Definition/General
Introduction:
Crohn disease is a chronic transmural inflammatory bowel disease that can affect any part of the GI tract
Terminal ileum is most commonly involved (80-90%)
Characterized by skip lesions and non-caseating granulomas
Part of inflammatory bowel disease (IBD) spectrum.
Origin:
Results from abnormal immune response to intestinal microbiota in genetically susceptible individuals
Dysregulated T-helper cell response
Defective barrier function
Environmental triggers in genetically predisposed patients.
Classification:
Ileocolonic (most common, 45%)
Small bowel only (30%)
Colonic only (20%)
Upper GI (5%)
Perianal disease
Montreal classification: Age, Location, Behavior (inflammatory, stricturing, penetrating).
Epidemiology:
Peak incidence in 2nd-3rd decades
Bimodal distribution (20s and 50s)
Higher prevalence in developed countries
Jewish population higher risk
Family history positive in 10-20%
Rising incidence in developing countries.
Clinical Features
Presentation:
Cramping abdominal pain (RLQ most common)
Diarrhea (bloody or non-bloody)
Weight loss and malnutrition
Fever (low-grade)
Fatigue and weakness
Perianal symptoms (fistulas, abscesses).
Symptoms:
Right lower quadrant pain
Chronic diarrhea (3-6 months)
Significant weight loss (>10% body weight)
Growth retardation (pediatric cases)
Iron deficiency anemia
Protein-energy malnutrition
B12 deficiency (terminal ileum involvement).
Risk Factors:
Genetic factors (NOD2/CARD15, IL23R mutations)
Family history of IBD
Jewish ancestry
Smoking (worsens disease)
Western diet (high fat, low fiber)
Stress
NSAID use
Appendectomy (protective).
Screening:
Colonoscopy with ileoscopy
CT/MR enterography
Small bowel follow-through
Capsule endoscopy
Inflammatory markers (CRP, ESR)
Calprotectin (stool)
Serological markers (ASCA, pANCA).
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Gross Description
Appearance:
Transmural thickening of bowel wall
Cobblestone appearance of mucosa
Skip lesions with intervening normal mucosa
Linear ulcers and fissures
Creeping fat (mesenteric fat wrapping)
Strictures and stenosis.
Characteristics:
Thickened, rubbery bowel wall
Narrow lumen in chronic cases
Deep fissuring ulcers
Serosa dull and thickened
Lymph node enlargement
Abscess formation possible.
Size Location:
Terminal ileum involved in 80-90%
Ileocecal valve commonly affected
Skip lesions throughout small bowel
Segmental involvement characteristic
Strictures 2-10 cm in length.
Multifocality:
Multifocal disease characteristic
Skip lesions pathognomonic
Discontinuous involvement
Fistula formation to adjacent organs
Perianal disease in 30-50%.
Microscopic Description
Histological Features:
Transmural inflammation (hallmark feature)
Non-caseating epithelioid granulomas (60-70% cases)
Chronic inflammatory infiltrate
Crypt architecture distortion
Fissuring ulceration
Neural hyperplasia
Lymphoid aggregates.
Cellular Characteristics:
Mixed inflammatory infiltrate: lymphocytes, plasma cells, macrophages, neutrophils
Epithelioid cells in granulomas
Multinucleated giant cells
Increased intraepithelial lymphocytes
Paneth cell hyperplasia
Goblet cell depletion.
Architectural Patterns:
Transmural distribution of inflammation
Submucosal and subserosal involvement
Lymphoid aggregates in submucosa
Neural proliferation
Fibrosis in chronic cases
Fistulous tracts
Muscular hypertrophy.
Grading Criteria:
No standardized grading system
Activity assessment: neutrophilic infiltration, crypt abscesses, surface erosions
Chronicity features: architectural distortion, basal plasmacytosis, granulomas
Complications: strictures, fistulas, dysplasia.
Immunohistochemistry
Positive Markers:
CD68 (macrophages in granulomas)
CD3 (T lymphocytes)
CD20 (B lymphocytes)
Lysozyme (Paneth cells)
S-100 (neural hyperplasia)
Ki-67 (increased proliferation).
Negative Markers:
Generally not required for diagnosis
CMV immunostain (negative, excludes viral colitis)
HSV immunostain (negative)
Mycobacterial stains (negative in granulomas).
Diagnostic Utility:
CD68 highlights epithelioid cells in granulomas
CMV/HSV stains exclude infectious causes
Ki-67 shows increased mucosal proliferation
Neural markers demonstrate neural hyperplasia.
Molecular Subtypes:
NOD2/CARD15 mutations (15-20% patients)
IL23R polymorphisms
ATG16L1 variants
IRGM gene associations
Microbiome alterations.
Molecular/Genetic
Genetic Mutations:
NOD2/CARD15 mutations (strongest genetic association)
IL23R polymorphisms
ATG16L1 variants (autophagy pathway)
IRGM mutations
PTPN22 variants
DLG5 gene polymorphisms
Over 160 susceptibility loci identified.
Molecular Markers:
Increased TNF-α production
IL-12/IL-23 pathway activation
Defective autophagy
Altered barrier function
Dysregulated innate immunity
Th1/Th17 response predominance.
Prognostic Significance:
Granulomas associated with better response to anti-TNF therapy
Perianal disease indicates worse prognosis
Stricturing/penetrating behavior progressive complications
Early age onset more aggressive course
Smoking worsens prognosis.
Therapeutic Targets:
Anti-TNF agents (infliximab, adalimumab)
Anti-integrin therapy (vedolizumab)
IL-12/23 antagonists (ustekinumab)
JAK inhibitors
Corticosteroids (acute flares)
Immunomodulators (azathioprine, methotrexate).
Differential Diagnosis
Similar Entities:
Ulcerative colitis
Infectious ileitis (Yersinia, Campylobacter)
Tuberculosis
NSAID enteropathy
Ischemic bowel disease
Lymphoma
Behçet disease.
Distinguishing Features:
Crohn disease: Transmural, granulomas, skip lesions
UC: Mucosal, continuous, crypt abscesses
TB: Caseating granulomas, AFB positive
Yersinia: Acute, self-limited, culture positive
NSAID: Diaphragm-like strictures, drug history.
Diagnostic Challenges:
Distinguishing from intestinal tuberculosis (endemic areas)
Separating acute vs chronic ileitis
Identifying early disease without granulomas
NSAID-induced enteropathy overlap
Infectious triggers vs primary IBD.
Rare Variants:
Microscopic (focal) Crohn disease
Crohn disease of stomach/duodenum
Granulomatous gastritis
Perianal Crohn disease
Crohn colitis mimicking UC.
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
[location] biopsy/resection, [number] pieces
Inflammation
Transmural chronic inflammation with [activity level]
Granulomas
Non-caseating epithelioid granulomas: [present/absent]
Activity
Activity: [inactive/mild/moderate/severe] - based on neutrophilic infiltration
Complications
Complications: [stricture/fistula/abscess/dysplasia - if present]
Diagnosis
Features consistent with Crohn disease, [active/inactive], [location]