells(so don't get washed away) and does not adhere to intestinal cells

concentrates at intercellular junctions where urea level is highest

their proteases and the ammonia and cytotoxins they produce hurt us and can lead to gastritis, PUD, and cancer

Acute gastritis

in pic see punctate erosions with hemorrhages. Petechial hemorrhage.
acute inflmmation of mucosa(PMNs) +/- necrosis +/- hemorrhage

the etiology either causes direct injury to mucosa or interferes with normal protective mechanisms

If mild, doesn't look like anything, but when severe get necrosis and hemorrhage

Chronic gastritis

Histo: chronic inflammation +/- gastric gland and mucosal atrophy +/- intestinal metaplasia
Grossly see thin, atrophic gastric wall(pretty severe)
Sometimes see intestinal metaplasia(and the clue to this is dense pink absorptive cells and goblet cells)
2 main causes = H. pylori and autoimmune

Autoimmune gastritis(antrum)

You see some intestinal metaplasia and chronic inflammation
Autosomal dominant
Pathogen: autoAb to Parietal cells leads to gland atrophy(and decreased HCL/IF) and inflammation

often see pernicious anemia and decreased acid production

Gastric Ulcer

top box is normal gastric mucosa, then the 4 characteristic zones: 1. fibrinopurulent exudate 2. necrotic tissue 3. granulation tissue 4.scar
Etiology: H. pylori, NSAIDS, and ZE
Most often have punched out, cookie cutter look
Location: In stomach seen in lesser curvature of antrum/pre-pylorus

duodenum: proximal

Complications of PUD

Hemorrhage: common, ranges from occult to severe
Perofration: more in duodenal ulcers, causes peritonitis
Obstruction: especially in pylorus leading to gastric outlet obstruction. Arises from edema, scar contraction, muscle hypertrophy of nearby ulcer

Zollinger-Ellison syndrome

A gastrinoma(often in pancreas and associated with MEN 1, a tumor of pancreas, pituitary, and parathyroid, 3 P's) causes gastrin hypersecretion which increases gastric HCl, which leads to severe peptic ulceration.

Uncommon, but a possible cause of PUD, GERD, and fatty diarrhea(bc not alkalinized enough to activate pancreatic enzymess

Dx of ZES

dx: serum gastrin > 1000 or if close might be ZES or could be gastric outlet obstruction

if questionable, measure secretin stimulation

Localization of tumor

somatostatin receptor scintigraphy and endosonography

Gastrinoma triangle: duodenum, head/body of pancreas and cystic duct/bile duct junction. Might find multiple tumors. High malignant potential(to liver and lymph nodes)

Epithelial/non-epi classification of gastric tumors

Epithelial: Benign = polyps and Malignant = Adenocarcinoma(intestinal or diffuse type)
Non-epithelial.

benign = leiomyoma
malignant = Lymphoma or Gi stromal tumors(very rare)

Leiomyoma

benign smooth muscle tumor. Most common gastric tumor
grossly: well circumscribed
Histo: smooth muscle cells(tumor produces submucosal nodule which stretches and thins overlying mucosa leading to ulceration)
Complications: ulceration and hemorrhage

Gastric leiomyoma

up top we see mucosa, and in bottom picture we see the underlying smooth muscle tumor. Very bland looking

Polyps

focal protrusion of mucosa into lumen; common
non-neoplastic polyps = hyperplastic polyps

occur following injury(ulcers), composed of aggregates of regenerating mucosal cells and inflammatory cells.

Malignant ulcer: features of which are heaped up margins, irregular sides, and shaggy base

Peptic ulcer has flat margins, vertical sides, and smooth base

Metastases of gastric malignancies

Lymph nodes: can be to local nodes, left supraclavicular node(Virchow node) or periumbilical

Local invasion: to pancreas, duodenum, peritoneal seeding
Distant sites(via hematogenous spread)

lungs, liver, brain, ovary(Krukenberg tumor)

Gastric Adenocarcinoma

Multifactorial. Pathogen is from pre-existing dz to intestinal metaplasia +/- dysplasia +/- adenocarcinoma. The pre-existing dz is often H. pylori infection, chronic atrophic gastritis, or pernicious anemia

Depth of spread is an important prognostic feature, although can spread of superficial

Early = spread only in mucosa +/- submucosa
Advanced = spread into muscularis propria +/- serosa (sxs arise with deeper layer involvement and mets, so few caught early

Early gastric adenocarcinoma(intestinal type)

pic shows malignant glands infiltrating through bundles of muscularis mucosae and into submucosa
Intestinal type arises from metaplastic intestinal epith(due to chronic gastritis w intestinal metaplasia) and has intestinal glands +/- mucin

Advanced gastric adenocarcinoma(intestinal type)

Boxes: left = malignant ulcer bed, white = 'glandular tumor infiltrating through muscularis mucosae, submucosa, and into muscularis propria,
Upper right = normal mucosa

Gastric adenocarcinoma(diffuse type)

histo shows three layers, from top = mucosa then submucosa, then muscularis
See extensive infiltration of tumor cells through wall of stomach. Single cells, no glands

(signet ring cells, there aren't always this many and they can be difficult to recognize)
Diffuse type (of gastric adenocarcinoma)

Pathogen: arises from gastric mucous cells and has poorly differentiated, dis-cohesive(don't form glands) mucous cells = 'signet ring cells'

growth: infiltrative spread of single cells, cell clusters, or sheets. Desmoplasia can lead to linitis plastica

Gastric adenocarcinoma, prognosis

Significant: 1. Depth of invasion(histologic stage) 2. Extent of nodal and distant metastases(clinical stage)

Not as significant: type of adenocarcinoma(diffuse or intestinal)

Gastric lymphoma

in pic see loosely aggregated clusters of epithelial cells that are remnants of deep compartment glands nearly destroyed by atypical malignant lymphocytic clone
lymphocytes = the tumor cells

Gastric lymphoma

dense monomorphic lymphocytic clone destroys and replaces glands
Can have any gross pattern(exophytic, infiltrating, ulcerating)
Low grade B cell lymphoma, most often due to H. pylori infection leading to chronic inflammation leading to influx of B cells
Some regress with H. pylori eradication, most have indolent growth, but can transform to high-grade lymphoma

Hyperplastic Polyps

Benign epithelial lesions of mucosa. Most in large bowel, and more with age
Gross: flat, pale, small
Crypts in upper half of polyp have a characteristic serrated or convoluted appearance with decreased numbers of goblet cells

Juvenile Polyp

hamartoma of the colonic mucosa, generally in kids <10yo
Pedunculated, cut surface with cystically dilated glands
Polyposis syndrome with increased risk of adenocarcinoma(but different from FAP)

Juvenile Polyp

histo appearance has cystic spaces filled with mucin and inflammatory cells, lamina propria is inflamed and mucosal surface is ulcerated and oozes blood
Bottom pic shows surface epithelium is eroded with inflamed granulation tissue

Adenomatous Polyps

On left we have sessile growth pattern and right is pedunculated
Benign neoplasms of mucosal epithelium, but they are the precursor lesions of majority of small bowel and colorectal carcinomas
Microscopic or large. Multistep carcinogenesis.
Most in sigmoid/rectum, then colon and every once in a while in small bowel/stomach

A Tubular Adenomatous Polyp is composed of large numbers of round to oval adenomatous glands.

By definition has low grade dysplasia(nuclei not round and more goblet cells, but nuclei still at base of cells)
Tubular type is most common, and has adenomatous epithelium arranged in tubular glands
Villous(more malignant transformations) has adenomatous epithelium that covers surface of finger-like projections of lamina propria

Adenomatous vs normal colonic epithelium

Normal: uniform basal nuclei and abundant cytoplasmic mucin
Adenomatous: pleomorphic, hyperchromatic nuclei

nuclear pseudostratification
loss of cytoplasmic mucin
3 types are Tubular, Villous(which has velvety appearance) and Tubulovillous

Early invasive adenocarcinoma

irregular, infiltrative glands of early invasive carcinoma
Found in 2-5% of adenomas removed at colonoscopy

FAP(Familial Adenomatous Polyposis

<1% of colorectal cancers, but AD inheritance. Mutations in APC gene
Many adenomas by late teens(not just colon) and all will develop adenocarcinoma.
Superficially may resemble pseudopolyps of UC

Gross appearance of colorectal carcinomas

Right Colon: usually polypoid or fungating exophytic masses
Left colon: more commonly annular lesions that produce an "apple-core" or napkin-ring appearance and present with bowel obstruction

Colorectal cancer that has infiltrated through full thickness of muscularis propria

Stage 1 = through submucosa
Stage 2 = through muscularis propria

Higher stages more likely to get distant mets or lymph node involvement

Mucinous Colorectal Cancer

>50% of tumor producing extracellular mucin
A morphologic variant of CRC(the other is signet ring cell carcinoma)

Carcinoid Tumor

Normal neuroendocrine cells at the crypt base(which give rise to carcinoid tumor) are also synaptophysin +
Only mild cytologic atypia in carcinoid
And often located in the appendix(especially in the tip)

GI stromal tumor. Usually c-kit positive.

Tx: Gleevec

Lymphoma

GI tract is main site of extranodal non-Hodgkin's lymphomas

Esophageal Varices

pic shows dilated and congested veins in submucosa.
Usually seen in distal part of esophagus(where there are most collaterals)

Esophageal Laceration

Caused by 1. Vomiting or 2. External Trauma(MVA)

Vomiting: 1. Mallory-Weiss tear: severe retching can lead to mucosal laceration and bleeding(think of someone who has had way too much to drink too fast) 2. Boerhaave Syndrome: Severe retching leads to esophageal rupture(a laceration through the wall) +/- bleed

All about increased intra-esophageal pressure

Ischemic Bowel Disease

Gross: edematous, purple/congested. Usually sharp demarcation between normal and infarcted
Etiology: 1. occlusive(arterial more than venous and SMA more than IMA) due to atherosclerosis or embolus 2. non-occlusve: hypotension, hypovolemia
Elderly
Presents with pain +/- Lower GI bleeding

Ischemic Bowel Disease

Histo: coag necrosis(ghostly outlines of architecture)

variable depth(surface>base)
distended submucosal veins, RBC extravasation
Inflammation(acute)

Meckel Diverticulum(rule of 2's)

occurs in ileum where vitelline duct goes in(retention of duct)
2% population, symptomatic by 2yo
Harbors ectopic gastric mucosa or pancreatic tissue which can lead to peptic ulceration of adjacent small intestinal mucosa +/- bleeding
2cm in length, within 2ft of ileocecal valve

Angiodysplasia

Histo: thin-walled, dilated mucosal and submucosal blood vessels
Caused by AV malformation(missing capillary beds)
Seen in elderly
All that's important about pathogen is that thin vascular walls are prone to rupture, and it leads to a variety of appearances

most often in cecum and right colon

Hemorrhoids

Gross and histo are the same: dilated submucosal veins +/- thrombosis
Caused by increased venous pressure(pregnancy, constipation)

hereditary predisposition

Superior plexus leads to internal hemorrhoids
Inferior plexus leads to external hemorrhoids

Kaposi's Sarcoma(HHV 8)

Gross: Skin and mucus membranes(everywhere). Red-purple-brown, macules-nodules, any size/shape
Histo: Spindle cells

blood-filled vascular spaces

Pathogen: Infected endothelial cells that have unregulated growth
Epi: HIV AIDS, immunosuppressed. and Mediterranean males and sub-Saharan African children

Entamoeba histolytica causes diarrhea

Fecal-oral transmission
More common/serious in immunocompromised
Gross: friable, erythematous mucosa and ulceration
Microscopic: FLASK-SHAPED ulcers extend through the muscularis mucosae and undermine the mucosa

Amebae in colon biopsies

frothy cytoplasm, bubbly pale. PAS makes them bright pink
Can cause liver abscesses(hematogenous spread)

C. difficile colitis

Histo shows 'exploding crypts' and pseudomembranes(that consist of fibrin, mucin and inflammatory cells
Often seen after antibiotic use, uses Toxins A and B

Cryptosporidium parvum

A protozoan parasite that colonizes the brush border of columnar epithelia and causes diarrhea
Parasite is beneath cell membrane, but not in cytoplasm(derives nutrients from cell and protected from host immune recognition)
Increased shedding of infected cells, and body replaces cells with ones that don't absorb as well(worsening malabsorption)

5 infectious causes of diarrhea we discussed in path of diarrhea lecture

Cryptosporidium parvum
CMV: infection of endothelium, ischemic necrosis of mucosa and ulceration(shallow or deep ulcers, bleeding, perforation)
Giardia lamblia: Beaver fever. highly infectious. Fecal-oral in child daycare and homosexual men. Widespread.
Whipple's dz: rare systemic infection that always involves small bowel leading to malabsorption
HSV: not a usual cause. Affects squamous mucosa(esophagus, skin, and anal mucosa)

Giardia-infected small bowel epithelium

pathogen: formation of a physical barrier to absorption by adherence of trophozoites to mucosal surface. Damage to the microvillus brush border leading to mucosal enzyme deficiency. Ex. might get an acquired lactase deficiency

Giardia

multiple leaf-shaped parasites floating in mucus and adherent to mucosa

Whipple's

Might also see multiple lipid-filled vacuoles
Leads to malabsorption
Systemic dz

Acute Pancreatitis

Pathogen: premature activation of digestive enzymes within acinar cells is the final common pathway
Gross: left box = fat necrosis and right box = hemorrhage(sometimes)

edematous, pale and indurated(firm)
fat necrosis is white, chalky part where peripancreatic adipose tissue has undergone saponification

Acute Pancreatitis

left box = fat necrosis and upper right = necrotic parenchyma and lower = preserved acini
Micro features are 1. acute inflammation 2. pancreatic tissue necrosis 3. peripancreatic fat necrosis 4. pseudocysts(collections of fluid surrounded by inflamed fibrous tissue and without a true epithelial lining 5. Hemorrhage and severe necrosis in acute hemorrhagic pancreatitis

Calcification in pancreas is pathopneumonic for Chronic Pancreatitis

Gross features = Classically(which is in late stages) shrunken and fibrotic
early on may be enlarged and indurated

Right box = Fibrosis and loss of acinar tissue. This is Chronic Pancreatitis

Micro features:

chronic inflammation and fibrosis
Exocrine components lost(islets are more resistant to injury). This feature helps you distinguish from adenocarcinoma!!
Preservation of overall lobular architecture

Ductal Adenocarcinoma

Gross: solid, firm, infiltrative mass. Chronic pancreatitis is common in adjacent tissue(can be hard to distinguish)

peripancreatic lymph nodes often enlarged due to mets

Left box = haphazard arrangement of glands, upper right = perineural invasion and lower right = nuclear pleomorphism

Microscopic features of Ductal Adenocarcinoma

This is the only pancreatic cancer we study, most common. Usual pattern is a proliferation of glandular structures, lined by malignant cells, within a fibrotic stroma

Haphazard arrangement (as opposed to the lobular architecture of chronic pancreatitis)
Tumor cell pleomorphism characterized by a variation in nuclear size of more than four-fold within the same gland
Perineural and vascular invasion are common
Neoplastic glands may be present well beyond the apparent gross borders of the tumor

Acute Appendicitis

Left box = erythema, middle = surface exudate and right = vascular dilation

surface would feel granular bc the exudate makes you lose

Gross: Edematous and erythematous with inflammation of the muscularis propria

surface exudates seen when there is transmural inflammation

Acute Appendicitis

left box = fibrin, then disrupted mucosa and then 'neutrophils'
Micro features: Varying degrees of acute inflammation, hemorrhage and necrosis

Pseudomembranous Colitis

Gross: Pseudomembranes are patchy yellow-white plaques adherent to the mucosal surface
Micro features: 'Volcano' lesions consisting of distended crypts filled with PMNs and mucin which give rise to the pseudomembranes composed of neutrophils, fibrin, and mucin

varying degrees of mucosal necrosis(usually superficial but can be full-thickness)

Diverticular dz

Pathogen: often occurs when the diverticula are blocked by stool or mucus. This would lead to diverticulitis
Boxes = muscularis propria and diverticulum
These occur more in sigmoid colon at points of weakness where vasa recta vessels penetrate the bowel wall
What's going on is a herniation from the lumen through the muscularis propria

Diverticulitis

Far left box = colon lumen, then upper = diverticulum extending through muscularis propria and containing debris, then lower = diverticulitis: disruption of mucosa with neutrophilic infiltrate
the outpouching has been destroyed by an ischemic/necrotic process, and now see inflammatory process