Definition/General
Introduction:
Crohn disease (CD) is a chronic inflammatory bowel disease characterized by transmural inflammation that can affect any part of the gastrointestinal tract
Shows discontinuous involvement with skip lesions
Demonstrates granulomatous inflammation in 60-70% cases
Associated with strictures, fistulas, and abscesses.
Origin:
Results from aberrant immune response to environmental triggers in genetically susceptible individuals
Shows Th1/Th17 mediated inflammation
Involves defective innate immunity
Demonstrates bacterial translocation and loss of epithelial barrier function
Associated with NOD2/CARD15 mutations.
Classification:
Location-based: Ileocolonic (most common, 50%)
Small bowel only (30%)
Colonic only (20%)
Behavior: Non-stricturing, non-penetrating (B1)
Stricturing (B2)
Penetrating (B3)
Perianal disease (p modifier).
Epidemiology:
Peak incidence at 20-40 years
Equal gender distribution
Higher incidence in developed countries
Increasing prevalence in India
Strong genetic component (concordance in twins 50%)
Environmental triggers important
Smoking worsens disease.
Clinical Features
Presentation:
Abdominal pain (crampy, right lower quadrant)
Diarrhea (less bloody than UC)
Weight loss
Fatigue and malaise
Fever
Perianal disease (fistulas, abscesses)
Extraintestinal manifestations.
Symptoms:
Chronic diarrhea (85% cases, less bloody)
Abdominal pain (crampy, postprandial)
Weight loss (60% cases)
Fever (40%)
Perianal symptoms (30% - fistulas, abscesses, tags)
Arthralgia
Skin lesions
Growth retardation in children.
Risk Factors:
Genetic susceptibility (NOD2, ATG16L1, IRGM)
Family history (15-20% cases)
Smoking (doubles risk)
Westernized diet
Urban environment
NSAID use
Stress
Oral contraceptives.
Screening:
Colonoscopy with ileoscopy
CT/MR enterography for small bowel
Capsule endoscopy for small bowel assessment
Fecal calprotectin for monitoring
CRP and ESR for activity
Serum ASCA antibodies.
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Gross Description
Appearance:
Skip lesions with normal intervening mucosa
Cobblestone appearance due to linear ulcers and mucosal edema
Aphthous ulcers (early lesions)
Deep fissuring ulcers
Strictures and wall thickening
Creeping fat (mesenteric fat wrapping).
Characteristics:
Transmural inflammation
Bowel wall thickening (>3mm)
Narrowed lumen due to strictures
Fistulous tracts and abscesses
Serosal involvement
Lymphadenopathy common.
Size Location:
Terminal ileum involved in 80% cases
Ileocolonic disease (50%)
Right-sided colonic predominance
Panenteric involvement possible
Perianal disease in 30% cases
Small bowel length variable involvement.
Multifocality:
Discontinuous disease (skip lesions characteristic)
Multiple involved segments
Normal mucosa between diseased areas
Asymmetric involvement
Rectal sparing common (unlike UC).
Microscopic Description
Histological Features:
Transmural chronic inflammation
Non-caseating granulomas (60-70% cases)
Lymphoid aggregates
Fissuring ulceration
Submucosal fibrosis
Neural hyperplasia
Focal cryptitis.
Cellular Characteristics:
Epithelioid granulomas with multinucleated giant cells
Lymphocytes and plasma cells
Increased eosinophils
Neutrophils in acute phases
Histiocytes
Fibroblasts in chronic areas.
Architectural Patterns:
Transmural lymphoid aggregates
Submucosal granulomas (pathognomonic)
Fissuring ulcers extending deep
Crypt architectural distortion (less than UC)
Pyloric gland metaplasia
Neural hyperplasia.
Grading Criteria:
Quiescent disease: granulomas without active inflammation
Mild activity: focal cryptitis
Moderate activity: ulceration, increased inflammation
Severe activity: extensive ulceration, abscess formation
Granuloma presence supports diagnosis regardless of activity.
Immunohistochemistry
Positive Markers:
CD68 highlights epithelioid cells in granulomas
CD3/CD20 shows lymphoid aggregates
Lysozyme positive in histiocytes
α1-antitrypsin in macrophages
Ki-67 in active areas.
Negative Markers:
Mycobacterial stains (AFB) negative
Fungal stains (GMS, PAS) negative
CMV immunostain negative
HSV immunostain negative
Helps exclude infectious granulomatous colitis.
Diagnostic Utility:
CD68 highlights granulomas better
Infectious stains exclude mycobacteria, fungi
Not required for diagnosis usually
p53 and Ki-67 in dysplasia surveillance
Exclude specific infections.
Molecular Subtypes:
No specific molecular subtypes
Fibrostenosing phenotype vs inflammatory phenotype
Response to anti-TNF variable
NOD2 mutations associated with ileal disease.
Molecular/Genetic
Genetic Mutations:
NOD2/CARD15 mutations (15% patients, 40% genetic risk)
ATG16L1 mutations (autophagy pathway)
IRGM mutations (immunity-related GTPase)
IL23R polymorphisms
PTPN22 variants
Over 200 susceptibility loci identified.
Molecular Markers:
Increased TNF-α
IL-17 and IL-23 pathway activation
Th1/Th17 cytokines
Defective autophagy
Epithelial barrier dysfunction
Calprotectin elevation.
Prognostic Significance:
Granulomas presence may predict better response
NOD2 mutations predict stricturing disease
Early age onset more aggressive
Perianal disease indicates severe phenotype
Smoking worsens prognosis.
Therapeutic Targets:
Anti-TNF therapy (infliximab, adalimumab, certolizumab)
Anti-integrin (vedolizumab, natalizumab)
Anti-IL12/23 (ustekinumab)
JAK inhibitors
Immunosuppressives (azathioprine, methotrexate, cyclosporine).
Differential Diagnosis
Similar Entities:
Ulcerative colitis - continuous involvement, rectal involvement, no granulomas
Infectious granulomatous colitis - mycobacteria, yersinia, histoplasma
Ischemic colitis - watershed areas, older age
Diverticulitis - sigmoid predominance
Appendicitis - terminal ileal involvement.
Distinguishing Features:
Ulcerative colitis: continuous disease, rectal involvement, crypt abscesses
Infectious colitis: organisms identified, acute onset
Tuberculous colitis: caseating granulomas, AFB positive
Ischemic colitis: ghost cells, hyalinized stroma
Diverticulitis: diverticular involvement, older patients.
Diagnostic Challenges:
Granulomas absent in 30-40% cases
Early disease may lack transmural features
Distinguishing from UC (indeterminate colitis 10%)
Infectious superimposition
NSAID-induced changes.
Rare Variants:
Microscopic (focal) Crohn disease
Granulomatous gastritis
Crohn disease of appendix
Metastatic Crohn disease (cutaneous granulomas)
Pediatric Crohn disease.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Colorectal biopsies from [sites], [number] fragments
Diagnosis
Chronic active colitis consistent with Crohn disease
Activity Grade
[Quiescent/Mild/Moderate/Severe] inflammatory activity
Histological Features
Shows transmural chronic inflammation with [granulomas present/absent] and focal cryptitis
Granulomas
Non-caseating epithelioid granulomas: [present/absent] in [location]
Special Studies
AFB stain: negative, GMS stain: negative
No molecular testing indicated
Infectious organisms excluded
Differential Diagnosis
Features consistent with Crohn disease. Infectious causes excluded.
Final Diagnosis
Crohn disease, [activity grade], [granulomas present/absent]