surgical pathology of ibd and its - pathcme.com · cooper et al 13% * insteroidrefractorycases...
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Surgical Pathology of IBD and its Mimics
Maui, HI 2018
Robert D. Odze, MD, FRCPCChief, Division of GI Pathology
Professor of PathologyBrigham and Women’s Hospital
Harvard Medical SchoolBoston, MA
Indeterminate Colitis
1. Classic features of UC/Crohn’s
2. Causes of uncertainty in IBD‐ Indeterminate colitis‐ IBD mimics
3. Adjunctive tests
4. Natural history and treatment
5. Summary
Lecture Outline
Classic Features of Ulcerative Colitis and Crohn’s Disease
Feature Ulcerative Colitis Crohn’s Disease
Disease distribution Diffuse and continuous Segmental
Rectal involvement Always (adults) Occasionally
Disease severity Increased distally Patchy and variable
Ileal involvement Occasional (‘backwash’) Often
Disease location in colonic wall Superficial (mucosal) Transmural
Transmural lymphoid ags. Rare, underneath ulcers Any location
Fissures Rare, fulminant colitis Deep, any location
Sinuses and fistulas Absent Present
Granulomas Related to ruptured crypts Not crypt related
Yantiss et al, Histopathology 2006;48:116‐132
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Ulcerative Colitis
Crohn’s Colitis
Overlap in Spectrum of Non‐Specific IBD “Colitis Indeterminate”
Disease Indeterminate Colitis
N=30
Crohn’s Features
Discontinuous 16 (53%)
Granulomas 0
Fissures 4 (13%)
Trans inflam 28 (93%)
Focal mucosal inflam 20 (67%)
UC Features
Continuous (with rectum) 14 (47%)
Diffuse mucosal inflam 10 (33%)
Toxic Megacolon 21 (70%)
*10% of cases in file
*90% had fulminant colitis
Price AB. J Clin Pathol 1978;31:567‐577
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Indeterminate Colitis
• Not a distinct entity/disease
• No diagnostic criteria
• Should be regarded an interim diagnosis
• Prevalence rate highly variable among institutions and pathologists (1‐20%)
Indeterminate Colitis
• Uncertain colitis
• Idiopathic chronic colitis
• IBD‐unclassified
• IBD‐NOS
• IBD‐unknown etiology
Synonyms
Informal Survey10 GI Pathologists
Def’n of Indeterminate Colitis
• IBD: unclear if UC or Crohn’s pathologically 5• Acute fulminant colitis (with fissures) 3• Cause of IBD unclear clinically and pathologically 2• Resections only 8• Biopsy or resections 2
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Indeterminate Colitis
“IBD with overlapping/unusual features making definite distinction between UC and Crohn’s disease difficult/impossible”
(Indeterminate Pathologist!)
Definition
Indeterminate Colitis
1. Fulminant (severe, toxic) colitis
2. Insufficient clinical, radiologic, endoscopic, pathologic info
3. Failure to utilize hardcore diagnostic criteria
4. Failure to recognize unusual pathologic variants of IBD
5. Failure to recognize non‐IBD mimics and superimposed diseases
6. Attempt to distinguish UC from Crohn’s in biopsies
7. Attempt to change IBD diagnosis based on pouch complications
Common Reasons
*
*
*Should never be performed
Fulminant Colitis
• Severe (toxic) colitis with or without megacolon
• 5‐20% of IBD (1.6‐2.4/100,000 adults, 0.2/100,000, children)
• Usually occurs as initial manifestation of IBD• Most cases represent UC (with some Crohn’s
like pathologic features)• Some represent Crohn’s, non‐IBD mimics, IBD
with superimposed disease
Fulminant colitis
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Fulminant ColitisEtiology
1. Ulcerative colitis: 60-90%2. Crohn’s disease: 10-30%3. Ischemic colitis: <1%4. Infectious colitis: <1%5. Radiation colitis: <1%6. Diverticular disease: <1%7. Drug-induced colitis: <1%
Fulminant (Ulcerative) Colitis
• Fissuring ulcers (usually superficial)
• Transmural inflammation (without lymphoid aggregates)
• Relative rectal sparing
• Transverse colon most severely involved
• Serositis
• Perforation
Crohn’s‐like Features
Fulminant Colitis
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Fulminant Colitis
Superficial fissuring ulcer
Transmural inflammation
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Relative Rectal Sparing
Clinical and Prognostic Significance of Early Fissuring Ulceration in Chronic UC
Feature Colitis with Colitis withoutFissures Fissures
N=21 N=58
Pancolitis 91% 55%Serositis 41% 5%Backwash 64% 27%Appendicitis 20% 10%Pouchitis 50% 9%Crohn’s (F/U) 0% 0%
Yantiss et al, Am J Surg Pathol 2006;30(2):165‐170
Important Clinical/Endoscopic Information
1. Clinical •Family hx, PSC, type of symptoms/signs, serology, prior surgery, perianal disease
2. Radiologic •Segmental vs diffuse, S. int involvement, strictures, fistulas, wall thickness
3. Endoscopic •Type/appearance of ulcers, distribution of disease, appearance of ileum
4. Pathologic •Prior biopsies (and resections)
Insufficient clinical info
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Crohn’s Disease
• Transmural lymphoid aggregates
• Granulomas (non‐crypt related)
• Segmental involvement (with few exceptions)
• S. Int (distal ileum) involvement (>5 cm, patchy, radiologic abn.)
• Perianal disease (fissures, fistulas, abscesses)
• Fissuring ulcers (with few exceptions)
• UGI involvement (with few exceptions)
Major (Hardcore) Features
Failure to utilize hard criteria
Crohn’s Colitis
Unusual Variants of IBD
1. UC with Crohn’s‐like features• Fulminant UC
• Segmental disease (cecal/periappendical patch, effects of healing and/or therapy)
• Rectal sparing (children)
• Granulomas (crypt related, infection)
• Ileum involvement (backwash, infection, drugs, bowel prep)
• UGI involvement (rare)
Unusual variants of UC and Crohn’s
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Rectal sparing
Cecal patches: skip lesions
Photo courtesy of Dr. Appelman
Right Colon Involvement in Patients with Left-Sided UC
Left-sided colitis Left-sidedand Colitis
Feature Ascending colitis onlyN=14 N=35
Appendectomy 7% 0%NSAID use 64% 50%Prednisone use 0% 7%Progression (pancolitis) 0% 3%Dysplasia 7% 0%Crohn’s disease (F/U) 0% 0%
Mutinga et al, Inflam Bowel Dis 2004;10:215-219
Patchiness/Rectal Sparing inTreated Ulcerative Colitis
Author Patients Histologic Feature
Patchiness Rectal Sparing
Odze (1993)* 14 -- 29%Bernstein (1995) 39 33% 15%Kleer (1998) 41 30% --Kim (1999) 32 38% 44%
*5-ASA:36%Placebo: 12%
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Feature Children AdultsN=70 N=44
Chronic-active proctitis 79% 95%*Microscopic skip areas 23% 0%*Relative rectal sparing 34% 5%*Complete rectal sparing 3% 0%
Atypical Presentation of Pediatric Patients With UC
Glickman et al, Am J Surg Pathol 2004;28(2):190-197
Granulomas in UC
• Up to 20% of UC cases
• Most crypt-rupture related
• Other etiologies- barium, particulate matter,- infections, drugs, etc.
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“Backwash” Ileitis (is Hogwash)Primary UC of the Ileum
• Original studies were ileocolonic Crohn’s. • Pathogenetic mechanism never proven• Flaws in contemporary studies
– No cecal involvement– Patchy long segment disease– Correlation with severity of colitis
• Association with PSC, extent of colitis, severity of colitis, +/- pouchitis, +/- colonic neoplasia
• ?Aggressive subtype of UCPatil & Odze, et al., Am J Gastroenterol 2017;112:1211-1214
Prospective Evaluation of Ileitis in UC Surveillance Patients
Feature UC Cases N=72
Non-UC ControlsN=90
P Values
Ileitis 16 (22%) 4 (4%) P<0.1
Smoking 12% 11% NS
NSAIDs 8% 17% NS
Bowel Prep - - NS
Other Meds - - NS
Hamilton, et al., Inflamm Bowel Dis 2016; (10):2448-55
Prospective Evaluation of Ileitis in UC Surveillance Patients
Feature IleitisN=16
Non-IleitisN=56
P Values
Smoking 6% 16% NS NS
Alcohol 95% 63% NS
NSAIDs 13% 7% NS
Bowel Prep - - NS
Medications - - NS
Disease Duration 16 7.6 NS
Pan Colitis 31% 13% NS
Moderate/Severe disease 13% 9% NS
Clinical Activity Score 0.91 0.75 NSHamilton, et al., Inflamm Bowel Dis 2016; (10):2448-55
UC Cases
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UC-Associated Ileitis
Upper GI Involvement in UC
1. Extremely rare, unclear etiology
2. Stomach/duodenum
3. UC-like histology
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Duodenojejunitis in UC
Diffusely granular Diffuse inflammation & distortion
Photo courtesy of Dr. Appelman
Duodenitis in UC
Duodenitis in UC
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Morphology of UGI Biopsies in UC
Feature Control(N=43-66)
UC(N=40-59)
Focal gastritis 9% 29%
Basal mixed inflam 8% 22%
Superficial plasma 6% 20%
Diffuse chronic duodenitis
0% 10%
Lin et al, Am J Surg Pathol 2010;34:1672‐1677
Unusual Variants of IBD
2. Crohn’s with UC‐like features
• Mucosal (non‐mural) disease
• Rectal involvement only (≈5‐10%)
• Diffuse colonic disease
Unusual variants of UC and Crohn’s
Superficial (UC-like) Crohn’s Colitis
1. Poorly defined criteria2. Ambiguous or Crohn’s-like features
clinically3. UC-like features pathologically4. Often shows ≥ 1 classic Crohn’s
feature (granulomas, perianal disease, etc)
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UC‐like Crohn’s
Clinical and Pathologic Analysis of Colonic Crohn’s Disease, Including a Subgroup with Ulcerative Colitis‐like Features
Features Ulcerative colitis-like Crohn’s disease
Isolated colonic Crohn’s
Ileocolonic Crohn’s
Total
N=10 N=6 N=16
Recurrence
Colonic 3/10 (30%) 3/5 (60%) 6/15 (40%)Non-colonic 2/10 (20%) 1/5 (20%) 3/15 (20%)
PouchitisRecurrent 2/2 (100%) 0/6 (0%) 2/4 (50%)Chronic/resistant 1/1 (100%) 0/6 (0%) 1/3 (33%)
Pouch anastomotic breakdown 0/2 (0%) 0/2 (0%) 0/4 (0%)
Fistula 1/10 (10%) 3/6 (50%) 4/16 (25%)
Total with adverse outcome 5/10 (50%) 4/6 (66%) 9/16 (56%)
Soucy et al, Mod Pathol 2012 Feb;25(2):295‐307
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The Importance of Diagnostic Accuracy in IBD
119 pts with IBD
Non‐GI Pathologist GI Pathologist
Dx Dx
UC:70 cases UC:40
CD:10
IC:20
CD:23 cases CD:19
UC:3
IC:1
43%
17%
Farmer et al Am J Gastroenterol 2000;95)11):3184‐3188
Mimics of IBD
Ischemic colitis
Radiation colitis
IBD‐like microscopic colitis
Diverticular disease‐associated colitis
Infectious colitis (Yersinia, TB, LGV, other)
Diversion colitis
Drug‐induced colitis (NSAIDs, Ipilimumab)
Vasculitis (Behcet Syndrome)
IBD mimics/superimposed diseases
IBDSuperimposed Diseases
CMV
Pseudomembranous colitis
Ischemia
Radiation
Drugs
Microscopic colitis
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UC with C. Difficile and CMV
CMV
CMV in IBD
• Should be considered in suddenly refractory patients
• Prevalence rate: 5‐20%
• May cause a flare that is segmental and disproportionally severe in Rt Colon/ileum
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CMV in IBD Resections
Author Prevalence*
Rate
Maroni et al 22%
Alcala et al 18%
Kaufman et al 4.6%
Eyre-Brook et al 11.5%
Swarbrick et al 0%
Cooper et al 13%
* in steroid refractory cases Adapted from Hommes et al, IBD (2004)
Chronic Active Ischemia
• UC‐like endoscopy
• UC‐like histology• Restricted to mucosa
involved by diverticulosis
• Rectum spared
• Some resemble Crohn’s
Diverticular Disease-Associated (“Segmental”) Colitis
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Feature Segmental Colitis
Ulcerative Colitis
Diverticular mucosa Yes Yes
Interdiverticular muc Yes Yes
Left Colon Yes Yes
Right Colon No Yes/No
Rectum No Yes
Yersinia Ileo‐colitis
Feature Yersinia Crohn’s
Ileum/Rt colon Yes Yes
Segmental No Yes
Fissures/sinuses Yes Yes
Anal disease No Variable
Necrotizing granulomas Yes Rare
Coalescing granulomas Yes No
Lymph node granulomas Yes Uncommon
Vascular cuff No Yes
Yersinia Vs. Crohn’s
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Radiation Colitis
Radiation colitis
Ipilimumab colitis
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Collagenous ColitisIBD‐Like
Prevalence and Significance of Inflammatory Bowel Disease‐Like Morphologic Features in Collagenous and
Lymphocytic Colitis
Feature Collagenous colitis Lymphocytic colitis
Active crypt inflammation 30% 38%Surface ulceration 2.5% 0%Paneth cell metaplasia 44% 14%Crypt atrophy or irregularity 7.6% 4.2%Lymphoid nodules 65% 69%Mixed inflammation 10% 5%Basal Plasmacytosis 20% 10%Basal lymphoid aggregates 10% 10%
Ayata et al, Am J Surg Pathol 2002;26(11):1414‐1423
Indeterminate ColitisAdjunctive tests
Test UC CD
ANCA 60-70% 10-40%ASCA <10% 50-60%Anti-cBir1* 6% 50%
*associated with S. Intestine, internal-penetrating and fibrostenosing disease
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New Serologic Markers
Disease OMPC*1 cBirl*2
(ANCA+)
(anti-flagellin)
Anti I2
CD 55% 44% 54%
UC 11% 4% 10%
Controls 5% - 19%
*1Internal perforating CD
*2Internal perforating and fibrostenosing
Value of Serologic Markers in Indeterminate Colitis:
Prospective Follow‐up Study
Serology 97 Pts with IC
n CD UC IC
97 17 14 66
ASCA+/ANCA‐*1 27% 31% 8% 62%
ASCA‐/ANCA+*2 21% 20% 35% 45%
ASCA+/ANCA+ 41% 50% 25% 25%
ASCA‐/ANCA‐ 49% 6% 9% 85%
Total 100% 18% 14% 68%
*1 PPV for CD=80%*2 PPV for UC=64%
Joosens et al Gastroenterology 2002;122:1242‐1247
Natural History and Treatment
• Variable natural history due to heterogenous study populations and inconsistent “criteria”
• Most cases (60‐90%) represent UC
• Pouch procedure complication rate =20% (UC:10%, CD: 30‐40%)
Indeterminate Colitis
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Pouch Complications in Indeterminate and Ulcerative Colitis*
Author IC
N
UC
N
Pouch Failure
IC/UC
Yu (2000) 82 1437 27%/11%
Delaney (2002) 115 1399 3.4%/3.5%
Rudolph (2002) 35 71 0%/6%
Dayton (2002) 79 565 2.5%/1.2%
Gramlich (2003) 115 231 1.7%/2.1%
Pishori (2004) 13 285 0%/2.1%
Brown (2005) 21 1135 10%/6%
*Adapted from Martland et al, Histopath 2007
Frequency and Clinical Evolution of Indeterminate Colitis*: A Retrospective Multi‐
centre Study in Northern Italy
• 50/1113 indeterminate IBD pts (4.6%)
• Follow up (mean: 72 mths):
– 37/50 (73%) had a definite diagnosis
• 20/37 (54%) UC
• 17/37 (46%) CD
– Cumulative probability of dx: 80% after 8 years
*No criteria utilized Meucci et al. Eur J Gastroenterol Hepatol 1999;11:909‐913
Biopsies in (Potential) IBD Patients
• Determine extent/distribution
• Determine severity
• Determine dysplasia/cancer
• Determine granulomas/ileal involvement
Major Role of Pathologist
Attempt to diagnose IC in biopsies
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Summary
1. Evaluate IBD cases only after obtaining all relevant patient info.
2. Most causes of uncertainty are due to fulminant disease, lack of awareness of hardcore criteria, histologic variability
3. Always consider IBD mimics and superimposed disorders
4. Avoid establishing diagnoses in biopsies
5. Most indeterminate cases are UC; patients can be treated safely with IPAA procedure.