53 Clinico-Pathologic Dilemmas in Inflammatory Bowel Disease

David Lewin MD Lawrence Comerford MD, MS

2011 Annual Meeting – Las Vegas, NV

AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600

Chicago, IL 60603

53 Clinico-Pathologic Dilemmas in Inflammatory Bowel Disease Bringing in another specialty to this session, the presentation will combine the expertise of a pathologist as well as a gastroenterologist. Inflammatory bowel disease topics will be covered, including ulcerative colitis vs. Crohns, terminal ileum ulcers and lesions.

• Identify clinically important issues in the diagnosis and treatment of inflammatory bowel disease. • Understand the importance of clinician/ pathologist communication in the diagnosis and treatment of

inflammatory bowel disease. FACULTY: David Lewin MD Lawrence Comerford MD, MS Entire Pathology Team Surgical Pathology Surgical Pathology (GI, GU, Etc.) 1.0 CME/CMLE Credit Accreditation Statement: The American Society for Clinical Pathology (ASCP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). Credit Designation: The ASCP designates this live event material for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. ASCP continuing education activities are accepted by California, Florida, and many other states for relicensure of clinical laboratory personnel. ASCP designates these activities for the indicated number of Continuing Medical Laboratory Education (CMLE) credit hours. ASCP CMLE credit hours are acceptable to meet the continuing education requirements for the ASCP Board of Registry Certification Maintenance Program. All ASCP CMLE programs are conducted at intermediate to advanced levels of learning. Continuing medical education (CME) activities offered by ASCP are acceptable for the American Board of Pathology’s Maintenance of Certification Program.

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Clinico‐Pathologic Discussion of Dilemmas in Inflammatory Bowel 

DiseaseDiseaseDavid Lewin MD

Department of Pathology

Lawrence W. Comerford MD, MSDepartment of Medicine, 

Division of Gastroenterology

Disclosures

• Dr. Lewin has no disclosures

• Dr. Comerford

Case‐based presentation

#1 ‐Differentiating Ulcerative Colitis from Crohn’s Colitis

#2 – Ileal Lesions – Crohn’s Disease?

#3 Dysplasia in Inflammatory Bowel Disease

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Case #1 UC vs CD

21 year‐old female college student presents with diarrhea (loose bowel movements daily) mild crampy abdominal pain, rectal bleeding for 2 months. 

No recent travel or antibiotic use; Non smokerNo recent travel or antibiotic use; Non‐smoker

Mildly anemic Hg 11; Stool cultures are negative for enteric pathogens, C. difficile, and ova and parasites

Differential Diagnosis

• Infectious colitis• Inflammatory Bowel Disease• Ischemic colitisIschemic colitis• Microscopic colitis• SCAD • Radiation colitis• Drug‐induced colitis• Solitary rectal ulcer syndrome

Endoscopy

• Colonoscopy: Diffuse ulcerated and friable mucosa throughout entire colon; < inflammation in rectum

• Unable to intubate terminal ileum• Unable to intubate terminal ileum

• Upper endoscopy normal

3

DIFFERENTIAL DIAGNOSIS OF INFECTIOUS AND ULCERATIVE

COLITIS

4

5

ANATOMIC EXTENT OF ULCERATIVE COLITIS

ENDOSCOPIC SPECTRUM OF SEVERITY

6

Endoscopic Features

Distribution

Involves the rectum

Continuous pattern; no skip lesions

More severe distally

May have a Cecal patch

Backwash ileitis

Crohn’s Disease

• Chronic inflammation potentially involving any location of the alimentary tract 

• 30% small bowel only, 40% ileocolic, 30% colon only

• Inflammatory Bowel Disease (IBD), ileitis, regionalInflammatory Bowel Disease (IBD), ileitis, regional enteritis, granulomatous enterocolitis

• Skip pattern, transmural (from mucosa to serosa)

• Stricture, fistula, abscess

• Unknown etiology             

• No cure ‐ Yet

ANATOMIC DISTRIBUTION

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Crohn’s Disease

CLINICAL PATTERNS

Perirectal fistula 

8

Crohn’s endoscopy

• Rectal sparing

• Skip patterns

• TI involvement

• Cobblestoning, ulceration

Endoscopic Features

Rectal involvement  UC > CD

Skip lesions  CD > UC

Cobblestoning CD > UC

Pseudopolyps UC > CD

TI involvement CD > UC  ( Backwash)

More severe distally UC> CD

Who are these guys?

Dr. Crohn with 2 Mt. Sinai gastroenterologists at 1928 ACP meeting

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IBD

Genetics ImmuneSystem

Cytokine ImbalanceImmunosuppressant and anti-TNF-α therapy can be effective.

Prevalence differs among ethnic groups Concordance rate for monozygotic twins (44%) > dizygotic twins (3.8%)Link to genetically

Etiology of Inflammatory Bowel Disease 

IBD

EnvironmentalInfluence

Antigen Trigger (Bacteria, food Ag, or toxins)Hygiene or Urban AreasSmokingNSAIDS

Link to genetically susceptible hosts (e.g. NOD 2/CARD 15)

Timmer. Digest Disease. 2003;21: 91–104.

GEOGRAPHICAL PREVALENCE OF IBD

Estimated 1 Million Americans with IBD

Ulcerative Colitis50%

Crohn’s Disease50%

Loftus EV. Gastroenterology. 2004;126:1504-1517.Podolsky DK. N Engl J Med. 2002;347:417-429.

Strange EF et al. Gut . 2005;55:1-15.

Approx 10% - 15% “indeterminate” colitis

Cases per 100,000 persons

Incidence (range) Prevalence (range)

Ulcerative Colitis 2.2 – 15.6 38 – 246

Crohn’s Disease 3.6 – 15.6 26 – 199

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Indeterminate colitis

• “IC” restricted to resected specimens

• “IBD Unclassified”  ‐ patients who appear to have IBD colitis but who cannot be readily classified when all clinical radiologicalclassified when all clinical, radiological, endoscopic, histologic, and serologic data are taken into account  

Indeterminate colitis

‐ 5‐10% of all colitis

‐ 5 year Norway study of 40 IC cases1:

18/40 UC    7/40  CD   8/40 non‐IBD 

‐ Diagnostic problems common in early & severe disease

1 Moum B.., Scand J Gastroenterol 1996;31:362‐366

Indeterminate colitis

CD vs UC

Radiology: SBFT, CTE, MRE

Small bowel endocapsule

Serology markers

Histology

Tincture of time

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Potential Roles for IBD Serologic Testing

• Assist in the initial diagnosis of IBD– Presence of diagnostic uncertainty– To assess need for endoscopy (esp. pediatrics)

• Differentiate Ulcerative Colitis (UC) fromDifferentiate Ulcerative Colitis (UC) from Crohn’s Disease (CD)– Indeterminate colitis– Strengthen diagnosis prior to surgery

• Helps identify patients at risk for aggressive disease

PROMETHEUS® IBD Serology 7

• ELISA tests (Enzyme Linked Immunosorbent Assay) – ASCA IgA– ASCA IgG– Anti‐CBir1† IgA– ANCA IgGANCA IgG– Anti‐OmpC* IgA

• IIF tests (Indirect Immunofluorescence)– pANCA– DNAse‐sensitive pANCA*

†Patent pending.*Proprietary and patented marker.

pANCA

• Identified in 60‐70% of UC patients

• Identified in  40% of Crohn’s disease patients

• pANCA (+) CD have phenotype similar to left sided p ( ) p ypUC

• CBir‐1 is (+) 44% of  pANCA (+) CD patients

• CBir‐1 is (+) 4% of  pANCA (+)  UC patients

Targan SR, Gastroenterology 2005;128:2020-8

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Indeterminate colitis

Correct diagnosis important:

Surgical decisions ( IPAA)

Medical treatment

Treatment Pyramid

Severe

Surgery

Cyclosporine

Disease SeverityAzathioprine/

6-MercaptopurineInfliximab

Mild

Moderate

SystemicCorticosteroids

Topical and/or Oral Aminosalicylates

y p

Hanauer, Medical Therapy for Ulcerative Colitis. 2000: 529-556.

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GROSS PATHOLOGY OF ULCERATIVE COLITIS

“ Sometimes we have to save lives, not colons”

Ulcerative ColitisSurgical Options

Conventional ileostomy(Brooke)

Continent ileostomy(K k h)

Ileo-anal anastomosiswith reservoir

CP980510-1

(Kock pouch)

Indeterminate colitisSevere Pouch complications1

CD 30‐45%   IC 20%    UC 10%

P h i i i l ti 2Pouches requiring surgical correction2

IC 50%      UC 3% (n=235)

1 Geboes G. Inflamm Bowel Dis 2008;14:850‐8572Koltun WA. Dis Colon Rectum 1991;34:857‐860

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ASLC V UC

• Plasmacytosis in the lamina propria extending to the mucosal base and mucosal distortion were present in all cases of UC and absent in all cases of ASLC.– Histopathologic features always distinguished UC and ASLC

• Biopsy specimens are only diagnostic when obtained within the first 4 days

Nostrant et al. Gastroenterology 1987;92:318

ASLC V ACUTE ONSET IIBDFindings ASLC IIBD Normal Architecture 44 (85) 4 (8) Distorted Crypt Architecture 0 34 (65) Branched Glands 5 (10) 41 (79) Villiform Surface 0 11 (21)Crypt Atrophy 1 (2) 5 (10) Goblet Cell Mucin Depletion 36 (70) 48 (92) Reactive Epithelial Hyperplasia 37 (73) 48 (92)

Surawicz et al. Gastroenterology 1994;107:755

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ASLC V ACUTE ONSET IIBD

Findings ASLC IIBD Acute and chronic inflammation

16 (31) 49 (94)

Crypt abscess 24 (37) 47 (90)Basal plasmacytosis 3 (6) 40 (77)Basal lymphoid aggregates 1 (2) 18 (35)Isolated giant cells 1 (2) 13 (25)Granulomatous crypt abscess

8 (15) 19 (37)

Surawicz et al. Gastroenterology 1994;107:755

architect2.jpg

archdist1.jpg

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Histologic Features For Ulcerative Colitis v CD

Feature K UC Epithelioid granulomas .41 -.41Langhan’s giant cells .4 -.28Crypt distortion .38 .34 Crypt architecture .36 .35Eosinophils .32 .31 Crypt branching .3 .30 Paneth cell metaplasia .29 .23 Villous mucosal configuration .26 .29 Crypt atrophy .24 .28 Focal inflammation .05 -.18

Theodossi et al. Gut 1994;35:961-968

Diffuse (UC) v Patchy (CD)Diffuse (UC) v Patchy (CD)

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pm40x.jpg

IBD SCORING SYSTEM

Feature IBD/normal UC/CD Neutrophilic infiltration 1 -1 Epithelioid granulomas 1 -6 UC/CD scoreCrypt architecture abn 3 1 Mucin depletion 1 Eosinophils 2 3 Paneth cell metaplasia 2 Diffuse inflammation 1 -2 Villous configuration 1

Theodossi et al. Gut 1994;35:961-968

<= -3 -2 to 2 => 3

<= 1 - “Normal -

2 to 4 CD Possible IBD

UC

=> 5 CD IBD UC

IBD

/

nl score

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Granulomas in Crohn’s Disease

• One of the best discriminating factors v UC• Types of Granulomas

– Well‐formed, non‐necrotizing granuloma• Diagnostic of CD

– Rule out TB and sarcoid

– Pericryptal microgranuloma• Occasionally seen in UC and other colitides

– Mucin Granuloma• Ruptured crypt with associated giant cells, non‐specific• Can be seen with ulcerative colitis

• Granulomas only seen in 20 ‐ 30% of Crohn’s biopsies

crohn4xcolgran.jpg

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mucingranuloma1.jpg

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Summary of Causes of Unusual Patterns of Disease in UC

• Treatment effect• Low‐grade disease in remission• Appendiceal involvement as a skip lesion• Cecum/ascending colon inflammation in left‐sided colitis

• Pediatric UC (initial presentation)• “Backwash” ileitis• Rare upper gi involvement (e.g., duodenitis)• Fulminant colitis

Adapted from Table 10-1, Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Ed. Odze RD, et al, 2004.

Before considering a pouch, make sure it is UC and not Crohn’s

GI pathologist to review the biopsies

Evaluate small bowelEvaluate small bowel

IBD serology

Rectal exam

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Case #2: Ileal Lesions

• 53 year old male

• Chronic diarrhea

• Multiple terminal ilealulcersulcers

• History of NSAIDs 

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Ileal Lesions

• Screening endosocopy (6,408 with terminal ilealintubation of 30,000 screening exams)– Gross lesions in 1% (68)

• Ulcer (29), Lymphoid hyperplasia (23), Erythema (8), other (8)(8)

– Histopathology in 0.3% (22)• Acute ileitis (17)• Chronic active ileitis (5)

– Four had a change in management

• Conclusion: Ileal intubation not required in screening colonoscopy

Kennedy G et al. Surg Endoscopy 2008;22:2606

Ileal Lesions

• Normal (Abdominal pain, screening, constipation, rectal bleeding)– 15/138 (11%) had changes

• No Crohn DiseaseN ifi Il iti 2 (2 2%)• Nonspecific Ileitis 2 (2.2%)

• Nodular lymphoid hyperplasia 13 (14.3%)

• Chronic Nonbloody diarrhea– 47/138 (34%) had changes

• Crohn Disease  9 (6.5%)• Nonspecific Ileitis 18 (13%)• Nodular lymphoid hyperplasia 33 (24%)

Morini S et al. Am J Gastroentrol2003;98:1512.

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Chronic Diarrhea Patient

• Distinguish backwash ileitis of UC vs CD– BWI: Activity level correlates with the level of cecal UC

– CD: Focal isolated ileal erosions, mucous gland metaplasia (27%), patchy edema with mild inflammation

• Isolated chronic ileitis– Crypt distortion, inflammation, plasmacytosis of lamina propria, ulceration, pyloric metaplasia

• 54% will develop CD on follow‐up– 36% will have focal enhanced gastritis

Goldstein N. AJCP 2006;126:365Petrolla AA. J Gastro 2008;43:524

Ileal Lesions

• Symptomatology and indication for endoscopy predict the likelihood that ileitis will progress to Crohn disease– Asymptomatic ileitis (11 of 14 with features of– Asymptomatic ileitis (11 of 14 with features of chronicity)

• None progressed to CD

– Symptomatic ileitis • 8/10 with features of chronicity progressed

• 2/5 with focal active ileitis progressed

Courville EL et al. AJSP 2009;33:1341

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Case #3 – Dysplasia in CD

• 42 year female with history of Crohn Disease

• Originally diagnosed in 2009

• Treatment with prednisone, imuran and h ihumira– All discontinued due to side effects

• Currently on no medications– 10 bowel movements per day

• Repeat colonoscopy performed

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Endoscopic Findings• The ICV was narrowed: could not intubate TI• Erythema, loss of vasculature, edema in the cecum, ascending colon and 

proximal transverse colon. • Proximal ascending colon, 5 cm distal to ICV large 4 cm sessile polyp 

surrounded in a field of inflamed mucosa concerning for a DALM lesion. – Multiple biopsies taken of the polyp and placed in a separate jar. – Biopsies were also taken of the adjacent mucosa and placed in a separate 

jarjar. • Flat nodular area in the ascending colon a few centimeters distal to the polyp 

– Biopsied and placed in the random right colon jar. • Few areas of normal appearing mucosa in the transverse colon and 

descending colon. • Flat polyp 2 cm in size in the transverse colon. • Descending colon, confluent erythema, edema and loss of vasculature to the 

distal sigmoid colon. • Normal Rectum • Surveillance biopsies were taken in each of 4 quadrants every 10 cm 

throughout the colon.

5 cm Proximal Ascending Colon Lesion 

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Biopsy Adjacent to 5 cm Lesion

Random Right Biopsies (Includes Flat Nodular Area)

Random Right Biopsies (Includes Flat Nodular Area)

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Flat Polyp Transverse Colon

Random Left Colon

Random Left Colon

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Rectal Biopsy

Colorectal Neoplasia in IBD

• UC and CD have an increased risk of developing colorectal carcinoma– Ulcerative colitis (UC)

• Risk 2% at 10 years 8% at 20 years 18% at 30 yearsRisk 2% at 10 years, 8% at 20 years, 18% at 30 years

– Crohn disease (CD)• Standardized incidence ratio for CRC 2.5 (95% CI, 1.7‐3.5)

• Relative risk 4.5 (95% CI, 1.3‐14.9)

Risk Factors

• Disease duration

• Extent of disease

• Association of PSC

• Family history of sporadic CRC

• Colonic strictures (in UC), multiple pseudopolyps

• Increased degree of macroscopic and histologic inflammation

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Screening/ Surveillance

• UC– Screening at 8 to 10 years disease duration– Surveillance

• 1‐2 years in extensive colitis (proximal to splenic flexure) and left sided (descending colon)left‐sided (descending colon)

• Standard (non‐uc) CRC surveillance in proctosigmoiditis(limited to rectum and sigmoid)

– No increase risk of colorectal cancer

• IBD + PSC– Screening and surveillance (yearly) at time of PSC diagnosis

Biopsies

• Polyps (mass lesions)– Resection of polyp if possible

– Biopsy of the mucosa next to the polyp in separate jarjar

• Random biopsies– No specific # recommended in guidelines, “sufficient”

• Studies show minimum of 33 with extensive disease

• 4‐quadrant biopsies every 10 cm

Gross Features of DALMs

• Adenoma‐like (endoscopicallyresectable)– Sessile/pedunculated

• Non‐adenoma‐like (not endoscopically resectable)

– Usually sessile (broad based)– Well circumscribed

– Smooth surface

– Visible borders

– Nonulcerated

– No stricture

– No mucosal tethering

– Poorly circumscribed

– Irregular surface

– Indistinct border

– Ulceration/necrosis

– Stricture

– Tethering

Farraye FA et al. Gastroenterology 2010;138:746–774

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Adenoma-like DALM

Non-adenoma-like DALM

Farraye FA et al. Gastroenterology 2010;138:746–774.

Farraye FA et al. Gastroenterology 2010;138:746–774.

ACG Practice Guidelines

• “From a practical perspective, therefore, it matters little whether a mass lesion is called an adenoma‐like mass, or dysplasia‐associated lesion or mass; the important issue is tolesion or mass; the important issue is to determine whether the lesion is completely resectable and the rest of the colon is free of dysplasia.”

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DMSG CLASSIFICATION

• Negative for dysplasia (Neg)

• Indefinite for dysplasia (Indef)

• Low‐grade dysplasia (LGD)

• High‐grade dysplasia (HGD)

• Carcinoma (CA)

CLOSE

8

CLOSE

Farraye FA et al. Gastroenterology 2010;138:746–774.

Follow‐up

• At resection:– Partial colectomy (Crohn disease)

• Multiple polyps with low grade dysplasia and multifocal flat low grade dysplasiamultifocal flat low grade dysplasia– No invasive carcinoma

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Resection Specimen: Villous Lesion

Flat Dysplasia: Resection Specimen

Flat Dysplasia: Resection Specimen

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SummaryClinico‐pathologic Information

#1 ‐Differentiating Ulcerative Colitis from Crohn’s Colitis

#2 – Ileal Lesions – Crohn’s Disease?

#3 Dysplasia in Inflammatory Bowel Disease

Extra Case #4 – Dysplasia in UC

• 61 year old male• Diagnosed with ulcerative colitis 9 years ago• Numerous therapies (including Lialda and Remicade) with limited improvement) p

• Steroid dependant x 8 years– Currently on 20 mg steroids and sulfazine

• Multiple bowel movements during day and night, no incontinence

• Outside colonoscopy revealed multiple polyps

Polyp #1

34

Polyp #2

35

Adjacent “Flat” Mucosa

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