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Colon involvement. the distributionofdisease can onlybemadebyknowing between DDACandtrueIBD mucosa. Thedistinction of thecrypts﬇in ﬊ ispresentbeneaththebase lymphoplasmacytic infiltrate (IBD). (Right)Abandof inflammatory boweldisease indistinguishable fromtrue mucosal changesare like variantofDDAC.The -like andCrohndisease- seen inboththeulcerative of inflammatoryinfiltrateis (Left) Achroniccolitispattern region ﬉. mucosa intheinterdiverticular mustinvolvethe be diagnosticofDDAC, a colonicdiverticulumſt.To around theluminalopeningof inflammation orerosions﬊ uncommon tofindsome (DDAC) ﬊.(Right)Itisnot disease-associated colitis consistent withdiverticular erythematous andgranular, into thecoloniclumenis the openingsofdiverticulaſt (Left) Themucosasurrounding • • MACROSCOPIC • • • • CLINICAL ISSUES • ETIOLOGY/PATHOGENESIS • TERMINOLOGY coli ratherthanSCAD Mural changesarerelatedmoretounderlyingdiverticulosis Mucosal changesaremildandnonspecific symptoms Treatment directedtowarddiverticulardiseasesuppresses rectal sparing) Predominately involvesdescendingandsigmoidcolon(with ○ Median age:64years Presents withhematochezia,abdominalpain, Unknown, TNF-αmayplayrole Segmental colitis-associateddiverticulosis(SCAD) Range: 40-86years Diverticular Disease-AssociatedColitis Diverticular Disease-RelatedColitis Chronic ActiveColitis KEY FACTS • TOP DIFFERENTIALDIAGNOSES • • • • , NSAID-associated colitis , Crohndisease,infectiouscolitis,diversion with diverticulosiscoli Changes inbothvariantsconfinedtosegmentinvolved aggregates Crohn disease-likevariantshowsmurallymphoid ○ mucosa Ulcerative colitis-likevariantshowschangesconfinedto disease Chronic colitis-likechangesmimickinginflammatorybowel ○ ○ mayornotbepresentinthesecases show murallymphoidaggregates Exception isCrohndisease-likevariantofSCADthatmay , ,perforation Diverticular Disease-AssociatedColitis Basal Lymphoplasmacytosis Colon 427 Sulfasalazine 5-aminosalicylic acid Topical steroids Decrease intraluminal pressure by increasing stool Decrease intraluminal bulk (high-fiber diet) of Surgical intervention usually dictated by severity rather than SCAD Basal lymphoplasmacytosis Crypt architectural disarray Paneth cell metaplasia Variable active inflammation with erosion or ulcer – – – Ostia or openings of diverticula on mucosal surface Sac-like outpouchings ± Peridiverticular may be present Bowel wall thickening or perforation depending on severity of disease Mucosal erythema or granularity involving interdiverticular segments of colonic mucosal surface Erosions or ulcers in severe cases Treatment directed toward diverticular disease may Treatment directed toward suppress symptoms – – for treatment of active diverticulitis SCAD Oral aminosalicylates and for mild Immunosuppressives for severe SCAD Chronic colitis-like mucosal changes mimicking IBD ○ ○ ○ ○ Mucosal and mural changes confined to segment involved with diverticulosis coli; other parts of colon are normal Depends on patient symptoms, severity of disease, and Depends on patient symptoms, severity of response to medical intervention with Colonic wall thickening in segment involved diverticulosis and associated luminal narrowing may be seen Diverticular abscess, fistula, or perforation Findings related to diverticulosis coli ○ ○ ○ ○ Findings related to SCAD ○ ○ Clinical course is related to severity of disease is related to severity Clinical course system has been disease severity scoring Endoscopic proposed other than may not need any intervention, Mild cases follow-up with continued symptoms treated Severe cases or patients or steroids with antiinflammatory patients with severe symptoms Resection restricted to therapy unresponsive to medical Options, risks, complications ○ Drugs ○ ○ ○ MICROSCOPIC IMAGING MACROSCOPIC Histologic Features • • Prognosis • CT Findings • • General Features • • Natural History • • • • • Treatment • • Diverticular Disease-Related Colitis Disease-Related Diverticular Colonic mucosa proximal and distal to diverticular segment is normal Geographical differences are related to differences in prevalence of diverticulosis coli, which is higher in West Estimated: ~ 0.36% Median: 64 years (range: 40-86 years) IBD Later age of onset compared to patients with Equal incidence in both sexes Histologic findings may mimic ulcerative colitis or Crohn Histologic findings may disease Patchy areas of erythema or or diffuse mucosal granularity coli ○ present in cases associated with severe diverticulitis Changes confined to segment involved with diverticulosis Crampy, Diarrhea Fistula tract formation and intestinal obstruction may be is typically spared Most common in ; rare in other segments ○ Ethnicity ○ ○ ○ Sex Incidence ○ Age into lumen, which then spreads to interdiverticular mucosa into lumen, which then spreads to interdiverticular Early mucosal inflammation around opening of diverticula Early mucosal inflammation around opening Disproportionate immune response in genetically susceptible host TNF-α has Similar to inflammatory bowel disease (IBD), of SCAD been postulated to play role in pathogenesis Stasis of colonic contents may promote bacterial inflammation proliferation that acts as trigger for mucosal Immune-mediated injury may play role ○ Chronic colitis involving interdiverticular mucosa in colonic Chronic colitis involving segment with diverticulosis Segmental colitis associated with diverticulosis (SCAD) Segmental colitis associated Diverticular disease-associated colitis (DDAC) disease-associated Diverticular CLINICAL ISSUES ETIOLOGY/PATHOGENESIS TERMINOLOGY • Endoscopic Findings • • • • • Presentation • Site • • • Epidemiology • • May Be Related to Severity of Diverticulitis • • • Immunologically Mediated • Exact Pathogenetic Mechanism Unknown Exact Pathogenetic • Definitions • Synonyms • Abbreviations • 428

Colon • • • • • NSAID-Associated Colitis • • • • Diversion Colitis • • Infectious Disease • • Crohn Disease • • • Ulcerative Colitis • Predominant Pattern/InjuryType • diagnostic ofSCAD Changes confinedtosegmentinvolved withdiverticulosisis Pancolonic involvementfavors NSAID-induced colitis Symptoms usuallyresolvewith cessation ofNSAIDs May alsopresentwithhematochezia orabdominalpain Can occurafteronlyweeksofuse Diversion colitisresolveswithrestitutionofbowelstream colon removedfromfecalstream Changes indiversioncolitisareconfinedtosegmentof Morphologic findingsmaybesimilartoSCAD Clinical settinghelpsinmakingthisdistinction Stool culturesdiagnostic colitides Shigella andSalmonellainfectionscanpresentassegmental ○ ○ diverticulosis colishouldbemadewithgreatcaution Diagnosis ofCrohndiseaseinsegmentinvolvedwith Also patchysegmentalcolitislikeSCAD ulcerative colitis Rectum isalmostalwayssparedinSCADbutinvolved etiology diverticulosis colisuggestsinfectionorIBDasunderlying Inflammation aboveorbelowsegmentinvolvedwith only segmentwithdiverticulosis Key todiagnosisisrecognizingthatcolitisinSCADinvolves Inflammatory, chronic ○ ○ 2 variantsdescribed disease Terminal ilealorupperGIinvolvementfavorsCrohn beyond diverticularsegmentfavorsCrohndisease Clinical orradiographicevidenceofdiseaseinvolvement – – – – – Crohn disease-likevariant – – – Ulcerative colitis-likevariant Mural lymphoidaggregatesmimickingCrohndisease Seen inresectionspecimens of IBD Best thoughtofasCrohn-likediverticulitisthanform Crypt rupturereactionmaybeseen similar todiversioncolitis Prominent basallymphoidaggregatesmaybeseen ulcerative colitis Changes confinedtomucosasimilarwhatisseenin older patientwithnoprevioushistoryofIBD Important nottodiagnosethisasCrohndiseasein body giantcellreaction Noncaseating granulomasmaybepresent,±foreign present insegmentinvolvedwithdiverticulitis Diverticular Disease-RelatedColitis 3. 2. 1. • • • Pathologic InterpretationPearls • Clinically RelevantPathologicFeatures 21. 20. 19. 18. 17. 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. SELECTED REFERENCES DIAGNOSTIC CHECKLIST to IBD Inflammation inSCADshowschroniccolitispatternsimilar lumen openings ofdiverticula(interdiverticularregion)intocolonic SCAD isdefinedbyinflammationofflatmucosabetween considered SCAD Inflammation withindiverticulum("diverticulitis")isnot involved withdiverticulosiscoli Endoscopic andpathologicfindingslimitedtosegment up. IntJColorectalDis.27(2):179-85,2012 Tursi Aetal:Segmentalcolitisassociatedwithdiverticulosis:a5-yearfollow- 59(119):2119-21, 2012 evaluation of486caseswithmeta-analysis.Hepatogastroenterology. Mann NSetal:Segmentalcolitisassociatedwithdiverticulosis:systematic Surg. 31(4):221-5,2018 diagnosis, ,andtreatmentofdiverticularcolitis.ClinColonRectal management, andoutcomesinthemanagementofdiverticulardisease: Kucejko RJetal:Considerationsandchangesintheevaluation, 12, 1992 diverticula: aclinicalsyndromeintheelderly. AmJGastroenterol.87(5):609- Peppercorn MA:Drug-responsivechronic segmentalcolitisassociatedwith Surg Pathol.20(1):94-102,1996 Makapugay LMetal:Diverticulardisease-associatedchroniccolitis.AmJ Roentgenol. 167(1):3-15,1996 Gore RMetal:CTfeaturesofulcerativecolitisandCrohn'sdisease.AJRAmJ bowel diseases.AmJGastroenterol.92(12Suppl):5S-11S,1997 Sartor RB:Pathogenesisandimmunemechanismsofchronicinflammatory 1998 Gledhill Aetal:Crohn's-likereactionindiverticulardisease.Gut.42(3):392-5, J Gastroenterol.95(4):1014-6,2000 study. GruppodiStudioperleMalattieInfiammatorieIntestinali(GSMII).Am Imperiali Getal:Segmentalcolitisassociatedwithdiverticula:aprospective 2000 diverticulosis ratherthanCrohn'scolitis.AmJSurgPathol.24(5):668-75, specimens isusuallyanidiosyncraticinflammatoryresponsetothe Goldstein NSetal:Crohn'scolitis-likechangesinsigmoiddiverticulitis Suppl):S11-6, 2004 West ABetal:Thepathologyofdiverticulosiscoli.JClinGastroenterol.38(5 disease. JClinGastroenterol.38(5Suppl):S8-10,2004 Peppercorn MA:Theoverlapofinflammatoryboweldiseaseanddiverticular diverticulosis. IntJColorectalDis.20(1):28-32,2005 Koutroubakis IEetal:Thespectrumofsegmentalcolitisassociatedwith coexistent colonicdiverticulosis.JClinGastroenterol.40(4):317-21,2006 Sultan Ketal:Thenatureofinflammatoryboweldiseaseinpatientswith up study..38(6):610-2,2006 Imperiali Getal:Segmentalcolitisassociatedwithdiverticula:a7-yearfollow- Gastroenterol Hepatol.5(1):27-31,2007 Lamps LWetal:Diverticulardisease-associatedsegmentalcolitis.Clin with diverticula.DigDisSci.53(7):1865-8,2008 Ierardi Eetal:Tumournecrosisfactoralphainsegmentalcolitisassociated 53(9):2452-7, 2008 colitis associatedwithdiverticulosis(SCADsyndrome).DigDisSci. Freeman HJ:Naturalhistoryandlong-termclinicalbehaviorofsegmental 2009 disease-like colitis:asystematicreview.DisColonRectum.52(6):1072-9, Mulhall AMetal:Diverticulardiseaseassociatedwithinflammatorybowel diverticulosis. ColorectalDis.12(5):464-70,2010 Tursi Aetal:Theendoscopicspectrumofsegmentalcolitisassociatedwith diverticular diseaseorautonomousentity?DigDisSci.56(1):27-34,2011 Tursi A:Segmentalcolitisassociatedwithdiverticulosis:complicationof Colon 429 involved with diverticulosis, as seen in this example, are diagnostic of Crohn disease. patients where architectural disarray and metaplastic features dominate the findings, and there is minimal increase in inflammation. Note the crypt branching and disarray ﬊ and the Paneth cells ﬊ in this sigmoid colon . (Right) Compact, transmural lymphoid aggregates ſt reminiscent of Crohn disease may be seen in some resections performed for diverticulosis coli ﬊. (Left) In cases where mural lymphoid aggregates raise the possibility of Crohn disease, the presence of peridiverticular abscesses, with foreign body type reaction, favors the diagnosis of diverticular disease associated colitis. (Right) Deep fissuring ulcers ﬈ away from the segment (Left) Marked of the lymphoplasmacytosis and lamina propria crypt neutrophilic cryptitis and abscesses ﬈ are characteristic of ulcerative colitis-like variant of DDAC. (Right) In this biopsy from the with sigmoid colon in a patient chronic DDAC, all features of a colitis, such as basal lymphoplasmacytosis, and architectural disarray, ﬊, Paneth cell metaplasia are present. (Left) A chronic inactive colitis pattern may be seen in some Crohn Disease Crohn Disease-Like Variant Ulcerative Colitis-Like Variant Ulcerative Diverticular Disease-Related Colitis Disease-Related Diverticular Peridiverticular Abscess Ulcerative Colitis-Like Variant Ulcerative Colitis-Like Variant Ulcerative 606

Multiple Organs to NSAIDinjury. histologic changesmaybedue nuclei ﬇.Theseischemic-type enlarged hyperchromatic withered crypts﬈with lamina propria﬊,and ﬈, fibrinst,hyalinized surface neutrophilicexudate shows colonmucosawith power H&E-stainedsection may beNSAIDs.(Right)High- lesion). Oneofmanycauses lymphoid follicle﬊(aphthous colonic epitheliumneara with ﬈inthe section showsfocalcryptitis (Left) High-powerH&E-stained submucosal ﬊. chronic, associatedwith intestinal mucosaand,when out") fromsurrounding well demarcated﬈("punched (NSAIDs), whichisclassically antiinflammatory drugs caused bynonsteroidal shows asmallbowelulcer power H&E-stainedsection inflammation. (Right)Low- and relativepaucityof surface mucindepletion﬈, corkscrew appearance), hyperplasia ﬈(with gastropathy: Foveolar features ofchemical section showshistologic (Left) High-powerH&E-stained • • • • • CLINICAL ISSUES • • ETIOLOGY/PATHOGENESIS • TERMINOLOGY Rx: Discontinueuse,preventinjury(alternateformulations) ○ GI complicationswithbothshort-andlong-termtreatment Endoscopy: Erosions,ulcers,,hemorrhage pain, diarrhea,,iron-deficiencyanemia Symptoms: Odynophagia,dyspepsia,heartburn,abdominal ○ Widespread NSAIDuse(prescription,overthecounter) ○ ○ Toxicity toGImucosa:2mechanismsofpathogenesis selective cyclooxygenase2(COX-2)inhibitors NSAIDs: Salicylates,propionicandaceticacidderivatives, Gastrointestinal (GI)tractinjuryresultingfromNSAIDuse Life-threatening GIbleeding:Highestmortality GI damagein30-50%ofusers(mostlyelderly,women) Drug action:↓prostaglandinsynthesis, ↓bloodflow Direct contact/irritation:Increasedmucosalpermeability Nonsteroidal AntiinflammatoryDrug(NSAID)Damage Chemical/ Focal ActiveColitis KEY FACTS • • • • • TOP DIFFERENTIALDIAGNOSES • • • • • MICROSCOPIC • • MACROSCOPIC :Hyalinizedlaminapropria,witheredcrypts Infectious colitis:LaminapropriaPMNs,pseudomembranes ○ Inflammatory boweldisease/Crohndisease Peptic : Surfacegastricfoveolarmetaplasia H. pylorigastritis:Epithelialneutrophil,surfacelymphocyte :NSAIDcolopathy/colitis,focalactivecolitis :NSAIDenteropathy/,"diaphragms" : Chemical/reactivegastropathy,erosivegastritis : Pill-inducedesophagitis,sloughingesophagitis Active inflammation,erosions,ulcersthroughoutGItract ○ Small bowel:Diaphragmdisease(classicNSAIDinjury) Erythema, erosions,ulcers,hemorrhagethroughoutGI Chronic cryptdistortion,basallymphoplasmacytosis Thin, concentric,web-likefoldswithpinholelumina NSAID-Related Ischemic-TypeInjury NSAID Enteritis/ Multiple Organs 607 NSAIDs/COX-2 inhibitors exacerbate inflammatory inhibitors exacerbate NSAIDs/COX-2 (IBD) colitis bowel disease Large, tubular epithelial casts sloughing off wall Seen in up to 50-70% of long-term NSAID users Seen in up to 50-70% of long-term NSAID is small Proportion of patients with significant disease Mostly in ; ~ 30% in proximal colon Main toxic mechanism (over direct contact) mechanism (over direct Main toxic stability ulcer healing, disease PGs promote □ use 1x/week, 34% use daily 70% of elderly patients 1.0-1.5% annual incidence of serious GI complications 41% of pill-induced is due to NSAIDs 50% develop erosions, 10-30% develop ulcers ~ 50% of patients with GI complications: Asymptomatic ~ 50% of patients with dyspepsia: Normal endoscopy Esophagitis dissecans superficialis (sloughing) – Erosions more often located in gastric body/fundus Ulcers mainly found in antrum Small intestinal injury is very common – NSAID colitis: Up to 10% of new colitis patients – women NSAID use is reportedly more common in At anatomic site of narrowing: Middle esophagus Most commonly seen in gastric antrum in distal ileum NSAID-related erosions/ulcers commonest Diaphragm disease: Rare but distinctive form – Mostly occurs in right colon Hypoalbuminemia, vitamin B12 deficiency Large intestine: NSAID-mediated PG inhibition NSAID-mediated Large intestine: – – metabolism Leads to delayed NSAID (prescription, over the counter) Widespread NSAID use – GI events: 2.5-4.5% of patients/year NSAID-related upper – users GI damage occurs in 30-50% of regular NSAID of GI tract Injury to esophagus less common than rest – NSAIDs Gastric injury in 10-45% of patients on long-term – Little correlation with symptoms and presentation ○ ○ Esophagus: Erosions, ulcers, exudates ○ Stomach: Erosions, ulcers, hemorrhage ○ ○ ○ ○ Sex ○ Age: Usually affects elderly more Esophagus: Pill-induced esophagitis ○ Stomach: Reactive/chemical (NSAID) gastropathy ○ Small Intestine: NSAID enteropathy/enteritis ○ ○ Large intestine: NSAID colopathy/colitis, focal active colitis ○ Symptoms can present months to years after use Upper GI tract: Odynophagia, dysphagia, dyspepsia, heartburn, , , vomiting, malabsorption Lower GI tract: Abdominal pain/cramps, mild diarrhea ○ Both: Chronic blood loss → iron deficiency anemia ○ cytochrome P450 2C9 enzyme Variation in gene encoding ○ Incidence ○ ○ ○ ○ ○ CLINICAL ISSUES Endoscopic Findings • • • • • Site • • • • Presentation • • • • Genetic Polymorphism • Epidemiology • Nonsteroidal Antiinflammatory Drug (NSAID) Damage (NSAID) Drug Antiinflammatory Nonsteroidal Via -mediated vascular endothelial injury Results in mucosal erosion, even ulcers PGs normally maintain mucosal integrity Via mucous and bicarbonate production Results in focal and localized ↑ (NO), cytotoxic peroxynitrite output All culminate in increased inflammatory response Increased permeability → immune response Allows prolonged, repeated exposure to chemicals Direct damage to cell membrane phospholipids Cellular injury, loss of function in tight junctions Subsequent intracellular damage to mitochondria Intracellular Ca release → free radical generation Leads to ↑ permeability by , antigens, ligation prevents intestinal NSAID damage Bile duct ligation prevents intestinal NSAID □ Also interferes with epithelial regeneration □ Also ↓ gastroduodenal toxicity, ↓ lower GI tract injury Leads to decreased platelet aggregation → Decreased (PG) synthesis □ □ Decreased mucosal blood flow in upper/lower GI tract □ □ □ Colon: Local toxicity from slow-release NSAIDs □ Rectum: Toxicity from NSAID suppositories Small bowel: Enterohepatic circulation □ □ □ □ □ □ NSAID-induced injury is pH dependent Leads to toxic effect within epithelial cells mucosa NSAIDs and bile synergistically injure intestinal □ Salicylates, propionic and acetic acid derivatives ↓ GI side effects but cardiovascular complications – Selective COX-2 inhibitors: ↓ gastric ulcer/hemorrhage – Inhibition of thromboxane synthesis by platelets – COX-1: Constitutively expressed in GI mucosa normally Local inhibition of COX-1 enzyme – – – – – – drugs Esophagus: Acid reflux aids absorption of – Intestinal tract: Increased mucosal permeability – Nonselective cyclooxygenase (COX) inhibitors – Selective COX-2 inhibitors: Celecoxib, etc. – Toxicity to GI mucosa: 2 mechanisms of pathogenesis mucosa Acidic nature of drugs irritates and damages Including chemical/reactive gastropathy Including chemical/reactive disease Including diaphragm ○ ○ Toxic effect from actual drug action (mostly in stomach) ○ ○ ○ ○ Toxic effect on GI mucosa due to direct contact, irritation Toxic effect on GI mucosa due to direct contact, ○ ○ ○ NSAIDs used for relief of inflammation, pain, , NSAIDs used for relief of inflammation, pain, Heterogeneous class of medications, including ○ Gastrointestinal (GI) tract injury resulting from NSAID use Gastrointestinal (GI) tract ○ NSAID-related enteropathy/enteritis ○ NSAID-related colopathy/colitis NSAID-induced gastroduodenal damage NSAID-induced gastroduodenal Nonsteroidal antiinflammatory drugs (NSAIDs) antiinflammatory Nonsteroidal ETIOLOGY/PATHOGENESIS TERMINOLOGY • • • • Environmental Exposure Definitions • • • Synonyms • Abbreviations • 608

Multiple Organs • • • • General Features • • • • Prognosis • • • • Treatment • • Natural History MACROSCOPIC ○ ○ Diaphragm-like strictures(diaphragm disease) Heavy, long-termNSAIDusersmay developlongstrictures ○ ○ ○ Erythema, erosions,andulcersthroughoutGItract Upper endoscopyandcolonoscopymaybenormal ○ ○ ○ Overall mortalitydependsonage,comorbidities Reye syndrome:Acuteliverfailureinchildrenonsalicylates Long-term usemayleadtotubulointerstitialrenaldisease Depends ontreatmentmodalityandcomplications ○ ○ ○ Gastroprotection withadjuvanttherapy ○ ○ ○ ○ Injury prevention:↓toxicitywithalternateformulations ○ ○ ○ Treatment options ○ ○ Options, risks,complications ○ Gastric antrumulcerstendtobemorechronic Gastric fundus/bodyerosionstendtohealwithindays – Multiple, thin,concentric, web-likesepta/folds Most commonin jejunumandileum Rectal ulcers/proctitiswithNSAID suppositories Multiple discreteulcerswithintervening normalmucosa Patchy, mostcommoninileocecal region 21.8/1,000 personyearsaftercerebrovascularaccident 17.7/1,000 personyearsaftermyocardialinfarction 5.5/1,000 personyearsafterupperGIevent Metronidazole, sulfasalazine:↓intestinalinflammation Misoprostol: Protectionagainst↑intestinalpermeability H2-receptor antagonists,protonpumpinhibitors Selective COX-2inhibitors,NO-releasingNSAIDs Rectal, parenteraladministration Buffered preparations,nonacidicprodrugs – Enteric-coated orsolublepreparations Endoscopic dilatationofstrictures forperforation,bleeding,andobstruction – Discontinue use:10%ofpatientsstopduetosideeffects – – – – – – – Risk factorsforGIcomplications – – – – – GI complicationsin~4%ofNSAIDusers1styear Susceptible tobleedingandperforation Malabsorption: Bileacids,protein(hypoalbuminemia) Strictures, obstruction,perforation Life-threatening GIbleeding:Worstcomplication Risk withbothshort-andlong-termtreatment 1-4 mmthickwith small,pinpointlumina Reduce gastricresidence/mucosalcontacttime Adverse effectscanlastfor>1yearaftercessation Tobacco andalcoholuse,stress,depression Concurrent Helicobacterpyloriinfection(controversial) Concurrent /anticoagulantuse Comorbidities: Renalfailure,cerebrovasculardisease Past GIadverseevent(ulcer,hemorrhage) High-dose ormultipleNSAIDuse Age >60-70years,longerdurationoftherapy □ Exacerbation ofquiescent,inactiveIBD Seen in~40%ofIBDpatientsusingNSAIDs Nonsteroidal AntiinflammatoryDrug(NSAID)Damage • • • • Histologic Features • • • • MICROSCOPIC Stomach: Chemical/reactive(NSAID)gastropathy ○ ○ ○ ○ Esophagus: Esophagitisdissecanssuperficialis ○ ○ Esophagus: Pill-inducedesophagitis Active inflammation,erosions,ulcersthroughoutGItract ○ ○ ○ ○ Large intestine:NSAID-induced colopathy/colitis ○ ○ ○ Small intestine:Diaphragmdisease ○ ○ ○ ○ ○ ○ ○ Small intestine:NSAID-inducedenteropathy/enteritis ○ ○ ○ ○ Stomach: Acuteerosive(hemorrhagic) ○ ○ ○ ○ ○ ○ – Underlying viableepitheliumispaleandedematous Bullae-like fluidcysts,littleassociatedinflammation Hyperkeratosis, necrosisofsuperficialepithelium a.k.a. sloughingesophagitis Spongiosis, epithelialnecrosis,intraepithelialneutrophils Crystalline pillfragmentsamidstulcer/granulationtissue Virtually pathognomonicforNSAID-relatedinjury – Lumen dilationproximaltostricture – – – Perpendicular tolongitudinalaxisofGItract – – – Mild, mixedinflammatoryinfiltrate inlaminapropria – Overlying mucosawithreactive epithelialchanges Due torecurrentulcerationand healingwithscarring – – – Submucosal fibrousbandsprotrudeintolumen Pyloric glandmetaplasiaseenwithchronicinjury Prominent submucosalfibrosis Mucosa overstricturesmaybenormalorulcerated Nonspecific neutrophilicandplasmacyticinfiltrates – – Superficial erosions;mayprogresstodeepulcers Increased intraepitheliallymphocytes – Mild villousatrophy(mefenamicacid,sulindac) Mucin depletion,lownuclear:cytoplasmic(N:C)ratio Reactive atypia,nuclearhyperchromasia Neutrophilic infiltratesinepithelium,laminapropria Surface erosionwithfibrinexudates Generally littletonoinflammation Lamina propriacongestion,edema,telangiectasia – – Smooth musclefiberproliferation Diffusely enlarged,hyperchromaticnuclei Loss ofintracellularmucin(mucindepletion) – Foveolar hyperplasiaofsurfaceepithelium Imparts characteristic2-toneappearance Endoscopic capsuleoftengetsstuckproximally Can causenarrowing,occlusion,obstruction Unevenly distributedalongbowellength Project/protrude intogutlumen Mildly increased intraepitheliallymphocytes Eosinophils also described;maybeprominent May bepredominantly neutrophilic/lymphocytic Erosions oftenseenattipofprotruding column "Neuromuscular vascularhamartoma" inoldreports Smooth muscle,nerves,vesselsalsocontained Perpendicularly tomucosalsurface Classically welldemarcated,"punchedout" Often multiple(in>50%ofcases) Diffuse villousbluntingnotfeatureofNSAIDinjury Splay apartmucousglandsinlaminapropria Bundles extendingtowardgastricsurface Corkscrew-appearing glands Multiple Organs 609 Especially around dilated mucosal vessels Larger hyperchromatic nuclei, normal N:C ratio Larger hyperchromatic nuclei, normal N:C Occlusion of lumina → mucosal ischemic changes Hyalinization of lamina propria □ Eosinophilic cryptitis, increased crypt apoptosis Nuclear enlargement and hyperchromasia edema Flattened surface , submucosal Enlarged fibroblasts, cytoplasmic vacuolization – arteries Intimal proliferation of small/medium-sized – – stricture) Crypt distortion (especially around areas of Serosal adhesions Systemic lupus erythematous, rheumatoid erythematous, rheumatoid Systemic lupus Scheiman JM: NSAID-induced gastrointestinal injury: a focused update for clinicians. J Clin Gastroenterol. 50(1):5-10, 2016 Cryer B et al: Gastrointestinal ulcers, role of aspirin, and clinical outcomes: pathobiology, diagnosis, and treatment. J Multidiscip Healthc. 7:137-46, 2014 De Petris G et al: Histopathological changes in the due to medications: an update for the surgical pathologist (part II of II). Int J Surg Pathol. 22(3):202-11, 2014 Sostres C et al: Gastrointestinal effects of aspirin. Nat Rev Gastroenterol Hepatol. 8(7):385-94, 2011 Scarpignato C et al: Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am. 39(3):433-64, 2010 Clinical history of radiation radiation injury ○ ○ ○ Chronic radiation injury ○ ○ ○ ○ lymphocytes More prominent collagen band/intraepithelial Usually lack erosions, ulcers, ischemic-type injury Patchy process, can affect entire GI tract (upper and lower) Erosions, ulcers, and mild (usually acute) inflammation Little crypt architectural distortion or chronic changes Few surface/crypt epithelial or lamina propria lymphocytes Submucosal edema/hemorrhage Submucosal of autoimmune diseases Clinical history ○ normal Surface epithelium usually lymphoid follicles (aphthoid lesion) Neutrophils near/over from NSAID injury Focal active colitis; indistinguishable inflammation into lamina propria Minimal extension of base of crypts Increased apoptosis in and focal hemorrhage Lamina propria edema than those induced by NSAIDs Colonic ulcers deeper lymphocytic infiltration of vessels Fibrinoid and common Predominantly left colon: Splenic flexure most Superficial mucosal necrosis, pseudomembranes Withered crypts with reactive cytologic atypia hyalinization Lamina propria edema, hemorrhage, and DIAGNOSTIC CHECKLIST SELECTED REFERENCES 1. 2. 3. 4. 5. • • • Microscopic Colitis (Collagenous/Lymphocytic) • • Pathologic Interpretation Pearls • • • • • • Artifact Bowel Preparation • • • • • • Behçet Disease • • Ischemic Colitis • • • • Radiation-Induced Enteritis/Colitis Nonsteroidal Antiinflammatory Drug (NSAID) Damage (NSAID) Drug Antiinflammatory Nonsteroidal No branching or shortening No branching Mucin depletion, nuclear enlargement, visible nucleoli Mucin depletion, nuclear hyaline thrombi Lamina propria hyalinization, per 100 crypts > 5 intraepithelial apoptoses 24 apoptoses/100 crypts) seen Moderate levels (up to Lack of diffuse crypt architectural distortion crypt architectural Lack of diffuse □ Granulomatous inflammation may be present May be indistinguishable from NSAID injury Patchy lamina propria inflammation Slightly increased intraepithelial lymphocytes Crypt architectural distortion (crypt branching, shortfall) Crypt architectural distortion (crypt branching, basal Significant lymphoplasmacytic infiltrate, especially – in erosive areas Ischemic-like changes – bodies within intestinal crypts Increase in apoptotic – – Focal active colitis: Neutrophils in crypt epithelium colitis: Neutrophils Focal active and size variation in crypt distribution Mild, focal – surface epithelium Regenerative ○ Fibrinoid necrosis of vessel walls with Giardia in may mimic NSAID injury Mixed vascular/perivascular necrotizing Surface erosions/ulcers, but intervening mucosa involved Viral inclusions (cytomegalovirus, herpes simplex virus); fungal pseudohyphae ○ ○ ○ Crypts: Neutrophils, abscesses, rupture, no distortion Acute, self-limited colitis, pseudomembranous ↑ neutrophils, histiocytes, lymphocytes in lamina propria Resolving phase: Focal active colitis Aphthous lesions may occur in both Crohn disease and NSAID damage Focally marked cryptitis/crypt abscesses, (Crohn disease) Pyloric gland metaplasia, inflammatory pseudopolyps Chronic inflammatory changes ○ ○ Increased mitoses in surface epithelium Erosion/ulceration only in severe cases Brunner gland hyperplasia, villous blunting cells Increased infiltrates of neutrophils, plasma Mucin depletion, nuclear hyperchromasia Component may be due to NSAIDs (vs. gastric acid injury) Component may be due to NSAIDs (vs. gastric mucin Surface gastric foveolar metaplasia with neutral More prominent collagen band/intraepithelial lymphocytes More prominent collagen band/intraepithelial Usually lack erosions, ulcers, reactive changes Neutrophils in gastric surface and glandular epithelium Neutrophils in gastric surface and glandular Organisms attached to surface mucous cells follicles Superficial lymphoplasmacytosis and lymphoid Usually show luminal or stromal by iron deposits Usually show luminal ○ ○ ○ ○ ○ DIFFERENTIAL DIAGNOSIS • • Vasculitis • • • • • • • • • • • • • Disease Inflammatory Bowel Disease/Crohn • • • Peptic Duodenitis • • Collagenous/Lymphocytic Gastritis • • • • • Iron Pill-Induced Gastritis/Esophagitis • Helicobacter pylori-Associated Gastritis 610

Multiple Organs term NSAIDuse. damage, oftenseenwithlong- indicating chronicmucosal and submucosalfibrosis﬊, pyloric glandmetaplasia﬈ base ofilealmucosawith H&E-stained sectionshowsthe use. (Right)Medium-power are commonlyduetoNSAID goblet cells).GItracterosions hyperchromatic nuclei,lossof atypia ﬊(large ﬈, fibrin﬈,andregenerative Disrupted surfaceepithelium mucosa withanerosion: section showsduodenal (Left) High-powerH&E-stained nuclei, mucinloss). crypts, largehyperchromatic epithelial atypia﬊(withered epithelium ſt,andreactive disruption ofthesurface inflammatory exudate﬈, erosion withacute stained sectionshowsagastric (Right) High-powerH&E- absence ofinflammation. gastropathy. Notetherelative setting ofchemical to foveolarhyperplasiainthe the gastricantralmucosadue corkscrew appearance﬈of section showstheclassic (Left) High-powerH&E-stained a 2-toneappearance. viable epithelium﬈,givingit contrast totheunderlying esophagus, whichisin squamous epitheliumſtinthe and necrosisofthesuperficial hyperkeratosis, hyalinization, stained sectionshows (Right) High-powerH&E- NSAIDs) causingthisinjury. fragments ﬊(possibly cells ſt,andcrystallinepill fibrin, reactive,bizarrestromal inflammatory exudate﬈, esophageal ulcerwithacute stained sectionshowsan (Left) Medium-powerH&E- Nonsteroidal AntiinflammatoryDrug(NSAID)Damage Chemical/Reactive Gastropathy Pill-Induced Esophagitis Duodenal Erosion Acute Erosive(Hemorrhagic)Gastritis NSAID Enteritis/Enteropathy Sloughing Esophagitis Multiple Organs 611 nuclei, mucin loss), and hyalinized lamina propria ﬈. NSAIDs are a common cause of localized small erosions, especially in the ileocecal valve and proximal colon. mucosa with an erosion ﬈ at the top of mucosal folds, suggestive of NSAID use. Similar lesions may be seen at the tips of the folds in diaphragm disease. (Right) Medium-power H&E-stained section shows jejunal mucosa with a discrete ulcer ﬈ sharply delineated from the surrounding uninvolved mucosa, suggestive of NSAID injury. (Left) High-power H&E-stained section shows ischemic-type injury in the colon with withered crypts ﬈ and hyalinized lamina propria ﬊. (Right) High-power H&E- stained section shows healing colonic erosion with crypt loss, flat regenerative surface epithelium ﬈ (absence of goblet cells, hyperchromatic (Left) Gross specimen of a small bowel photograph multiple, segment shows ſt in concentric, ring-like folds stenotic the wall that result in "diaphragms," which may cause obstruction. This of appearance is characteristic (Right) NSAID intestinal injury. Low-power H&E-stained section shows small bowel "diaphragms," which are thought to result from repeated rounds of by injury/erosion followed healing and submucosal scarring, leading to fibrous bands ﬈ protruding into the gut lumen. (Left) Medium-power H&E- stained section shows ileal Diaphragm Disease Diaphragm NSAID-Related Colonic Erosion NSAID-Related Small Bowel Erosion Nonsteroidal Antiinflammatory Drug (NSAID) Damage (NSAID) Drug Antiinflammatory Nonsteroidal Diaphragm Disease Diaphragm Ischemic-Type Colonic Injury NSAID Enteritis/Enteropathy