Background

This is one half of inflammatory bowel disease, its partner is ulcerative colitis. The presenting symptoms are varied including fever, mild diarrhea, and abdominal pain. The attacks may be episodic lasting weeks to months. Bleeding, especially in patients with colon involvement, may occur. Crohn's disease differs from ulcerative colitis in being able to involve the entire gastrointestinal tract from mouth to anus. In addition, a number of organ systems may be involved (see clinical presentations).

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
SYNONYMS	Terminal ileitis, Regional enteritis, Granulomatous colitis, Crohn's colitis, inflammatory bowel disease
INCIDENCE	3/100,000 in USA
Clinical features of Crohn's disease: a clinical study of one hundred patients found in an unselected population. Kangas E, Matikainen M, Auvinen O, Harju E, Inkovaara J, Maki M.	Int Surg 1986 Oct-Dec;71(4):256-9 Abstract quote One hundred patients (mean age 34 years, range from 12 to 70 years) were treated at Tampere University Hospital during the thirteen year period, 1972-1984. Our hospital takes responsibility for the treatment of patients with Crohn's disease found in an unselected population of 400,000 inhabitants. In 73% of cases Crohn's disease was diagnosed before the age of forty. The mean interval between the first clinical signs and the diagnosis was 3.3 years. In 57% of the patients the diagnosis was reached within one year. In nine patients the primary diagnosis was colitis ulcerosa. Most patient were anemic and were in the state of inflammation and/or catabolism suggested by low blood hemoglobin concentration and high ESR and CRP values on admission. Three percent of the patients had macroscopic Crohn's disease in all parts of the gastrointestinal tract, whereas 22% had it only in the small intestine and 18% only in the colon. Fifty of the hundred patients had lesions in the terminal ileum and 20% in the anus. The specific finding for the present series was a high frequency of rectal lesions, in 29% of the patients. Histologically the condition was more often (P less than 0.001) revealed by the laparatomy specimen than the endoscopic biopsy, which gave a positive histology more often (P less than 0.001) in the lower than in the upper gastrointestinal tract. No gastrointestinal malignancies were found.
AGE-RANGE AND MEDIAN	Peak 2-3rd decades Minor peak in 6-7th decades
SEX (MALE:FEMALE)	Females slightly more common
GEOGRAPHIC DISTRIBUTION	Whites:Nonwhites 2-5:1
Smoking
Jewish ethnicity

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
CALCIPHYLAXIS
Calciphylaxis in a patient with Crohn's disease in the absence of end-stage renal disease. Barri YM, Graves GS, Knochel JP. Department of Medicine, Presbyterian Hospital of Dallas, TX 75231, USA.	Am J Kidney Dis 1997 May;29(5):773-6 Abstract quote Calciphylaxis is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small and medium-sized vessel calcification previously described in patients with end-stage renal disease and hyperparathyroidism. Early diagnosis may be important in improving the poor outcome in these patients since early intervention may forestall the development of life-threatening complications. We describe a patient with Crohn's disease complicated by short-bowel syndrome and modest renal insufficiency (not requiring renal replacement therapy) who developed calciphylaxis. It appears that longstanding Crohn's disease and the short-bowel syndrome accelerated the development of calciphylaxis as the chronic renal disease was not end stage. Considering the possibility of calciphylaxis in this setting may avoid delaying the diagnosis and its consequences.
LUPUS ERYTHEMATOSUS
Fatal evolution of systemic lupus erythematosus associated with Crohn's disease. Chebli JM, Gaburri PD, de Souza AF, Dias KV, Cimino KO, de Carvalho-Filho RJ, Lucca FA. Division of Gastroenterology, Department of Medicine, Juiz de Fora University, School of Medicine, Juiz de Fora, MG, Brazil.	Arq Gastroenterol 2000 Oct-Dec;37(4):224-6 Abstract quote The authors describe the case of a young Brazilian woman who was treated of ileocolonic Crohn's disease sparing rectum, as confirmed by colonoscopy and histopathological examination. After a 4-year course of sulfasalazine treatment, she presented with skin facial lesions in vespertilio, fever, arthralgias and high titers of anti-ANA and LE cells. A sulfasalazine-induced lupus syndrome was diagnosed, because after sulfasalazine withdrawal and a short course of prednisone, the clinical symptoms disappeared and the laboratory tests returned to normal. Mesalazine 3 g/day was started and the patient remained well for the next 3 years, when she was again admitted with fever, weakness, arthralgias, diplopy, strabismus and hypoaesthesia in both hands and feet, microhematuria, haematic casts, hypocomplementemia and high titers of autoimmune antibodies. A diagnosis of associated systemic lupus erythematosus was made. Although a pulsotherapy with methylprednisolone was started, no improvement was noticed. A cyclophosphamide trial was tried and again no positive results occurred. The patient evolved to severe clinical manifestations of general vasculitis affecting the central and peripheral nervous system and lungs, having a fatal evolution after 2 weeks. Although uncommon, the association of both disease may occur, and the authors call attention to this possibility, making a brief review of literature.
PSORIASIS
Connections between psoriasis and Crohn's disease. Najarian DJ, Gottlieb AB. University of Virginia School of Medicine, and the Clinical Research Center, University of Medicine and Dentistry of New Jersey-The Robert Wood Johnson Medical School.	J Am Acad Dermatol. 2003 Jun;48(6):805-21. Abstract quote The prevalence of psoriasis in patients with Crohn's disease (CD) is higher than chance would allow if they were mutually exclusive diseases. A close examination reveals genetic and pathologic connections between these diseases. An appreciation for the role of tumor necrosis factor-alpha in both diseases has proven very important. Increased levels of this inflammatory cytokine have been measured in CD lesions, and in 1997 a clinical trial demonstrated the response of this disease to infliximab, a monoclonal antibody specific for tumor necrosis factor-alpha. A subsequent clinical trial evaluated infliximab in a patient with CD and psoriasis, another disease in which increased levels of tumor necrosis factor-alpha are seen in lesions. Scientists noticed the marked skin improvement of this patient and later demonstrated the efficacy of infliximab for psoriasis in a randomized, double-blind, placebo-controlled trial. Thus, an appreciation for connections between psoriasis and CD can suggest novel therapeutic strategies with ensuing benefits to patients. This article reviews epidemiologic, genetic, and pathologic connections between psoriasis and CD and discusses pharmaceuticals targeting inflammatory mediators common to each disease. (J Am Acad Dermatol 2003;48:805-21.) Learning objective: At the completion of this learning activity, participants should understand how psoriasis and Crohn's disease are related at epidemiologic, genetic, and pathological levels and should appreciate how to use this knowledge to treat these diseases.

 

PATHOGENESIS	CHARACTERIZATION
GENERAL
Morphology of colorectal lymphoid aggregates in cancer, diverticular and inflammatory bowel diseases. Nascimbeni R, Fabio FD, Betta ED, Mariani P, Fisogni S, Villanacci V. 1Cattedra di Chirurgia Generale of the University of Brescia, Brescia, Italy.	Mod Pathol. 2005;18:681-685 Abstract quote   The present study compares the characteristics of colorectal lymphoid aggregates in patients with carcinoma, diverticular disease, Crohn's disease, or ulcerative colitis of the large bowel. A total of 77 patients (41 colorectal cancer, 27 diverticular disease, six ulcerative colitis, three Crohn's disease) undergoing colorectal resection were included. Acetic acid staining, hematoxylin and eosin staining, CD3, CD20, and MIB1 immunostaining were employed in order to assess density, diameter, subepithelial or basal location, cellular profile, and proliferation of lymphoid aggregates in normal-appearing and actively inflamed large bowel. In normal-appearing tissue, mean density of lymphoid aggregates was lower in patients with ulcerative colitis and Crohn's disease than in those with colorectal cancer or diverticular disease. A larger mean diameter of aggregates was observed in patients with Crohn's disease. In inflammatory bowel diseases, a marked increase of the mean density of lymphoid aggregates was observed in actively affected specimens. In Crohn's disease more than in ulcerative colitis, the aggregates had a predominant basal or transmural distribution. In diverticular disease, active inflammation determined a less significant increase of subepithelial aggregates harboring a lower proportion of germinal centers. No significant variations of CD3, CD20, and MIB1 were recorded among the four disease groups. The lymphoid aggregate derangements observed not only in the actively affected mucosa but also in the unaffected colorectal lining of patients with Crohn's disease and ulcerative colitis support a relevant involvement of lymphoid aggregate system in the pathogenesis of inflammatory bowel diseases.
Molecular Discoveries Alter Our View of Inflammatory Bowel Disease A Review From Scientific, Clinical, and Laboratory Perspectives Eric B. Staros, MD	Am J Clin Pathol 2003;;119:524-539 Abstract quote Within the past decade, knowledge of the molecular basis of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis, has advanced owing to the explosive growth of research involving the human genome. Furthermore, a shared interest between molecular biologists and clinical researchers has contributed to an emerging understanding of IBD. Nucleotide-binding oligomerization domain 2 (NOD2) belongs to an apoptotic regulatory family of genes and has been linked to CD. In addition, research into nuclear factor kappa B (NF–kappa B), the proteasome, interleukins, and tumor necrosis factor alpha has improved our understanding of IBD. Our understanding of these molecules and other scientific discoveries offers hope for new diagnostic tests and therapeutic agents. In the future, genetic markers will predict disease susceptibility, therapeutic responsiveness, and long-term sequelae of modern therapeutics. Also on the horizon, molecular markers promise to define disease heterogeneity, thereby providing a rational basis for patient-specific therapies. The molecular discoveries that are changing our views of IBD will affect the clinician, the laboratory professional, and the patient.
BACTERIAL 16S rRNA
Cutaneous manifestations of Crohn's disease, its spectrum, and its pathogenesis: intracellular consensus bacterial 16S rRNA is associated with the gastrointestinal but not the cutaneous manifestations of Crohn's disease. Crowson AN, Nuovo GJ, Mihm MC Jr, Magro C. Central Medical Laboratories, Winnipeg, Manitoba, Canada.	Hum Pathol. 2003 Nov;34(11):1185-92 Abstract quote.   The classic pathology of skin disease discontinuous from the inflamed gastrointestinal (GI) tract in patients with Crohn's disease (CD) includes pyoderma gangrenosum (PG), erythema nodosum (EN), and so-called metastatic Crohn's disease. The purpose of this study was two-fold: First, we explored the full spectrum of cutaneous lesions associated with Crohn's disease, and second, we sought to explore a potential molecular basis of the skin lesions in patients with CD. In this regard, we analyzed skin and GI tract biopsies from affected patients for the consensus bacterial SrRNA to determine whether direct bacterial infection was associated with either condition. Formalin-fixed, paraffin-embedded sections were studied and correlated to clinical presentation and histories from 33 patients with CD. Consensus bacterial RNA sequences were analyzed using an RT in situ PCR assay on both skin biopsy and GI biopsy material. The GI tract material included biopsies from 3 patients who had skin lesions and from 7 patients in whom there were no known skin manifestations. There were 8 cases of neutrophilic dominant dermal infiltrates, including pyoderma gangrenosum, 6 cases of granuloma annulare/necrobiosis lipoidica-like lesions, 5 cases of sterile neutrophilic folliculitis, 5 cases of panniculitis, 4 cases of vasculitis, 2 cases of psoriasis, 2 cases of lichenoid and granulomatous inflammation, and 1 case of classic metastatic CD. Intracellular bacterial 16S rRNA was detected in 8 of 10 tissues of active CD in the GI tract, of which 3 of the cases tested were from patients who also developed skin lesions at some point in their clinical course; in contrast, none of the skin biopsies had detectable bacterial RNA. The dermatopathological manifestations of CD discontiguous from the involved GI tract mucosa have in common a vascular injury syndrome, typically with a prominent extravascular neutrophilic and/or histiocytic dermal infiltrate. In addition, this study, the first to document in situ intracellular consensus bacterial SrRNA in the GI tract in CD, suggests that hematogenous dissemination of viable microbes is not associated with the cutaneous manifestations of this disease. Bacteria do, however, appear to play a role in bowel lesions of patients with CD.
CYTOKINES
Role of cytokines in the pathogenesis of inflammatory bowel disease. Papadakis KA, Targan SR. Division of Gastroenterology, Cedars-Sinai Medical Center, University of California, Los Angeles 90048, USA.	Annu Rev Med 2000;51:289-98 Abstract quote Recent advances in the drug treatment of inflammatory bowel disease (IBD) have paralleled our understanding of the pathophysiology of ulcerative colitis and Crohn's disease. Several proinflammatory and immune-regulatory cytokines are upregulated in the mucosa of patients with IBD, and differences and similarities in the cytokine profiles of ulcerative colitis and Crohn's disease have been elucidated. Several clinical trials involving a chimeric anti-TNF-alpha (tumor necrosis factor-alpha) antibody have shown marked clinical benefit in the majority of patients with Crohn's disease, verifying the importance of TNF-alpha in the pathogenesis of Crohn's disease. In preliminary studies, treatment with recombinant human interleukin-10 has been beneficial in Crohn's disease but not in ulcerative colitis. Future treatment of IBD may include combination or sequential cytokine and anticytokine administration in defined groups of patients based on their mucosal cytokine profiles.
Comparative Studies of the Colonic In Situ Expression of Intercellular Adhesion Molecules (ICAM-1, -2, and -3), 2 Integrins (LFA-1, Mac-1, and p150,95), and PECAM-1 in Ulcerative Colitis and Crohn's Disease Ben Vainer, M.D.; Ole Haagen Nielsen, M.D., D.M.Sc.; Thomas Horn, M.D., D.M.Sc. From the Department of Medicine M (B.V., O.H.N.), Division of Gastroenterology, Glostrup Hospital; and the Department of Pathology (T.H.), Herlev Hospital, University of Copenhagen, Denmark.	Am J Surg Pathol 2000;24:1115-1124 Abstract quote A dysregulated local immune defense with a constant influx of leukocytes provides a basis for continuous intestinal inflammation in ulcerative colitis (UC) and Crohn's disease (CD). Cell adhesion molecules are pivotal for the migration of leukocytes from the circulation toward the colonic epithelium. A study quantifying the cells expressing intercellular adhesion molecules (ICAMs), 2 integrins, and platelet–endothelial cell adhesion molecule-1 (PECAM-1) in the colon was performed to illustrate the leukocyte migration pathway in inflammatory bowel disease. Serial colonic sections (10 UC, 10 CD, and 10 controls) were stained immunohistochemically for ICAM-1, ICAM-2, ICAM-3, CD11a, CD11b, CD18, and PECAM-1. Cell adhesion molecule expression was evaluated quantitatively with reference to topographic localization. In UC, polymorphonuclear leukocytes (PMNs) in contact with the crypt epithelium and in crypt abscesses expressed CD11b. CD tissue was characterized by CD11a-, CD11c-, and ICAM-1-expressing cells. ICAM-1 was detected on endothelial cells, leukocytes, and apical parts of epithelial membranes, whereas ICAM-2 was expressed on basal epithelial membranes. Most infiltrating leukocytes expressed ICAM-3, whereas perivascular mononuclear cells expressed PECAM-1. Interestingly, the epithelial basement membrane in UC stained for CD18. In conclusion, CD11b, CD18, and ICAM-2 seem to be important for PMN transepithelial migration in UC, whereas CD11a, CD11c, ICAM-1, and ICAM-3 seem central in leukocyte locomotion and aggregation in CD. Differentiated upregulation of cell adhesion molecules is suggested to be essential for the diversities between UC and CD.
MYCOBACTERIUM
Absence of Mycobacterium avium subsp. paratuberculosis in the microdissected granulomas of Crohn's disease. Baksh FK, Finkelstein SD, Ariyanayagam-Baksh SM, Swalsky PA, Klein EC, Dunn JC. 1Department of Pathology, Lancaster General Hospital, Lancaster, PA, USA.	Mod Pathol. 2004 Oct;17(10):1289-94. Abstract quote   The etiology of Crohn's disease remains unknown with inflammatory, infectious, and/or genetic causes suspected. Granulomatous inflammation is a characteristic feature of the disorder, resembling the tissue response to mycobacterium. Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent in Johne's disease, a chronic ulcerative intestinal condition in cattle, and has been implicated as a likely candidate. We carefully microdissected the granulomas from the paraffin-embedded resection specimens of 18 patients with well-established Crohn's disease. The DNA obtained was PCR amplified for the IS900 and IS1311 repeat elements of MAP, PCR product size maintained at 101 and 124 base pairs, respectively. Archival tissue from bovine Johne's disease was used as a positive control. MAP-specific DNA, confirmed by sequencing and comparison with prototype strain sequence, was appropriately amplified from the positive control. None of the Crohn's disease cases yielded a positive amplification product, failing to support a role for the organism in the pathogenesis of this illness.
NOD2 GENE
The Nod2 gene in Crohn's disease: implications for future research into the genetics and immunology of Crohn's disease. Cho JH. Department of Medicine (GI), University of Chicago Hospitals, Illinois 60637, USA.	Inflamm Bowel Dis 2001 Aug;7(3):271-5 Abstract quote The association of the Nod2 gene on chromosome 16 with increased susceptibility to Crohn's disease holds the promise of catalyzing fundamental genetic and therapeutic advances. Coding region variants in the leucine-rich repeat region of Nod2 may affect host interactions with bacterial lipopolysaccharide. Genetic differences in pattern-recognition proteins (such as Nod2) of the innate immune system represent an increasingly important paradigm for understanding host-environment interactions. The central problem for complex disease gene identification through genome-wide searches has been that of locus heterogeneity; it is hoped that this heterogeneity will recede with the identification of Nod2, as the first pieces of a puzzle accelerate placement of subsequent pieces. The potential for genetic approaches to positively impact the treatment of Crohn's disease and ulcerative colitis is unparalleled among complex, multigenic disorders.
YERSINIA
Pathogenic yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn's disease. Lamps LW, Madhusudhan KT, Havens JM, Greenson JK, Bronner MP, Chiles MC, Dean PJ, Scott MA.	Am J Surg Pathol 2003 Feb;27(2):220-7 Abstract quote Previously, we detected pathogenic (invasive) DNA in the appendices of two patients who later developed Crohn's disease (CD). This subsequent investigation is the first to evaluate a series of specimens from CD patients for the presence of pathogenic DNA. A total of 54 intestinal resection specimens from 52 patients with confirmed CD were evaluated. Lesional tissue was tested by polymerase chain reaction analysis for the presence of genes occurring only in pathogenic Primer pairs are specific for each species, with no known cross reactions with other bacteria. Forty normal bowel specimens, 30 cases of acute appendicitis, and 50 cases of various active colitides served as disease controls. Medical records were reviewed following polymerase chain reaction and histologic evaluation. A total of 17 of 54 resections (31%) contained DNA by polymerase chain reaction. Mesenteric lymph nodes were also positive in eight of these cases. All controls were negative. -positive patients had carried the diagnosis of CD for a median of 10 years before resection (range 1 month to 40 years). We report the first documentation of DNA in a series of CD cases. Further studies are needed, including serial study, over time, of -positive CD patients, as well as prospective studies of newly diagnosed CD patients for evidence of infection. Like previous studies associating infectious organisms with CD, much work remains to elucidate whether the presence of DNA is an epiphenomenon or actually a factor in the pathogenesis of CD.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
Barium enema-radiology	String sign-characteristic narrowing of the small bowel lumen
Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup. Vasiliauskas EA, Plevy SE, Landers CJ, Binder SW, Ferguson DM, Yang H, Rotter JI, Vidrich A, Targan SR. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.	Gastroenterology 1996 Jun;110(6):1810-9 Abstract quote BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCA) have been consistently detected in a subgroup of patients with Crohn's disease (CD). This study was designed to determine whether serum ANCA expression in patients with CD characterizes an identifiable clinical subgroup. METHODS: The study population consisted of 69 consecutive patients with an established diagnosis of CD as determined by a combination of characteristic clinical, radiographic, endoscopic, and histopathologic criteria. Sera from the patients were analyzed for the presence of ANCAs using the fixed neutrophil enzyme-linked immunosorbent assay (ELISA) assay. Perinuclear ANCA (pANCA)-positive and cytoplasmic ANCA (cANCA)-positive results by ELISA were confirmed by indirect immunofluorescence staining. Clinical profiles of the ANCA-positive patients with CD were compared with those of patients with CD not expressing ANCA (ANCA-negative). RESULTS: pANCA-positive patients with CD have endoscopically and/or histopathologically documented left-sided colitis and symptoms of left-sided colonic inflammation, clinically reflected by rectal bleeding and mucus discharge, urgency, and treatment with topical agents. One hundred percent of patients with CD expressing pANCA had "UC-like" features. CONCLUSIONS: In patients with CD, serum pANCA expression characterizes a UC-like clinical phenotype. Stratification of CD by serum pANCA provides evidence of heterogeneity within CD and suggests a common intestinal mucosal inflammatory process among a definable subgroup of patients with CD and UC expressing this marker.
Tumor necrosis factor-alpha in serum of patients with inflammatory bowel disease as measured by a highly sensitive immuno-PCR. Komatsu M, Kobayashi D, Saito K, Furuya D, Yagihashi A, Araake H, Tsuji N, Sakamaki S, Niitsu Y, Watanabe N. Division of Laboratory Diagnosis, Department of Clinical Laboratory Medicine, Sapporo Medical University, School of Medicine, South-I, West-16, Chuo-ku, Sapporo 060-8543, Japan.	Clin Chem 2001;47(7):1297-301 Abstract quote BACKGROUND: The significance of serum concentrations of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of inflammatory bowel disease (IBD) is uncertain. We measured TNF-alpha in serum from IBD patients by immuno-PCR to analyze the relationship between TNF-alpha and pathophysiologic state in IBD. METHODS: Serum samples were collected from 54 healthy blood donors, 29 patients with ulcerative colitis (UC; 46 samples), and 7 patients with Crohn disease (CD; 8 samples). DNA label was generated by PCR amplification using biotinylated primer and was bound with streptavidin to biotinylated third antibody. TNF-alpha sandwiched by antibodies was detected by PCR amplification of the DNA label. RESULTS: TNF-alpha could be measured in all samples. The median serum concentration in IBD patients overall was approximately 390-fold higher than in healthy donors (median increase, 380-fold for UC, 640-fold for CD). The median serum TNF-alpha concentration was 1.7-fold higher in the active stage of UC than in the inactive stage (P <0.05), and this difference could be detected in individual patients. CONCLUSIONS: Sensitive measurement of serum TNF-alpha could provide an important pathophysiologic marker for the presence and activity of IBD.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
Site of involvement	Small intestine alone 40% Small and large intestine 30% Colon alone 30%
GASTROINTESTINAL TRACT	Characteristic skip lesions with diseased segments of bowel interspersed with normal segments, leading to cobblestone mucosa Mesenteric fat wraps around bowel forming creeping fat Intestinal wall is thickened and rubbery with narrowing of the lumen Aphthous ulcers, focal mucosal ulcers, in early disease, leading to linear ulcers Numerous fissures and sinus tract formation
Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn's disease. Ruuska T, Vaajalahti P, Arajarvi P, Maki M. Department of Clinical Medicine, University of Tampere, Finland.	J Pediatr Gastroenterol Nutr 1994 Aug;19(2):181-6 Abstract quote Eighty-eight consecutive children with inflammatory bowel disease were studied, and upper gastrointestinal endoscopy was performed in 80 of them as one of the initial investigations before commencing medical or nutritional treatment. Forty-one children were found to have Crohn's disease and 47, ulcerative colitis. Upper gastrointestinal endoscopy revealed pathology in 32 (80%) cases of Crohn's disease, esophagitis in 16, and esophageal ulcer in two, nonspecific gastritis in 22, duodenitis or duodenal ulcer in 18, and Helicobacter pylori infection in two cases. Granulomas were detected in 10 patients in the upper gastrointestinal tract: one esophageal, eight gastric, and three duodenal. Of the ulcerative colitis patients, seven had esophagitis, one had esophageal ulcer, 17 had nonspecific gastritis, two had gastric ulcers, two had duodenal ulcers, and five had H. pylori infection; altogether 30 (75%) yielded pathological findings. Radiological studies using barium meal revealed pathology in only eight of all inflammatory bowel disease cases. Symptoms at admission were not conclusive for definite diagnosis because 63% of patients with Crohn's disease had signs of colitis (such as diarrhea, bloody diarrhea) compared to 94% of ulcerative colitis patients. Upper gastrointestinal endoscopy may be used to achieve a specific diagnosis, thus being helpful when planning treatment. Also a considerable incidence of nonspecific gastritis, duodenitis, and esophagitis with or without concomitant H. pylori infection may be anticipated in children suffering from both ulcerative colitis and Crohn's disease.
EXTRAGASTRO-INTESTINAL
EYE
Uveitis
JOINTS
Migratory polyarthritis
Sacroiliitis
Ankylosing spondylitis
LIVER
Hepatic sclerosing cholangitis
LUNGS
Noninfectious lung pathology in patients with Crohn's disease. Casey MB, Tazelaar HD, Myers JL, Hunninghake GW, Kakar S, Kalra SX, Ashton R, Colby TV.	Am J Surg Pathol 2003 Feb;27(2):213-9 Abstract quote Lung involvement in Crohn's disease is not well characterized. We reviewed our experience with 11 lung biopsies (seven wedge and four transbronchial) from patients with Crohn's disease to study this association further. Negative cultures, special stains for organisms Gomori-methenamine-silver [GMS], acid fast), and polymerase chain reaction for (four cases) were required for inclusion. The group included five women and six men with a mean age of 47 years (range 13-84 years). A diagnosis of Crohn's disease preceded the lung disease in nine patients. In two patients the diagnosis of Crohn's disease followed the diagnosis of their pulmonary disease 1 and 15 months later. Radiologically, eight patients had diffuse infiltrates, two had bilateral nodular infiltrates, and one had a mass. Chronic bronchiolitis with nonnecrotizing granulomatous inflammation was present in four patients, one of whom was taking mesalamine. Two patients had an acute bronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vague granulomatous features. One patient on mesalamine had cellular interstitial pneumonia with rare giant cells. Four patients demonstrated organizing pneumonia with focal granulomatous features, two of whom were taking mesalamine, and one of these two responded to infliximab (anti-tumor necrosis factor) monoclonal antibody therapy. Noninfectious pulmonary disease in patients with Crohn's disease has variable histologic appearances, including granulomatous inflammation and airway-centered disease resembling that seen in patients with ulcerative colitis. Drugs may contribute to pulmonary disease in some patients.
SKIN	J Am Acad Dermatol 1992;26(part 2):371-383 Usually affects lower legs Trunk Groin Axilla Face, rarely
Metastatic Crohn's disease: a histopathologic study of 12 cases. Emanuel PO, Phelps RG. Division of Dermatopathology, Mount Sinai School of Medicine, New York, NY 10029, USA.	J Cutan Pathol. 2008 May;35(5):457-61. Abstract quote Perhaps, the most intriguing cutaneous sequela of Crohn's disease (CD) is 'metastatic' CD, defined as sterile granulomatous skin lesions arising at sites discontinuous from the gastrointestinal tract. Though various histopathologic patterns have been described, a lack of a large series has precluded a comprehensive characterization and distinction from the pathologic differential diagnoses. The histopathology features of 12 new cases of metastatic CD were reviewed. Non-suppurative granulomata with a slight cuff of lymphocytes in a nodular or diffuse pattern with an associated superficial and deep perivascular mixed inflammatory infiltrate was the most common pattern. Other common features included an accompanying infiltrate which was often rich in eosinophils, and ulceration of the overlying epidermis. These features are emphasized as potentially useful in distinguishing this entity from its greatest mimicker, cutaneous sarcoidosis.
Genital-cutaneous	Am J Dermatopathol 2000;22:443-446 Two patients with active Crohn's disease, one presented with erythematous nontender swelling of the scrotum and the other presenting with erythematous nontender swelling of the penis Biopsy showed mixed chronic inflammation with characteristic sarcoidal granulomas but also areas of cystic cavities within the collagen, unassociated with inflammation Genital cutaneous Crohn's may be the most common presentation in younger persons
Erythema nodosum
Clubbing of the fingertips
Granulomatous lymphangitis of the scrotum and penis Report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation Michael J. Murphy1, Barry Kogan2 and J. Andrew Carlson3 1 Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut, USA,2 Division of Urology, Albany Medical College, Albany, New York, USA,3 Divisions of Dermatology and Dermatopathology, Albany Medical College, Albany, New York, USA	Journal of Cutaneous Pathology 2001;28 (8), 419-424 Abstract quote Background: Acquired lymphedema of the genitalia is a rare childhood presentation and is more common in elderly individuals secondary to pelvic/abdomenal malignancy or its therapy or worldwide due to filariasis. Objective: Herein, we report a case of a healthy 11-year-old boy who presented with a 1-year history of chronic, asymptomatic scrotal and penile swelling. Biopsy revealed edema, lymphangiectases and peri- and intralymphatic sarcoidal type granulomas. This histologic pattern of granulomatous lymphangitis is most commonly associated with orofacial granulomatosis (granulomatous cheilitis and Melkersson-Rosenthal syndrome) and Crohn’s disease. Treatment with topical steroids and physical support has resulted in marked improvement. No systemic disease (Crohn’s disease) is evident 1 year later. Literature review revealed 44 cases of genital lymphedema with non-infectious granulomas. The majority of these young patients had Crohn’s disease, frequently with anal involvement and a minority, both with and without Crohn’s disease, had orofacial granulomatosis. Conclusions: Granulomatous lymphangitis should be considered in the differential diagnosis of chronic idiopathic swelling of the genitalia, particularly in younger individuals. Further clinical examination, additional laboratory studies and close follow-up for co-existing or subsequent development of Crohn’s disease should be performed. The overlap between granulomatous lymphangitis of the genitalia, Crohn’s disease and orofacial granulomatosis suggest that granulomatous lymphangitis of the genitalia may represent a forme fruste of Crohn’s disease.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GASTROINTESTINAL TRACT	Transmural involvement with non-caseating granulomas in about 50% of cases and patchy skip lesions, lymphoid aggregates throughout bowel wall Mucosa may show scattered crypt abscesses Architectural distortion with progressive atrophy, pyloric metaplasia, and Paneth cell metaplasia Ulceration
VARIANTS
DYSPLASIA
Hyperplastic-like mucosal change in Crohn's disease: an unusual form of dysplasia? Kilgore SP, Sigel JE, Goldblum JR. Department of Anatomic Pathology, Cleveland Clinic Foundation, Ohio 44195, USA	Mod Pathol 2000 Jul;13(7):797-801 Abstract quote Patients with Crohn's disease are at increased risk of developing intestinal adenocarcinoma. Dysplasia is both a marker and a precursor of adenocarcinoma in this setting. In a review of our cases of Crohn's-related adenocarcinoma, we noted a peculiar hyperplastic-like mucosal change (HPC) in mucosa both adjacent to and distant from the adenocarcinoma in some cases. However, the significance of this change is unknown. We evaluated 30 cases of Crohn's-related adenocarcinoma and 30 age- and site-matched resection specimens with Crohn's disease without adenocarcinoma to determine the prevalence of this mucosal alteration in these groups. HPC was recognized by a diffuse expanse of flat mucosa with an architecture resembling that seen in colorectal hyperplastic polyps and composed of cells with cytologically bland basal nuclei and apical cytoplasmic mucin distention. The relationship of the HPC to the adenocarcinoma was noted in the Crohn's-related adenocarcinoma cases. An immunohistochemical stain for p53 (antibody DO7) was performed on all cases with HPC in both groups. HPC was identified in 10 of 30 (33%) cases of Crohn's-related adenocarcinoma compared with 3 of 30 (10%) cases in the control group (P = .03). In the 10 cases of Crohn's-related adenocarcinoma with HPC, this alteration was found adjacent to the adenocarcinoma in 3 cases, distant to the adenocarcinoma in 5 cases, and both adjacent to and distal from the adenocarcinoma in 2 cases. In two specimens, HPC was seen immediately adjacent to adenocarcinoma in the absence of adjacent dysplasia. p53 immunoreactivity was noted in HPC in 5 of 10 (50%) Crohn's-related adenocarcinomas.In contrast, p53 immunoreactivity was not seen in HPC in the three control cases with this mucosal alteration. In conclusion, HPC is found significantly more commonly in mucosa both adjacent to and distant from Crohn's-related adenocarcinoma when compared with age- and site-matched controls. In addition, p53 immunoreactivity is more commonly seen in HPC in cases of Crohn's-related adenocarcinoma compared with controls. These data suggest that this mucosal alteration may, in some cases, represent an unusual form of dysplasia in this setting.
FOCALLY ENHANCED GASTRITIS
The Clinical Significance of Focally Enhanced Gastritis. Xin W, Greenson JK. Department of Pathology, University of Michigan Health System, Ann Arbor, MI.	Am J Surg Pathol. 2004 Oct;28(10):1347-1351 Abstract quote   Focally enhanced gastritis (FEG) is typified by small collections of lymphocytes and histiocytes surrounding a small group of foveolae or gastric glands, often with infiltrates of neutrophils. Several studies have found that FEG is commonly seen in Crohn’s disease patients with a positive predictive value of 94%. Additional studies have found that FEG is present in up to 20% of pediatric ulcerative colitis patients, suggesting that FEG is a marker for inflammatory bowel disease (IBD) in general. We reviewed all gastric biopsies from a single calendar year (1999) to study the incidence of FEG and its relationship to IBD. A total of 34 cases of FEG were found among 971 gastric biopsies from 927 patients. Only 4 FEG patients were found to have IBD (2 Crohn’s, 1 ulcerative colitis and 1 chronic colitis, type indeterminate, 11.8%, positive predictive value of 5.9%). Five FEG patients were status post bone marrow transplantation (14.7%). There were no other clinical correlations and gastric histopathology did not predict which patients with FEG had IBD. We conclude that FEG is not a common histologic finding in our patient population and that the positive predictive value of this finding is much too low to be thought of as a specific marker for IBD. An isolated biopsy diagnosis of FEG should not be interpreted as being suggestive of Crohn’s disease.
ILEAL EROSIONS
Isolated ileal erosions in patients with mildly altered bowel habits. A follow-up study of 28 patients. Goldstein NS. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.	Am J Clin Pathol. 2006 Jun;125(6):838-46. Abstract quote   This study evaluated 28 patients to characterize the morphologic features associated with typical Crohn disease (CD). All patients had similar complaints, an endoscopically normal colon, and small isolated, aphthoid erosions in the terminal ileum. The mean length of follow-up was 5.8 years. Of 28 patients, 25 (89%) were female (mean age, 32.3 years). Four patients were ingesting nonsteroidal anti-inflammatory drugs. All 28 lesions were morphologically similar, with focal lamina propria edema, mild active inflammation, and crypt disarray. Most had a lymphoid aggregate within the region of edema. Erosion was identified histologically in 21 cases. Following colonoscopy, symptoms resolved in all 28 patients. Typical, full-blown CD developed in 8 patients (29%) after a mean interval of 3.6 years. CD lesions were morphologically identical to non-CD lesions. Most focal ileal erosions in patients with mildly altered bowel habits are idiopathic and clinically insignificant. They represent early CD in approximately 30% of patients. The interval between initial examination and typical CD can be long. Pathologists should remain diagnostically vigilant when examining ileal biopsy specimens obtained from patients with previous abnormal ileal biopsy findings, regardless of the interval. Persistent, mild morphologic abnormalities have a high likelihood of being CD.

SPECIAL STAINS/ IMMUNO- HISTOCHEMISTRY	CHARACTERIZATION
AMACR
AMACR Immunostaining is Useful in Detecting Dysplastic Epithelium in Barrett's Esophagus, Ulcerative Colitis, and Crohn's Disease. Dorer R, Odze RD. Department of Pathology, Brigham and Women's Hospital, Boston, MA.	Am J Surg Pathol. 2006 Jul;30(7):871-877. Abstract quote   alpha-Methylacyl-CoA racemase (AMACR) catalyzes the racemization of alpha-methyl, branched carboxylic coenzyme A thioesters, and is overexpressed in a variety of neoplasms, such as prostate and colon cancer. The aim of this study was to evaluate AMACR expression in the metaplasia-dysplasia-carcinoma sequence in Barrett's esophagus (BE), ulcerative colitis (UC), and Crohn's disease (CD) and to determine whether its expression can be used to detect dysplastic epithelium in these conditions. One hundred thirty-four routinely processed biopsy and/or resection specimens from 134 patients with BE [M/F ratio: 5.7, mean age: 67 y (36 negative (intestinal metaplasia only), 14 indefinite for dysplasia (IND), 16 low-grade dysplasia (LGD), 32 high-grade dysplasia (HGD), and 36 invasive adenocarcinoma (ACA)] and 74 specimens from 74 patients with inflammatory bowel disease (IBD) [56 with ulcerative colitis, 18 with Crohn's disease, M/F ratio: 1.8, mean age: 55 y (17 negative, 7 IND, 26 LGD, 10 HGD, and 14 ACA)] were immunostained with a monoclonal AMACR antibody (p504S). The degree of cytoplasmic staining in all cases was evaluated in a blinded fashion according to the following grading system: 0, negative (0% cells positive); 1+, 1% to 10% cells positive; 2+, 10% to 50% cells positive; or 3+, >50% cells positive. In patients with BE, AMACR was not expressed in any negative foci (0%) but was significantly increased (P<0.0001) in foci of LGD (38%), HGD (81%), and ACA (72%). Three of 14 (21%) IND foci from 3 BE patients were only focally positive (grade 1: 7%, 2: 14%). However, 1 of these 3 patients had follow-up information available and had developed ACA subsequently. Similarly, in patients with IBD, AMACR was not expressed in any foci considered negative for dysplasia, but was significantly increased (P<0.0001) in foci of LGD (96%), HGD (80%), and ACA (71%). Only 1/7 (14%) IND focus from 1 patient was focally positive (grade 1). The sensitivity for the detection of LGD and HGD in BE and IBD was 38% and 81%, and 96% and 80%, respectively, for the 2 types of disorders. The specificity was 100% for both BE and IBD. AMACR is involved in the neoplastic progression in BE and IBD. The high degree of specificity of AMACR for dysplasia/carcinoma in BE and IBD suggests that it may be useful to detect neoplastic epithelium in these conditions.

 

DIFFERENTIAL DIAGNOSIS	CHARACTERIZATION
GENERAL
Biopsy diagnosis of colitis: possibilities and pitfalls. Tsang P, Rotterdam H. Department of Pathology, Cornell University Medical College, New York, New York, USA	Am J Surg Pathol 1999 Apr;23(4):423-30 Abstract quote The histopathologic diagnosis of inflammation is common in colorectal biopsies but is of limited value, if not further specified. We reviewed 280 endoscopic colorectal biopsy specimens for nonneoplastic disease from 100 consecutive patients in order to assess (a) the frequency of inflammation in excess of the physiologic infiltrate, (b) the frequency with which the cause of the inflammation could be specified, and (c) the interobserver variability in diagnosing inflammation. Based on the reviewers' impression, each case was classified into one of three categories: (I) normal or nonspecific change, (II) nonspecific inflammation, and (III) inflammation suggestive or diagnostic of specific cause. Inflammation was diagnosed in 68% of cases. The majority of these cases (75%) showed features typically associated with specific types of colitis, including Crohn's disease (n = 16), ulcerative colitis (n = 13), inflammatory bowel disease not otherwise specified (n = 5), infectious colitis (n = 6), ischemic colitis (n = 4), solitary rectal ulcer syndrome (n = 3), radiation colitis (n = 2), and lymphocytic colitis (n = 2). Interobserver variability was greatest in biopsy specimens interpreted by the reviewers as normal or showing nonspecific changes, most of which had been diagnosed as mild inflammation by the original pathologists. Etiologic classification of colitis was lacking in 59% of the cases interpreted by the reviewers as suggestive or diagnostic of a specific cause. We conclude that (a) the majority of colorectal biopsy specimens from patients with nonneoplastic disease in this series show inflammation, (b) the majority of such cases allow a specific cause of colitis to be suggested or firmly diagnosed, and (c) pathologists tend to overdiagnose the physiologic inflammatory infiltrate as evidence of colitis and underdiagnose specific etiologic types of colitis.
APPENDICITIS
Histopathology of interval (delayed) appendectomy specimens: strong association with granulomatous and xanthogranulomatous appendicitis. Guo G, Greenson JK.	Am J Surg Pathol. 2003 Aug;27(8):1147-51. Abstract quote Patients who present with a ruptured acute appendicitis are often treated with antibiotic therapy and drainage followed by a delayed or interval appendectomy. We noticed interval appendectomy specimens with granulomatous inflammation and postulated that interval appendectomy may lead to granulomatous appendicitis. To test this hypothesis, we reviewed the histopathology of all interval appendectomy specimens within a 4-year period and compared them with a control group of patients who had acute appendicitis and underwent routine acute appendectomy. All slides were randomized and reviewed blindly to assess the inflammatory patterns, with special attention given to the presence of granulomas and other Crohn-like features. Twenty-two cases of interval appendectomy were found. The interval between symptom onset and appendectomy ranged from 30 to 95 days with a mean of 58 days, whereas all 44 control patients had surgery within 72 hours of symptoms onset. Thirteen (59.1%) of the 22 interval appendectomy cases contained granulomas compared with only 3 of 44 controls (P < 0.0001). Eight (36.4%) of the interval appendectomy cases had xanthogranulomatous inflammation compared with none in the acute appendicitis group (P < 0.0001). A Crohn-like appearance was seen in 11 (50.0%) of the interval appendectomy cases and 1 of the controls (P < 0.0001). Follow-up data were available in 8 of 11 cases with Crohn-like features; none developed Crohn disease during an average follow-up period of 23 months. Delayed or interval appendectomy specimens often have a characteristic inflammatory pattern that includes granulomas, xanthogranulomatous inflammation, mural fibrosis/thickening, and transmural chronic inflammation. Without the appropriate clinical history, these changes may be misinterpreted as Crohn disease.
DIVERTICULITIS
Crohn's Colitis-Like Changes in Sigmoid Diverticulitis Specimens Is Usually an Idiosyncratic Inflammatory Response to the Diverticulosis Rather Than Crohn's Colitis Neal S. Goldstein, M.D.; Carmen Leon-Armin, B.S. (Pathology Assistant); Anju Mani, M.D. From the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI, U.S.A.	Am J Surg Pathol 2000;24:668-675 Abstract quote The clinical outcome and optimum classification of patients who have sigmoid resection specimens that show the histologic features of Crohn's disease (CD) and diverticulitis is not well defined. Historically, these patients were considered to have coexistent diseases, but recent studies have suggested that the CD-like changes are part of the inflammatory reaction of the diverticulitis. Sorting out these issues has been complicated by the lack of distinction between patients with and without CD in other regions of the bowel, short clinical follow-up periods, and small numbers of patients. We report on the clinical outcome and histology of 29 patients who had sigmoid resection specimens with diverticulitis and CD-like changes. Of the 25 patients who had no prior or concurrent CD at the time of surgery, 23 remained free of CD during the follow-up period (median, 6.0 yrs) and two developed CD in other regions of the bowel. All four patients with CD prior to their sigmoid resection continued to have active CD postoperatively. There were no histologic features of the sigmoid resection specimens that could be associated with the outcome of the patient. These results suggest that CD-like changes within the sigmoid resection specimen are an idiosyncratic inflammatory response to the diverticulosis rather than coexistent CD in the overwhelming majority of patients who do not have prior or concurrent CD at the time of sigmoid resection. Pathologists should be wary about making the diagnosis of sigmoid CD in the context of diverticulitis unless there is CD in other parts of the bowel.
FOCAL ACUTE COLITIS
The clinical significance of focal active colitis in pediatric patients. Xin W, Brown PI, Greenson JK.	Am J Surg Pathol. 2003 Aug;27(8):1134-8. Abstract quote The clinical significance of focal neutrophilic infiltrates in crypt epithelium in colorectal biopsies or focal active colitis has been studied in adult populations, but little is known about this entity in children. The incidence of Crohn's disease in adult patients presenting with focal active colitis has varied between 0% and 13% in previous studies, whereas the incidence of infectious-type colitis has been reported to be nearly 50%. We reviewed 31 cases of focal active colitis diagnosed in pediatric patients without a history of inflammatory bowel disease between 1989 and 2000. Pathologic variables studied included number and location of inflamed crypts and distribution and character of lamina propria inflammation. Clinical follow-up was obtained from patient charts. Two patients were lost to follow-up. Follow-up on the remaining 29 patients ranged from 4 months to 7 years with a mean of 4.2 years. Eight patients (27.6%) developed Crohn's disease. Nine patients (31%) appeared to have acute infectious-type colitis, one with C. difficile. Eight patients (27.6%) had focal active colitis, which did not correlate with their symptoms or ultimate clinical diagnosis. These were termed idiopathic focal active colitis. Two patients were found to have allergic colitis, one had ulcerative colitis, and one had Hirschsprung's disease. Pediatric patients with focal active colitis have a much higher incidence of Crohn's disease than adults with same entity. Hence, it is important to document the presence of focal active colitis in pediatric patients.
LYMPHOCYTIC AND COLLAGENOUS COLITIS
Focal lymphocytic colitis and collagenous colitis: patterns of Crohn's colitis? Goldstein NS, Gyorfi T. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.	Am J Surg Pathol 1999 Sep;23(9):1075-81 Abstract quote The morphologic findings in mildly active colonic Crohn's disease (CD) include crypt disarray, patchy edema, and small lymphoid aggregates with neutrophils, sometimes associated with aphthous ulcers. We describe four patients with CD whose colonic biopsies focally showed a lymphocytic colitis morphology, and one patient with CD whose biopsies showed a collagenous colitis morphology. The lymphocytic and collagenous colitis patterns of injury preceded the eventual clinical pathologic diagnosis of CD in four patients. Colonoscopic abnormalities were found in four patients. The lymphocytic colitis pattern was focal, involving some biopsy fragments, whereas other biopsy fragments were normal or had minimal nonspecific inflammation. In one patient, moderate numbers of neutrophils were admixed with the lymphoplasmacytic infiltrates. The presence of colonoscopic abnormalities, focal changes, and moderate admixed neutrophils could assist in the distinction from lymphocytic or collagenous colitis, both of which are colonoscopically normal, usually diffuse, and devoid of, or contain only a sparse number of, neutrophils. A limited number of biopsy fragments may be incorrectly interpreted as lymphocytic or collagenous colitis. The temporal relationships suggest that these morphologic patterns precede typical active CD.
NSAID COLITIS
POUCHITIS
Crohn's-like complications in patients with ulcerative colitis after total proctocolectomy and ileal pouch-anal anastomosis. Goldstein NS, Sanford WW, Bodzin JH. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48324, USA.	Am J Surg Pathol 1997 Nov;21(11):1343-53 Abstract quote Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become an established surgical procedure for ulcerative colitis. Occasional patients who have undergone IPAA develop persistent or recurrent episodes of pouchitis (chronic pouchitis), from which a subset also develop gastrointestinal and systemic complications that are identical to those seen in Crohn's disease. These complications include enteric stenoses or fistulas in the pouch or pouch inlet segment, perianal fistulas or abscesses, pouch fistulas, arthritis, iridocyclitis, and pyoderma gangrenosum. The development of Crohn's-like gastrointestinal complications in a patient with chronic pouchitis frequently engenders concern that the pathologist misinterpreted the proctocolectomy specimen as ulcerative colitis instead of Crohn's disease. We describe eight patients who developed chronic pouchitis and Crohn's-like complications after IPAA and total proctocolectomy. In each case, concern was voiced about misinterpretation of the proctocolectomy specimen as ulcerative colitis instead of Crohn's disease after the development of the Crohn's-like complications. Preoperatively, all eight patients had characteristic clinical, radiographic, and pathologic features of ulcerative colitis. Review of the pathology specimens indicated that all eight had ulcerative colitis. Crohn's-like complications are most likely related to chronic pouchitis, which probably is a form of recrudescent ulcerative colitis within the novel environment of the pouch. A diagnosis of Crohn's disease after IPAA surgery should only be made when reexamination of the original proctocolectomy specimen shows typical pathologic features of Crohn's disease, Crohn's disease arises in parts of the gastrointestinal tract distant from the pouch, pouch biopsies contain active enteritis with granulomas, or excised pouches show the characteristic features of Crohn's disease, including granulomas. There were no histologic differences in the total colectomy specimens between the eight ulcerative colitis study patients and 16 control ulcerative colitis patients who had a favorable clinical outcome after IPAA surgery groups. Crohn's-like complications and chronic pouchitis does not necessarily imply an incorrect original interpretation of ulcerative colitis by the pathologist.
ULCERATIVE COLITIS
Contemporary morphologic definition of backwash ileitis in ulcerative colitis and features that distinguish it from Crohn disease. Goldstein N, Dulai M. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.	Am J Clin Pathol. 2006 Sep;126(3):365-76 Abstract quote Terminal ileum (TI) sections from 250 ulcerative colitis (UC) total colectomy specimens resected during 3 periods and endoscopic TI biopsy specimens from 100 contemporary chronic UC and 100 Crohn disease (CD) patients were reviewed. The respective proportions of cases resected during the 3 periods with moderately or markedly active cecal UC were 72%, 34%, and 2% and with moderate or marked backwash ileitis (BWI), 21%, 18%, and 0%. The activity level of BWI correlated with level of cecal UC. In contemporary initial endoscopic TI biopsy specimens, 6% of chronic UC patients had BWI, all with moderately to markedly active cecal chronic UC. In CD cases, 75% had chronic or active enteritis, consisting of patchy lamina propria edema containing mildly active inflammation, crypt disarray, and focally blunted or flattened villi. Mucous gland metaplasia was present in 27% of CD biopsy specimens. BWI should be restricted to active enteritis that involves the ileum in a contiguous pattern from the cecum that has a similar or greater degree of active inflammation. Mild BWI predominantly involves the superficial mucosa in a contiguous pattern. Focal isolated ileal erosions, mucous gland metaplasia, or patchy edema with mild active inflammation are features of CD.
Prognostic Significance of Superficial Fissuring Ulceration in Patients With Severe "Indeterminate" Colitis. Yantiss RK, Farraye FA, O'brien MJ, Fruin AB, Stucchi AF, Becker JM, Reddy SI, Odze RD. From the *Departments of Pathology, University of Massachusetts Medical School/UMass Memorial Health Care, Worcester, MA and Weill Medical College of Cornell University, New York, NY; daggerDivision of Gastroenterology and Departments of double daggerPathology and section signSurgery, Boston University Medical Center, Boston, MA; and the parallelSection of Gastroenterology and paragraph signDepartment of Pathology, Brigham & Women's Hospital, Boston, MA.	Am J Surg Pathol. 2006 Feb;30(2):165-170. Abstract quote   Some colectomy specimens from patients with severe colitis contain superficial fissuring-type ulcers but do not have any other features of Crohn's disease (CD). This finding may cause difficulty with regard to distinguishing ulcerative colitis (UC) from CD and, thus, lead to a diagnosis of "indeterminate" colitis. The aim of this study was to evaluate the clinical and pathologic features, and outcome, of a cohort of patients with colitis and superficial fissuring ulcers, but without any other features that may suggest a diagnosis of CD. We retrospectively identified 21 patients (male-to-female ratio, 10/11; mean age, 38 years) with severe chronic active colitis, all of whom had at least one (range, 1-3) superficial fissuring ulcer in their colectomy specimens (but without any other features of CD), as well as a control group of 18 patients (male-to-female ratio, 10/8; mean age, 41 years) with equally severe disease, but without fissuring ulcers. Both groups were evaluated for a variety of clinical and pathologic features, such as clinical presentation, degree, extent, and duration of colitis, and follow-up information, such as the development of pouchitis, pouch fistulae, and any other features of CD. Overall, 81% of the study patients presented clinically with fulminant colitis and underwent an emergent or urgent colectomy, compared with only 41% of the control patients (P = 0.02). Nine (43%) study patients had active serositis in their colectomy specimens, whereas only 1 (6%) control patient had this finding (P = 0.002). However, no significant differences were noted in either the extent or severity of disease or the presence of active ("backwash") ileitis, between the study and control groups. Upon follow-up (mean, 42 months; range, 4-121 months), the study patients with superficial fissuring ulcers developed pouchitis significantly more often (68% vs. 20%, P = 0.007) than the control group following an ileal pouch-anal anastomosis (IPAA) procedure. One patient from each group developed an anal fissure and another from each group developed an anastomotic stricture. In addition, 1 study patient developed a pouch-cutaneous fistula, and 1 control patient developed an enterocutaneous fistula to a loop ileostomy. Finally, 1 control patient ultimately had her pouch excised because of recurrent intractable pouchitis. However, none of the other study or control patients developed any clinical or pathologic manifestations of CD. We conclude that superficial fissuring ulcers may occur in patients with severe chronic active UC, particularly those who present with fulminant disease. Affected individuals should not be considered to have CD or "indeterminate" colitis and should not be denied an IPAA procedure. Nevertheless, the presence of superficial fissuring-type ulcers in patients with severe chronic active UC denotes a subgroup with a higher risk of pouchitis following surgical resection.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	Increased incidence of adenocarcinoma in long standing disease (5-6x increased risk vs. normal population)
Clinical features of gastroduodenal Crohn's disease in adolescents. Griffiths AM, Alemayehu E, Sherman P. Department of Paediatrics, Hospital for Sick Children, University of Toronto, Ontario, Canada.	J Pediatr Gastroenterol Nutr 1989 Feb;8(2):166-71 Abstract quote Ten cases of gastroduodenal inflammation were diagnosed by endoscopy among a series of 196 children with evidence of Crohn's disease involving other regions of the intestinal tract. Endoscopic and histologic confirmation of upper gastrointestinal tract involvement was performed only in those cases with suggestive symptoms. The mean age at presentation in the 10 cases with gastroduodenal inflammation was 14.6 +/- 1.9 (+/- SD) years, with involvement identified at the time of initial diagnosis of Crohn's disease in five of the 10. Eight of 10 cases occurred in boys. The major presenting symptoms were weight loss in five cases, epigastric pain in three, and recurrent vomiting in two. Hematemesis and melena occurred in only one of the 10 cases. Endoscopic and histological evidence of mucosal inflammation was seen in all 10 cases. Three of 10 cases had noncaseating granuloma present in biopsies of the stomach or duodenum. Two cases also had endoscopic and histological evidence of esophageal involvement. All cases were initially treated with oral corticosteroids, and in each instance a good clinical response was noted. Sucralfate (n = 1), 6-mercaptopurine (n = 1), and H2 receptor antagonists (n = 3) were used as adjunct therapy. After follow-up for 2.7 years (range, 0.5-5.5 years), none of the 10 cases required surgical intervention. Therefore, at least in the short-term, the outlook for adolescents with gastroduodenal Crohn's disease appears to be good and their medical management need not differ from those patients with Crohn's disease involving only more distal portions of the small intestine.
TUBULOGLANDULAR ADENOCARCINOMA
Intestinal Low-grade Tubuloglandular Adenocarcinoma in Inflammatory Bowel Disease. Levi GS, Harpaz N. Mount Sinai School of Medicine, New York, NY.	Am J Surg Pathol. 2006 Aug;30(8):1022-29 Abstract quote Chronic idiopathic inflammatory bowel disease (IBD) with extensive colonic involvement predisposes to the development of colorectal adenocarcinoma. Among the types of cancer occurring in this setting is an unusually well-differentiated low-grade tubuloglandular adenocarcinoma (LGTGA) that has not been studied systematically thus far. A review of 149 IBD-associated cancer resections performed at our institution yielded 17 patients (11%) with 21 tumors classified as LGTGA based on the following histologic characteristics: very well-differentiated small to medium diameter glands with round or tubular profiles, low-grade cytologic characteristics and absence or paucity of desmoplastic reaction. Twelve patients had ulcerative colitis, 4 Crohn disease, and 1 indeterminate colitis. Their median age was 41.5 years (range, 28 to 58 y). Five patients had separate synchronous cancers of conventional types. LGTGAs ranged from 0.4 to 10 cm in size and varied in gross appearance. They included 5 flat lesions that were not identified visually but were detected either by palpation of the unfixed surgical specimen (1 case) or histologically in random sections (4 cases). The invasive glands usually bore a close histologic resemblance to overlying low-grade or indefinite dysplastic crypts. Twelve carcinomas (57%) with well-defined superficial regions of LGTGA progressed histologically to conventional adenocarcinoma in deeper regions. These tumors were significantly more advanced than 9 carcinomas that maintained low-grade histology throughout. Follow-up of 13 patients (76%) for a mean 4.0 years (range, 0.75 to 9.0 y) disclosed 10 (77%) with favorable outcomes and 3 (23%) with adverse outcomes. Two adverse outcomes were attributable to synchronous advanced-stage conventional cancers and the third to progression from LGTGA to poorly differentiated adenocarcinoma. The mucosa overlying and surrounding LGTGA showed low-grade dysplasia (LGD) in 18 cases (86%), indefinite dysplasia with focal LGD in 1 case (5%), and LGD with focal high-grade dysplasia (HGD) in 2 cases (10%). Immunohistochemical studies disclosed expression of MUC2 in 72%, MUC6 in 0%, CK7 in 69%, and CK20 in 100%. Coexpression of CK7 and CK20 was conserved in regions of conventional adenocarcinoma derived from LGTGA. Silencing of immunohistochemical expression of hMLH1 occurred in 6 of 11 tumors tested (55%), implicating defective DNA replication error repair in their pathogenesis. We conclude that LGTGA is a distinct clinicopathologic entity characterized by direct derivation from LGD mucosa of IBD, very well-differentiated morphology, frequent coexpression of CK7 and CK20, and frequent silencing of hMLH1. Histologic progression from LGTGA to conventional types of adenocarcinoma parallels clinical progression to more aggressive neoplasia. The potential of LGD to give rise directly to LGTGA, and by way of LGTGA to more aggressive cancers, reinforces recommendations in favor of aggressive management of IBD patients diagnosed with LGD.
TREATMENT
INFLIXIMAB
Infliximab (Remicade), a new biological treatment for Crohn's disease. D'Haens GR. Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.	Ital J Gastroenterol Hepatol 1999 Aug-Sep;31(6):519-20 Abstract quote Tumour necrosis factor plays a pivotal role in Crohn's disease intestinal inflammation. Blocking this cytokine by means of the chimeric monoclonal antibody infliximab has led to a rapid reduction in mucosal inflammation. More than 65% of refractory Crohn's disease patients treated with infliximab showed a remarkable improvement in their symptoms, which was maintained by repeated infusions every 2 months up to 44 weeks. Patients with draining enterocutaneous fistulae also benefited from infliximab treatment, with more than 60% of fistulae healed after 3 infusions. Adverse events following infliximab infusions were mild and transient, occurring with the same frequency in infliximab and placebo-treated patients. In conclusion, infliximab appears to offer a promising novel therapeutic agent for refractory and fistulizing Crohn's disease. Long-term risks and benefits remain to be determined.
Clinical experience with infliximab therapy in 100 patients with Crohn's disease. Farrell RJ, Shah SA, Lodhavia PJ, Alsahli M, Falchuk KR, Michetti P, Peppercorn MA. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.	Am J Gastroenterol 2000 Dec;95(12):3490-7 Abstract quote OBJECTIVE: The aim of this study was to assess our clinical experience with infliximab, a monoclonal antitumor necrosis factor antibody, following its approval for treatment of refractory Crohn's disease (CD). METHODS: We followed 100 consecutive patients with CD (53 women and 47 men; mean age, 41 yr) who received a total of 233 infliximab (5 mg/kg) infusions. Adverse events were noted and clinical response assessed every 2 wk for 6 months after each infusion using the Harvey Bradshaw Index (HBI) for active disease, the Perianal Disease Activity Index (PDAI) for fistulous disease, and steroid withdrawal rates for steroid-sparing efficacy. RESULTS: Indications for therapy were active disease (n = 57), perianal fistulous disease (n = 33), and steroid dependency (n = 10). Significant infusion reactions occurred in 16 patients (6.9% of infusions) including anaphylactic shock in one patient. Fourteen patients experienced infectious adverse events, 13 of whom were on concurrent steroids. Sixty percent of patients with active disease experienced > or = 50% HBI reduction at 2 wk; mean duration of response, 8.2 wk. Three of 26 first-time nonresponders with active disease (12%) responded to a second infusion. Sixty-nine percent of patients with fistulous disease experienced >50% reduction in their PDAI at 2 wk; mean duration of response, 10.9 wk. Four of 10 steroid-dependent patients (40%) discontinued steroid therapy, one of whom recommenced steroid therapy at 24 wk. CONCLUSIONS: Our clinical response rates mirror the efficacy reported in the controlled trials for active and fistulous disease. Steroid-sparing efficacy was seen in 40% of steroid-dependent patients. Concurrent steroids did not reduce the risk of significant infusion reactions (6.9%), but did increase the risk of infections.
Use of infliximab in pediatric patients with inflammatory bowel disease. Serrano MS, Schmidt-Sommerfeld E, Kilbaugh TJ, Brown RF, Udall JN Jr, Mannick EE. Department of Pediatrics, Louisiana State University Medical Center, New Orleans, LA	Ann Pharmacother 2001 Jul-Aug;35(7-8):823-8 Abstract quote BACKGROUND: The concentration of tumor necrosis factor, a proinflammatory cytokine, is increased in the gastrointestinal mucosa of patents with active Crohn's disease (CD) and ulcerative colitis (UC). Neutralization of tumor necrosis factor decreases the mucosal inflammatory response of adults with CD. Little information is available on the use of monoclonal antibody to tumor necrosis factor (infliximab) in children and adolescents with CD or UC. OBJECTIVE: To evaluate the clinical response and side effects of patients to infliximab. METHODS: A retrospective review of data regarding 18 pediatric and adolescent patients with active CD (n = 15) and UC (n = 3) poorly controlled with conventional therapy. All patients received one to six intravenous infusions of infliximab 5 mg/kg, while receiving their usual medications. RESULTS: All patients experienced clinical improvement, including decrease in the frequency of stooling and resolution of extraintestinal symptoms such as arthropathy, malaise, and skin manifestations after treatment with infliximab. All but one patient had a documented decrease in the erythrocyte sedimentation rate. Prednisone dosage was tapered in all but two patients, and discontinued in seven patients. Intravenous infusion of infliximab was well tolerated. One patient developed a rash several days after the infusion. A patient who received six infliximab infusions developed recurrent Staphylococcus aureus infections, as well as septic arthritis and chronic osteomyelitis during the follow-up period, raising the issue of the long-term safety of infliximab. CONCLUSIONS: Treatment of our patients with refractory CD and UC with infliximab was associated with remarkable clinical improvement. Although the drug may have an important role in their management, further assessment of long-term safety and efficacy is needed.

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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

• Pathologists Who Make A Difference
• Search for a Physician Specialist
• Gross or Clinical Photo
• Gross or Clinical Photo
• Microscopic Photo
• Microscopic Photo
• Microscopic Photo
• Crohn's Disease Resource Center
• National Association for Colitis and Crohn's Disease

Last Updated May 1, 2008

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