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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.