The Differential Diagnosis of

Chronic Colitis
Rhonda K. Yantiss, M.D.
Professor of Pathology and Laboratory Medicine
Department of Pathology and Laboratory Medicine
Weill Cornell Medicine, New York, New York, USA
ESTABLISHING A DIAGNOSIS OF ULCERATIVE
COLITIS OR CROHN DISEASE
Classic ulcerative colitis is diffuse and continuous, extending from rectum in retrograde fashion

Loss of normal folds

Granular, nodular mucosa

Normal ileum

Short colon, but similar diameter throughout

Classic ulcerative colitis is superficial, involving mucosa and superficial submucosa

Diffuse chronic inflammation in lamina propria with crypt architectural abnormalities

Histologic Diagnosis of Ulcerative Colitis
Biopsy of the Untreated Patient
•Changes of chronicity
•Chronic inflammation with plasma cells are required
•Crypt architectural abnormalities and cellular metaplasia
are common but not required
•Disease activity (neutrophils) is not required for a
diagnosis but generally present in untreated patient
•Endoscopically abnormal (be cautious when making a
diagnosis of IBD if there isn’t endoscopic colitis)
35-year-old woman with rectal bleeding

Looks like chronic colitis

Mononuclear cell rich inflammation with lymphoid aggregates
Quiz: Is this ulcerative colitis?

Plasma cells

Neutrophils

Per endoscopy report: rectal polyp with normal background mucosa (rectal tonsil)
Ulcerative colitis

Eosinophils Plasma cells uniformly present

Early ulcerative colitis

No crypt distortion
Early ulcerative colitis

Lots of plasma cells

Quiz: Is this ulcerative colitis?

Lots of plasma cells

Crypts lost, but architectural abnormalities lacking

 Plasma cells mixed with other cell types

Crypts lost, but not distorted

Acute self-limited colitis can mimic ulcerative colitis; plasma cells present 1-2 weeks after symptom onset
 Ulcerative Colitis
Mucosal Architectural Abnormalities
•Result from repetitive cycles of injury and
repair
•Crypt architecture
•Variable size, shape, and orientation
•Loss of crypts
•Villiform surface contour
Crypt branching Horizontal crypts

Variable crypt size and shape

Ulcerative colitis

Marked crypt irregularities with branching

Mucosal remodeling: Marked crypt hyperplasia
Mucosal remodeling: Villiform architecture in the sigmoid colon
Ulcerative colitis: Mucosal remodeling

Paneth cell metaplasia Pyloric metaplasia infrequent

Quiz: Can you diagnose chronic colitis based on crypt distortion and no inflammation?

Treacherous—this is a patient with chronic ischemic colitis, not ulcerative colitis

Ulcerative colitis disease activity

Cryptitis Crypt abscesses Crypt ulcer/destruction

 Grading Disease Activity
•Correlation with endoscopy
• The more extensive the pathologic changes, the more likely they
correlate with endoscopic findings
• Mild activity doesn’t correlate all that well
• Severe activity correlates very well with endoscopy
•Clinical value of histologic grade
• Most clinicians treat clinical, not histologic activity
• Some data suggest that severity of histologic activity is associated
with higher risk of neoplasia (which makes sense)
Rosenberg, et al. Clin Gastroenterol Hepatol 2013; 11(8): 991-996.
Rubin, et al. J Clin Gastroenterol 2013;11: 1601-1608.
 Classic Crohn Disease
•Patchy or segmental, transmural, chronic
inflammatory disease
•Can involve any part of the gastrointestinal tract
•Usually involves the small bowel, especially the
terminal ileum
•80% of cases (at least) affect the ileum
•Occasionally involves colon only (any part of the
colon in segmental or diffuse fashion)
 Cecum

Thick-walled stenosis

Creeping fat Loss of mucosal folds

Classic Crohn disease

Classic Crohn disease

Mural disease with scarring and lymphoid inflammation

 Crohn disease of ileum

Splayed, expanded muscularis mucosae

Pyloric metaplasia

Crypt distortion with displaced Paneth cells

 Ileal Biopsy for Crohn Disease
Challenging Aspects of Interpretation
•Criteria for chronic ileitis similar to those for colitis
•Plasma cell-rich inflammation may not be appreciated due
to lymphoid aggregates
•Crypt and villous architecture sometimes hard to assess in
poorly oriented samples
•Pyloric metaplasia easiest to recognize, but not sensitive or
specific
•Neutrophils (activity) not required, but often present
in patchy distribution
Ileal Crohn disease

Patchy disease: Normal and inflamed fragments

Ileal Crohn disease: Patchy disease within fragments

Severely inflamed with aphthous ulcers

Essentially normal
 Ileal Crohn disease

Aphthous erosion

Pyloric gland metaplasia

Plasma cell-rich inflammation around crypts

Normal ileum

Intraepithelial lymphocytes over lymphoid aggregate

Lamina propria cellularity decreases as move away from lymphoid aggregate

Crohn disease

Lymphoid aggregate

Inflammation expands mucosa away from lymphoid aggregates

Crohn disease

Focal neutrophilic cryptitis

Plasma cells in villi and around crypts

Ileal Crohn disease

Goblet cell hyperplasia, pyloric metaplasia Remodeled crypts, increased Paneth cells
 Not All Pyloric Metaplasia
Reflects Crohn Disease
•Pyloric metaplasia is a
marker of remote injury
•NSAIDs
•Radiation
•Most asymptomatic
patients with pyloric
metaplasia do not
develop Crohn disease
Courville, et al. Am J Surg Pathol 2009; 33(9): 1341-1347.
Classic Crohn disease: Mucosal pseudopolyps, segmental mural thickening
Crohn disease

Transmural lymphoid aggregates Sinus tract lined by granulation tissue

 Colonic Crohn Disease in Biopsies

•Some cases show diffuse colitis similar to

ulcerative colitis
•Tends to be more patchy than ulcerative colitis
•Focal intense inflammation
•Complete sparing of tissue fragments in
samples from same area
•Patchy inflammation within a single fragment
Colonic Crohn disease

Patchy with striking variability among tissue fragments

Colonic Crohn disease

Patchy in a single biopsy

Crohn colitis

Focal colitis with mixed inflammation, but lots of plasma cells

Colonic Crohn disease

Epithelioid granuloma
Quiz: Can you diagnose Crohn colitis based on a granuloma?

No-that is just a granuloma, not necessarily Crohn disease, or a marker of disease activity
Crohn Disease in Colonic Biopsy Samples

•Crohn disease is typically patchy with wide

variation in severity of injury
•Plenty of ulcerative colitis cases show patchy
disease (especially if treated, or early in disease)
•In absence of granulomata or ileal disease,
almost impossible to definitively diagnose Crohn
colitis based on biopsy alone
EVOLVING VIEWS OF ULCERATIVE COLITIS
IT’S NOT JUST COLITIS ANYMORE
Classic Features of Ulcerative Colitis and
Crohn Disease
Ulcerative Colitis Crohn Disease
Colon only Any part of GI tract
Diffuse, continuous disease Segmental disease
Rectal involvement Variable rectal involvement
Disease worse distally Variable disease severity
No fissures or fistulae Fissures and fistulae
Disease in mucosa/submucosa Transmural lymphoid aggregates
No ileal involvement, except distal 1-2 cm Ileal involvement in 80%, upper GI tract
(backwash) involvement also common
Epithelioid granulomata
Perianal disease
 Evolving Views of Ulcerative Colitis
•Historical views of disease
•Based on resection specimens, barium studies, rigid
sigmoidoscopy
•Modern era
•Colonoscopic access to proximal colon
•Disease shows greater variability than previously
appreciated
• Changes with time and treatment
•Blurring distinction between ulcerative colitis and Crohn
disease
•Discontinuous
ulcerative colitis
•Left-sided colitis with
sparing of intervening
colon and inflammation
of right colon
•Cecal patch
•Peri-appendiceal
inflammation
 Unusual Features of Ulcerative Colitis
Rectal Sparing in Early-Onset Disease
•Initial presentation of pediatric patients
•30-42% have some degree of rectal sparing
• 6% have histologically normal rectal mucosa
•Only 32% show diffuse disease
•Early ulcerative colitis in adults
•53% have diffuse disease
•31% show milder rectal inflammation compared
to abdominal colon
Washington, et al. Am J Surg Pathol 2002; 26:1441; Glickman, et al. Am J Surg Pathol 2004; 28:190.
Robert, et al. Am J Clin Pathol 2004; 122: 94-9.
 Ulcerative Colitis
Mucosal Healing with Therapy

• Neutrophilic inflammation (activity) subsides, then chronic inflammation regresses

• Mucosal remodeling
• Architecture can revert to normal over time
• Corollary: The longer the quiescent period, the more “normal” the mucosa becomes
Fulminant ulcerative colitis mimics Crohn disease: Deep fissuring ulcers in abdominal colon

Lymphoid inflammation confined to ulcers

 Granulomatous Inflammation
of Ulcerative Colitis
•20% of ulcerative colitis
cases
•Usually related to crypt
rupture
•Other etiologies
• Barium
• Particulate matter
• Infections
• Drugs
 Mucin granuloma of ulcerative colitis

Crohn granuloma
Be careful diagnosing Crohn disease based on pericryptal granulomata

Granulomata containing mixed inflammatory cells are a clue to ruptured crypts, not Crohn disease
Giant cells in the lamina propria are not helpful in subclassifying colitis
 Backwash ileitis of ulcerative colitis

Mild inflammation generally allowed if distal few centimeters of ileum

Non-classic features of ulcerative colitis: bad ileitis

Looks sort of like ulcerative colitis in the ileum

 Non-Classic Features of Ulcerative Colitis
”Backwash Ileitis” Probably Isn’t Backwash
•May not have severe pancolitis (no reflux of luminal
inflammation)
•Possible etiologies
• Bowel preparation or medications, especially NSAIDs
• Stasis secondary to decreased colonic motility
• Bacterial overgrowth
• Infection
• Ischemia
• Involvement of ileum by ulcerative colitis
•Not associated with IPAA complications
Patil, et al. Am J Gastroenterol 2017; 112(8): 1211-1214.
Chronic, focally active gastritis in 30% of ulcerative colitis patients

Lin, et al. Am J Surg Pathol 2010; 34(11): 1672-1677

Ulcerative colitis: Diffuse duodenitis

Usually following colectomy, associated with pouchitis

 Non-Classic Features of Ulcerative
Colitis
•Ulcerative colitis can show rectal sparing, especially in
early phases or with therapy
•Ulcerative colitis may show mural inflammation, especially
in fulminant colitis
•Ulcerative colitis can show granulomatous inflammation
related to ruptured crypts
•Ulcerative colitis is usually confined to colon, but limited
ileal involvement with ulcers can be present
•Ulcerative colitis can involve upper GI tract
DIFFERENTIAL DIAGNOSIS OF
CHRONIC COLITIS
 Case 1

60-year-old man with severe diarrhea; rule out IBD (colonoscopy showed mildly congested colonic mucosa)
 Neutrophils

Minimal basal plasma cells

Patient taking olmesartan; symptoms and changes resolved when drug discontinued
 Medications that Mimic Idiopathic
Inflammatory Bowel Disease
•Olmesartan (causes sprue-like lesions as well)
•Ipilimumab
• Monoclonal antibody to CTLA-4 (regulates cytotoxic T-cells)
• Treatment of melanoma
•Idelalisib
• Targets phosphatidylinositol-3-kinase δ
• Low-grade lymphoma and leukemia
•Emerging evidence regarding immune checkpoint
inhibitors (pembrolizumab and related compounds)
Ipilimumab-induced colitis
Ipilimumab-induced colitis
Ipilimumab-induced colitis with pseudopolyps

Be careful with new diagnoses of IBD in cancer patients; check medication list
Ipilimumab-induced colitis

Crypt cell apoptosis

Minimal basal plasmacytosis

 •70-year-old woman
Case 2 complained of 3
weeks of diarrhea
Fibrinous exudates over ulcers
following augmentin
therapy for a dental
procedure
•Presumed antibiotic-
Loss mucosal folds associated diarrhea
•No response to
metronidazole and
Terminal ileum
vancomycin
•Negative C. difficile
assay
Terminal ileum

Ulcers with granulation tissue

Lamina propria inflammation

 Pyloric metaplasia

Terminal ileum
 Ulcers with granulation tissue

Terminal ileum
 Follow-Up

•Patient started treatment with prednisone and

6-mercaptopurine for presumed Crohn disease
•Initial improvement of symptoms and return to
normal stools
•Developed pain with defecation and found to
have an anal fissure at 4 weeks
•New onset bloody diarrhea during steroid taper
Sigmoid colon biopsy

Crypt architectural distortion with patchy inflammation

Sigmoid colon biopsy

Cryptitis with increased lamina propria cellularity

 Sigmoid colon biopsy

Cryptitis

Architecturally distorted crypts

 Fibrin thrombus

Fibrin thrombi

Look for CMV

CMV inclusions
 Follow-Up
• Email notification that the case would be discussed at a multi-
disciplinary teaching conference
• Presumably to discuss CMV complication of IBD treatment
• During presentation, it was noted that the clinical course was
complicated by Pneumocystis jiroveci pneumonia
• Unbeknownst to us, an immunology expert from another
institution was in the audience, PowerPoint presentation in hand
• The gastroenterologist was surprisingly interested in the
pathology presentation that followed
We call this a set up
No plasma cells
 Follow-Up
•Patient had common variable immunodeficiency
•No detectable B-cells, no immunoglobulin,
negative titers to mumps, diphtheria, and
tetanus
•Exacerbations
•Augmentin therapy
•Corticosteroids may have played a role in anal
fistula and likely precipitated CMV
Common Variable Immunodeficiency
•Immunodeficiency resulting from failed plasma cell
maturation
•Upper GI tract involvement mimics celiac disease and
produces symptoms of malabsorption
•Involvement of the lower GI tract closely simulates
features of inflammatory bowel disease
• Patchy distribution with ileal involvement mimics Crohn disease
• Diffuse inflammation simulates ulcerative colitis
• Lymphocytic colitis- or collagenous colitis-like pattern of injury
Common variable immunodeficiency

Patchy inflammation simulates Crohn disease

Common variable immunodeficiency Crohn disease

Plasma cells

More plasma cells

Peri-cryptal granulomatous inflammation simulates Crohn disease

Prominent apoptotic debris in crypts Granulomatous inflammation and apoptotic debris

Rare plasma cells (fewer than expected for IBD) Common variable immunodeficiency
Mimics of Inflammatory Bowel Disease
Common Variable Immunodeficiency
•Plasma cells are always numerous in active IBD;
if hard to find, think of alternative diagnosis
•CMV causes colitis in IBD patients, but can
suggest an alternative diagnosis, especially if
mucosa is minimally inflamed
•Apoptosis is not a striking feature of IBD and
should prompt evaluation for CVID, viruses, or
other conditions
 Case 3
•35-year-old woman with prior diagnosis of Crohn
disease limited to the right colon
•Uveitis
•Intermittent oral ulcers
•Demyelinating peripheral neuropathy
•Severe sacroiliitis and large joint arthritis
•HLA-B27 negative
Biopsies of chronically inflamed granulation tissue and ulcer
Right colectomy for severe bleeding despite high-dose adalimumab (Humira) therapy

Multiple giant ulcers with intervening normal mucosa

Ulcers with superficial lymphoplasmacytic inflammation and sparing of deep bowel wall

Normal mucosa

Not the pattern of Crohn disease

Dense inflammation confined to ulcers

Inflammation tracking down vessels

Striking lymphohistiocytic phlebitis with relative arterial sparing
Dense lymphocytic inflammation around veins and venules
 What Is This?
• Probably not Crohn disease
• Disease confined to right colon
• Indurated ulcers without inflammation of intervening mucosa
• Superficial inflammation
• HLA-B27 negative (unlike most patients with extra-intestinal disease)
• Enterocolic lymphocytic phlebitis
• Usually limited to one organ in the gastrointestinal tract
• Venulitis with or without granulomatous inflammation
• Cured by resection
• Behcet disease
• Lymphocytic small vessel vasculitis affecting veins and venules
 Behcet Disease
• Immune-mediated disorder occuring in 2nd-4th decades of life
• Major criteria
• Ocular manifestations (uveitis, retinal vasculitis, iridocyclitis)
• Oral or genital aphthous ulcers (often relapsing)
• Pustular dermatitis, erythema nodosum
• Pathergy (exuberant reaction at sites of minor trauma)
• Other findings
• Gastrointestinal involvement with ulcers (75% ileocecal region)
• Osteoarthritis affecting large joints, especially sacroiliitis
• CNS involvement
• Frequently associated with HLA-B51
Mucosal inflammation adjacent to ulcer Normal intervening mucosa

No crypt distortion
Behcet disease

Lymphocytic venulitis
 Mimics of Inflammatory Bowel Disease
Behcet Disease
• Think about Behcet disease when many “IBD-like” extra-
intestinal manifestations are present
• Aphthous ulcers
• Uveitis
• Sacroiliitis and large joint arthritis
• Erythema nodosum, pustular dermatoses
• Features atypical for Crohn disease
• Large indurated ulcers in right colon with normal intervening
mucosa
• No mural lymphoid aggregates, strictures
• Lymphocytic vasculitis, predominantly affecting veins and venules

• Don’t make a diagnosis of IBD based on inflamed ulcer alone

 Case 4
• 66-year-old woman with diarrhea, cramps, 30
pound weight loss over 10 months
• Friable sigmoid colon with stricture
• Biopsies interpreted to show chronic colitis
 Fistulous tracts

Neuronal hypertrophy
Mural fibrosis and lymphoid aggregates Pseudopolyps
Is this Crohn disease?

Transmural lymphoid aggregates

Oops! Diverticulum associated with fistula
Pulse granuloma Fecal material
Diverticular Disease-Associated Colitis

•Obstructive symptoms and hematochezia

•Extra-intestinal manifestations
(arthropathies, pyoderma gangrenosum)
•Colitis in area affected by diverticulitis
•Ulcers, friability, strictures
•Rectal sparing
 Strictures and pseudopolyps

Diverticular disease associated colitis

Hypertrophic muscularis propria with fibrosis

Diverticular disease associated colitis

Diverticular disease associated colitis

Diffuse chronic colitis

 Cryptitis with crypt abscesses

Diverticular disease associated colitis

 Epithelioid granulomata

Diverticular disease associated colitis

 Perivascular granulomatous inflammation

Diverticular disease associated colitis

Mimics of Inflammatory Bowel Disease
Diverticular Disease-Associated Colitis
•Chronic colitis involving diverticulosis is
much more likely diverticulitis than IBD
•Virtually every feature of IBD can occur in
association with diverticular disease
•Be cautious when making a new diagnosis in
older patients, especially when there is
rectal sparing
Case 5: Young man with rectal pain and bleeding

Courtesy Dr. Laura Lamps, University of Michigan, Ann Arbor, MI

Lots of chronic inflammation and crypt architectural distortion
Chronic inflammation with plasma cells and cryptitis
Spirochete immunostain
 Syphilis
•Increasing incidence of primary and secondary syphilis in
the United States and Europe
• Rates more than doubled in 10 years
•Men affected more than women (>90% of reported cases) in
the United States
• 229/100,000 MSM population
• 1/100,000 women and congenital cases (constant level)
• Often occurs in patients co-infected with HIV (20-70%)
•Anorectal and gastric disease most common sites of GI
infection
 Syphilis: dense plasma cell-rich inflammation with minimally branched crypts

Courtesy Dr. Laura Lamps, University of Michigan, Ann Arbor, MI

Syphilis: plasma cell-rich inflammation with disproportionately less crypt injury and cryptitis
 Chlamydia trachomatis

•Increasing incidence in western countries

•Most (>95%) cases in men who have sex with
men
•Frequent (>80%) concomitant infection with
HIV
 Chlamydia

Plasma cell-rich inflammation with preserved crypt architecture and minimal crypt destruction
 Syphilis Chlamydia

Syphilis and Chlamydia are histologically indistinguishable; both should be mentioned in differential diagnosis
 Syphilis: Plasma cell-rich perivascular inflammation with fibrosis in mucosa and submucosa

Not much crypt distortion

Courtesy Dr. Joel Greenson, University of Michigan, Ann Arbor, MI

Syphilis: peri-cryptal and mucosal fibrosis (rare in IBD)

Courtesy Dr. Laura Lamps, University of Michigan, Ann Arbor, MI

 Distinguishing syphilitic proctitis from ulcerative colitis

Macrophage-rich inflammation in deep mucosa

Courtesy Dr. Elizabeth Montgomery, Johns Hopkins University, Baltimore, MD

Distinction Between Sexually Transmitted
Infections and Inflammatory Bowel Disease
• Syphilis and Chlamydia • Ulcerative Colitis and Crohn Disease

• Superficial and deep band- • Most inflammation in the mucosa

like inflammation
• Lymphohistiocytic aggregates
• Perivascular mononuclear
cell-rich inflammation with
plasma cells
• Submucosal fibrosis
• Minimal crypt distortion
• Cryptitis, but not destructive
• Macrophages inconspicuous
(exception: Crohn-related
granulomata)
• Muscularis mucosae hypertrophic,
but intact; not fibrotic
• Crypt distortion, atrophy
• Crypt destruction with neutrophils
• Lamina propria eosinophils
 Inflammatory Bowel Disease
Take Home Points
•Features of chronic colitis change with time and
treatment, and may revert to normal
•Ulcerative colitis can show “Crohn-like” features
in biopsies
•Inflammatory bowel disease is idiopathic; always
exclude other possibilities, especially when the
story doesn’t fit