Residency · Residency · Pathology

Inflammatory Bowel Disease: Crohn vs. Ulcerative Colitis

Overview

Inflammatory bowel disease (IBD) encompasses Crohn disease (CD) and ulcerative colitis (UC), two chronic relapsing-remitting inflammatory conditions of the gastrointestinal tract. The pathologist must distinguish these entities from each other and from infectious, ischemic, and drug-induced mimics. Approximately 5 to 15 percent of cases are classified as indeterminate colitis when a definitive distinction cannot be made.

Ulcerative Colitis

Distribution Pattern

Ulcerative colitis involves the colon in a continuous, circumferential pattern that begins at the rectum and extends proximally without skip lesions. Exceptions to this rule include the cecal patch and periappendiceal inflammation that may be seen in left-sided UC. Backwash ileitis consists of mild, nonspecific, superficial, non-granulomatous ileal inflammation occurring in the setting of pancolitis. The disease is classified by extent: proctitis, left-sided colitis, or pancolitis.

Histologic Features -- Active Disease

The hallmark feature is crypt architectural distortion, manifesting as crypt branching, shortening, irregularity, and dropout. Diffuse chronic inflammation produces dense basal lymphoplasmacytosis, with plasma cells accumulating between crypt bases and the muscularis mucosae. Basal plasmacytosis is the earliest and most reliable feature in new-onset UC, often present before architectural distortion develops. Active inflammation manifests as cryptitis (neutrophils infiltrating crypt epithelium) and crypt abscesses (neutrophils filling crypt lumina). Mucin depletion results from goblet cell loss with decreased mucin production. Surface epithelial damage produces erosions and ulceration, but these are limited to the mucosa and submucosa. Paneth cell metaplasia (Paneth cells in the left colon, where they are not normally found) is a marker of chronic injury. Pseudopolyps (inflammatory polyps) form from residual inflamed mucosa between ulcerated areas.

Histologic Features -- Quiescent/Treated Disease

In quiescent disease, persistent crypt architectural distortion may be the only remaining finding. Additional features include crypt atrophy and decreased crypt density, Paneth cell metaplasia in the left colon, resolution of active inflammation (no neutrophils), and a smooth or atrophic mucosal surface.

Dysplasia in UC

Dysplasia develops in longstanding disease, typically after 8 or more years. Risk is increased with pancolitis, primary sclerosing cholangitis, and family history of colorectal cancer. Low-grade dysplasia shows pencillate hyperchromatic nuclei with pseudostratification and preserved architecture, with nuclei not reaching the luminal surface. High-grade dysplasia shows marked atypia, loss of polarity, cribriform glands, and back-to-back glands. The key distinction from reactive atypia is that true dysplasia occurs in non-inflamed mucosa, while reactive changes accompany active inflammation. p53 immunohistochemistry is valuable: aberrant staining (overexpression or null pattern) supports dysplasia over reactive changes. Current terminology classifies dysplasia as polypoid versus non-polypoid, replacing the older DALM versus ALM nomenclature.

Crohn Disease

Distribution Pattern

Crohn disease can affect any site in the GI tract from mouth to anus, though the ileum and right colon are most commonly involved. Skip lesions (segmental involvement with intervening normal mucosa) are characteristic. Inflammation is transmural, extending through the full thickness of the bowel wall. Perianal disease (fissures, fistulae, abscesses) is present in 25 to 30 percent of cases. The terminal ileum is involved in approximately 70 percent of cases.

Histologic Features

Non-caseating granulomas are the most specific finding but are present in only 30 to 50 percent of biopsies (they are more frequently found in resection specimens). These are small, well-formed granulomas composed of epithelioid histiocytes and multinucleated giant cells. It is essential to distinguish them from crypt rupture granulomas (foreign body reactions to mucin from ruptured crypts, which are not specific for Crohn disease) and from infectious granulomas (tuberculosis, fungi).

The inflammation in Crohn disease is focal and patchy, unlike the diffuse pattern in UC. Aphthous ulcers (small superficial ulcers overlying lymphoid aggregates) represent the earliest lesion. Deep fissuring ulcers appear as knife-like clefts extending into the muscularis propria or serosa. Submucosal fibrosis and widening contribute to stricture formation. Transmural lymphoid aggregates are found throughout the bowel wall, especially at the serosal surface. Neural hyperplasia (thickened nerve fibers in the submucosa) and pyloric gland metaplasia in the ileum (metaplastic mucus-secreting glands replacing normal ileal mucosa) are additional features. Compared to UC, crypt architecture is relatively preserved in mucosal biopsies. Creeping fat (mesenteric fat wrapping around the bowel serosa) is a characteristic gross finding.

Distinguishing CD from UC

Indeterminate Colitis

This designation is used when features overlap and a definitive diagnosis cannot be rendered. It is typically applied to colectomy specimens showing fulminant colitis with transmural inflammation, which can occur in severe UC. Some cases are reclassified with time, additional biopsies, or clinical follow-up. The term "IBD-unclassified" is preferred for biopsy-level diagnosis, while "indeterminate colitis" is reserved for resection specimens.

Mimickers of IBD

Infectious Colitis

Acute self-limited colitis shows preserved crypt architecture (no distortion) with neutrophilic inflammation but no basal plasmacytosis. C. difficile colitis produces pseudomembranes (volcano-like eruptions of fibrin, mucin, and neutrophils). CMV colitis shows viral cytopathic effect with enlarged cells containing nuclear and cytoplasmic inclusions, and may complicate existing IBD. Amebiasis produces flask-shaped ulcers with trophozoites containing ingested red blood cells. Tuberculosis shows caseating granulomas that are AFB-positive.

Ischemic Colitis

Ischemic colitis occurs in watershed areas (splenic flexure, rectosigmoid) and produces superficial mucosal necrosis with ghost outlines of crypts, hyalinized lamina propria, hemosiderin deposition, and withered (atrophic, mucin-depleted) crypts.

Diversion Colitis

Diversion colitis occurs in defunctionalized bowel after diverting colostomy or ileostomy. It shows lymphoid follicular hyperplasia and aphthous-type ulcers, mimicking Crohn disease. Clinical history is essential for correct diagnosis.

Drug-Induced Colitis

NSAIDs can cause diaphragm strictures and focal active colitis. Immune checkpoint inhibitors can produce severe colitis mimicking IBD. Mycophenolate causes crypt apoptosis with IBD-like changes.

Dysplasia Surveillance in IBD

Surveillance should begin 8 years after diagnosis for pancolitis and 15 years for left-sided colitis. Chromoendoscopy-targeted biopsies are preferred over random 4-quadrant biopsies. All dysplasia should be confirmed by a second expert GI pathologist. Management depends on whether the dysplasia is endoscopically visible and resectable.

<image>A medical illustration comparing ulcerative colitis and Crohn disease histology. Left panel (Ulcerative Colitis): Low-power view showing diffuse mucosal involvement with marked crypt architectural distortion (branching and shortened crypts), crypt abscesses, diffuse basal lymphoplasmacytosis with plasma cells between crypt bases and muscularis mucosae, mucin depletion, and Paneth cell metaplasia in a left colonic biopsy. Inflammation is confined to mucosa and superficial submucosa. Right panel (Crohn Disease): Low-power view showing focal inflammation with a well-formed non-caseating granuloma in the lamina propria, adjacent normal-appearing mucosa (patchiness), and a deep fissuring ulcer extending into the submucosa. High-power inset shows a granuloma composed of epithelioid histiocytes and a multinucleated giant cell.</image>

<image>A medical illustration of dysplasia in inflammatory bowel disease. Panel A: Non-dysplastic UC mucosa showing crypt distortion but no cytologic atypia. Panel B: Low-grade dysplasia showing hyperchromatic pencillate nuclei with pseudostratification confined to the lower portion of the epithelium, with maintained glandular architecture. Panel C: High-grade dysplasia with full-thickness nuclear stratification, loss of polarity, cribriform architecture, and marked nuclear pleomorphism. Panel D: p53 immunostain showing diffuse strong nuclear overexpression in a dysplastic focus (left) contrasted with wild-type scattered staining in adjacent non-dysplastic mucosa (right).</image>

<image>A medical illustration of IBD mimickers. Panel A (Acute self-limited colitis/infectious): Preserved crypt architecture with neutrophilic cryptitis but no basal plasmacytosis or crypt distortion. Panel B (C. difficile colitis): Classic pseudomembrane with volcano-like eruption of fibrin, mucin, and neutrophils streaming from the surface epithelium. Panel C (CMV colitis): Enlarged endothelial cell in the lamina propria showing characteristic intranuclear owl-eye inclusion and smaller granular cytoplasmic inclusions, highlighted with CMV immunostain inset. Panel D (Ischemic colitis): Superficial mucosal necrosis with ghost outlines of crypts, hyalinized lamina propria, and withered atrophic crypts at the base.</image>

Clinical Pearls

Basal plasmacytosis is the earliest and most reliable histologic feature of new-onset UC, often present before crypt architectural distortion develops. Its absence should raise suspicion for an alternative diagnosis. Granulomas adjacent to ruptured crypts (crypt rupture granulomas) are not specific for Crohn disease and can be seen in any condition causing crypt injury; only isolated, well-formed granulomas distant from injured crypts support Crohn disease.

In fulminant colitis (toxic megacolon), UC may show transmural inflammation, deep ulceration, and even V-shaped fissures that mimic Crohn disease. The term "indeterminate colitis" should be used in resection specimens when this occurs. Biopsies from IBD patients with refractory or worsening colitis should always be examined for CMV inclusions, especially if the patient is immunosuppressed; CMV immunohistochemistry is more sensitive than H&E for detection.

A new diagnosis of IBD in a patient over age 60 should prompt consideration of ischemic colitis, segmental colitis associated with diverticulosis, and drug-induced colitis before labeling as true IBD. p53 immunohistochemistry is valuable in distinguishing true dysplasia from reactive epithelial changes in inflamed IBD mucosa, with aberrant staining (diffuse overexpression or complete loss) favoring dysplasia.

References

• Odze RD, Goldblum JR. Odze and Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 4th ed. Elsevier; 2023.
• Magro F, et al. European consensus on the histopathology of inflammatory bowel disease. J Crohns Colitis. 2013;7(10):827-851.
• Riddell RH, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol. 1983;14(11):931-968.
• Laine L, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastroenterology. 2015;148(3):639-651.
• DeRoche TC, et al. Histological evaluation in ulcerative colitis. Gastroenterol Rep. 2014;2(3):178-192.

Read this lecture as Markdown