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This is the other half of inflammatory bowel disease, the partner of Crohn's disease. Like Crohn's, it is a recurrent disease with attacks lasting several weeks to months, then subsiding only to recur. Symptoms include a bloody diarrhea and crampy lower abdominal pain. In some patients, a severe attack may lead to electrolyte disturbances.


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SYNONYMS Ulcerative colitis
INCIDENCE 4-12/100,000
AGE Peaks between 20-25 years
SEX Women favored


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.

Apoptosis Regulation Differs Between Ulcerative Colitis–Associated and Sporadic Colonic Tumors
Association With Survivin and bcl-2

Tetuo MikamiMD
Tsutomu YoshidaMD
Fumiyuki AkinoMD
Tadashi MotooriMD
Mioko YajimaMD
Isao OkayasuMD

Am J Clin Pathol 2003;119:723-730 Abstract quote

To clarify kinetics in ulcerative colitis (UC)-associated lesions, cell proliferation, apoptosis, and expression of apoptosis-inhibitory proteins were studied. Ki-67 labeling and survivin and bcl-2 expression were examined immunohistochemically in 22 low-grade dysplasias (LGDs), 25 high-grade dysplasias (HGDs), and 13 adenocarcinomas associated with UC, and for comparison in 21 sporadic adenomas with LGD, 22 sporadic adenomas with HGD, and 21 invasive adenocarcinomas.

Apoptosis was studied with nick-end labeling and immunohistochemical analysis of single-stranded DNA. In UC-associated LGDs, Ki-67–positive cells were more frequent in the lower than the upper half of the crypt, related to bcl-2 expression, while in sporadic adenomas such cells were more common in the upper half. No difference in apoptosis was found between UC-associated LGDs and sporadic adenomas with LGD or between UC-associated HGDs and sporadic adenomas with HGD. However, UC-associated carcinomas exhibited a lower apoptotic count than their sporadic invasive counterparts. This seemed related to higher survivin expression without a significant difference between the 2 types of invasive lesions regarding bcl-2 levels.

Apoptosis is less frequent in UC-associated than in sporadic invasive colon carcinomas, this being linked to elevated survivin expression. The control of apoptosis may be different in the 2 types of tumorigenesis.


Cyclin D1 and p21 in ulcerative colitis-related inflammation and epithelial neoplasia: A study of aberrant expression and underlying mechanisms.

Wong NA, Mayer NJ, Anderson CE, McKenzie HC, Morris RG, Diebold J, Mayr D, Brock IW, Royds JA, Gilmour HM, Harrison DJ.

Hum Pathol 2003;34:580-588 Abstract quote

It is unclear whether and how cyclin D1 and/or p21(WAF1/CIP1) dysregulation contribute to ulcerative colitis (UC)-related inflammation and colorectal carcinogenesis. Cases of quiescent UC (QUC; n = 15), active UC (AUC; n = 23), UC-related dysplasia (n = 35) and UC-related colorectal adenocarcinomas (CRCs; n = 11) were studied with cyclin D1 and p21(WAF1/CIP1) immunohistochemistry. The CRCs were also studied with beta-catenin, bcl2, and p53 immunohistochemistry, p53 and k-ras mutation analyses, and cyclin D1 gene fluorescence in situ hybridization. QUC showed cyclin D1 (negative/weak staining) and p21(WAF1/CIP1) (surface epithelial and upper-third crypt staining) expression similar to that of normal colorectum.

Moderate or strong cyclin D1 immunostaining was seen in 9% of AUC cases, 40% of dysplasia cases, and 36% of UC-related CRCs. Although these carcinomas showed neither cyclin D1 gene amplification nor any association between k-ras mutation and cyclin D1 overexpression, the latter was closely related to nuclear beta-catenin expression.

Increased lower-third crypt p21(WAF1/CIP1) staining was seen in 57% of AUC cases; decreased upper-third crypt p21(WAF1/CIP1) staining, in 23% of dysplasia cases; and absent or weak p21(WAF1/CIP1) staining, in 55% of UC-related CRCs. The latter change was always associated with p53 mutation but could not be related to p53 or bcl2 expression. In conclusion, AUC shows up-regulated cyclin D1 and p21(WAF1/CIP1) expression.

Cyclin D1 up-regulation and p21(WAF1/CIP1) down-regulation occur early in UC-related carcinogenesis. Cyclin D1 up-regulation is less common in UC-related CRCs than in sporadic CRCs, and is related to beta-catenin nuclear signaling. p21(WAF1/CIP1) down-regulation is seen at an equal or higher frequency among UC-related CRCs compared with sporadic CRCs and is attributable to p53 mutation.


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.

Altered distribution of beta-catenin, and its binding proteins E-cadherin and APC in UC related colorectal cancers

Mod Pathol 2001;14:29-39

Analysis of 33 UC related and 42 sporadic colorectal cancers

Both tumor groups showed an overall shift from membranous to cytoplasmic expression with an increase in nuclear localization of beta-catenin and decrease in cytoplasmic APC expression

Abnormal beta-catenin expression was more closely linked to E-cadherin alterations in UC related tumors than sporadic


Genetic Alterations in Chronic Ulcerative Colitis-Associated Adenoma-Like DALMs Are Similar to Non-Colitic Sporadic Adenomas

Robert D. Odze, M.D., F.R.C.P.C.; Charlotte A. Brown, Ph.D.; Christopher J. Hartmann; Amy E. Noffsinger, M.D.; Franz Fogt, M.D., Dr.med., MRC Path.

From the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, U.S.A. (R.D.O.); the Department of Pathology, University of Pennsylvania-Presbyterian Medical Center, Philadelphia, Pennsylvania, U.S.A. (C.A.B., C.J.H., F.F.); and the Department of Pathology, University of Cincinnati, Cincinnati, Ohio, U.S.A. (A.E.N.).

Am J Surg Pathol 2000;24:1209-1216 Abstract quote

Recent molecular studies have shown that there are differences in the prevalence and timing of certain molecular events between chronic ulcerative colitis (CUC)-associated dysplastic lesions and non-CUC-related sporadic adenomas. However, little is known regarding the molecular features of a specific subtype of CUC-related dysplasia-associated lesion or mass (DALM) that clinically, endoscopically, and pathologically resemble sporadic adenomas, and whether these lesions can be separated from non-CUC-related sporadic adenomas on the basis of their molecular genotype.

Therefore, the purpose of this study was to evaluate loss of heterozygosity (LOH) of 3p, APC, and p16 in a specific group of CUC-associated ``adenoma-like'' DALMs and to compare the results of this tumor with those in a well-defined group of CUC-associated non-adenoma-like DALMs and non-CUC-associated sporadic adenomas.

Polypectomy or resection specimens from 21 CUC patients with an adenoma-like DALM, 8 CUC patients with at least one non-adenoma-like DALM (12 lesions in total), and 23 non-CUC patients with a sporadic adenoma were evaluated for LOH of 3p, APC, and p16 by PCR analysis. The results were compared among the three different study groups and correlated with the clinical features of the patients and the pathology of their tumors. Chronic ulcerative colitis-associated adenoma-like DALMs showed LOH of 3p in five of 18 (28%) cases. This value was not significantly different from the 5% of non-CUC sporadic adenomas (p = 0.14) that were positive. However, 50% of CUC-associated non-adenoma-like DALMs were positive for LOH of 3p, and this value was significantly higher (p = 0.01) than the other groups. The frequency of LOH of APC did not differ significantly between the three patient groups (33%, 33%, and 43% in the three groups, respectively). Similar to the 3p results, CUC-associated adenoma-like DALMs and non-CUC-associated sporadic adenomas showed a similar low frequency of positivity for LOH of p16 (5% and 4%, respectively) in comparison to 56% of CUC-associated non-adenoma-like DALMs (p = 0.003). For all markers, no significant differences were detected in the CUC-associated adenoma-like DALM group between lesions that occurred within colitis compared with those that occurred in areas not involved by colitis.

Chronic ulcerative colitis-associated non-adenoma-like DALMs have a different molecular genotype than CUC-related adenoma-like DALMs and non-CUC sporadic adenomas. Our data also suggests that the latter two groups of neoplasms may in fact represent a similar, if not identical, pathogenetic entity.



Cytomegalovirus Infection in Steroid-refractory Ulcerative Colitis: A Case-Control Study

Kambham, Neeraja MD*‡; Vij, Rohini MD, MS†‡; Cartwright, Christine A MD†; Longacre, Teri MD*

From the Departments of *Pathology and †Medicine, Stanford University, Stanford, CA.

The American Journal of Surgical Pathology : Volume 28(3) March 2004 pp 365-373 Abstract quote

Cytomegalovirus (CMV) infection is reported to be a cause of steroid-refractory ulcerative colitis (UC), but the strength of this association has not been tested in a case control study. Controlled studies have also not been performed to determine the sensitivity of available immunohistochemical techniques to detect CMV in this setting.

The pathology database at Stanford Hospital was searched for UC patients with a diagnosis of severe colitis between the years 1992 and 2002 and medical records were reviewed. Forty patients were identified with refractory UC, defined as poor response to high-dose systemic steroids for >2 weeks. Another group of 40 patients with severe, but nonrefractory, UC was case-matched for age and year of biopsy. A series of 40 patients who underwent colectomy for reasons other than inflammatory bowel disease with representative sections of normal colon were selected as noncolitis controls.

CMV inclusions were detected on hematoxylin and eosin (H&E) in 2 of 40 patients with refractory UC, but not in other patients. Immunohistochemistry (IHC) detected CMV in 10 of 40 (25%) patients with refractory UC and 1 of 40 (2.5%) patients with nonrefractory UC ( P = 0.007). The CMV-positive cases initially identified on IHC but not on H&E were re-reviewed for viral inclusions on H&E: 3 had rare, but typical, inclusions; 3 had atypical inclusions; and 3 had no inclusions. CMV was not detected by H&E or IHC in 40 noncolitis controls. Of 10 steroid-refractory UC patients with CMV detected, 7 were refractory to cyclosporin or 6-mercaptopurine/azathioprine (70%) and 6 had undergone proctocolectomy (60%) prior to detection of the CMV. Two patients with recognized CMV infection were treated with gancyclovir, improved, and were able to taper off steroids and avoid proctocolectomy.

This study provides evidence that unrecognized and therefore untreated CMV infection is significantly associated with steroid-refractory UC. Moreover, IHC is more sensitive than H&E for detection of CMV and should be considered as part of the routine evaluation of steroid-refractory UC patients, before proceeding with other medical or surgical therapy that may be unnecessary once the CMV is treated.


Diffuse Duodenitis Associated With Ulcerative Colitis

Riccardo Valdez, M.D.; Henry D. Appelman, M.D.; Mary P. Bronner, M.D.; Joel K. Greenson, M.D.

From the University of Michigan Health System, Department of Pathology, Ann Arbor, Michigan, U.S.A. (R.V., H.D.A., J.K.G.); and the University of Washington, Department of Pathology, Seattle, Washington, U.S.A. (M.P.B.).

Am J Surg Pathol 2000;24:1407-1413 Abstract quote

Backwash ileitis and postcolectomy pouchitis are well-recognized complications of ulcerative colitis (UC), whereas inflammation of the proximal small intestine is not. In contrast, small intestinal disease at any level is common in Crohn's disease (CD). Despite this well-established and accepted dogma, rare cases of histologically proven diffuse duodenitis (DD) associated with UC appear in the literature.

In this study, we report our experience with similar cases exhibiting this unusual inflammatory phenomenon.

Routine histologic sections from four cases of DD associated with well-documented UC were reviewed and the findings correlated with all available medical records. Multiple endoscopic biopsies showing histologic features of UC and colectomy specimens confirming severe ulcerative pancolitis were available for all cases. Varying degrees of active chronic inflammation and architectural mucosal distortion identical to UC were observed in pre-and postcolectomy duodenal biopsies of one of four and four of four cases, respectively. Similar inflammatory patterns were present postoperatively in the ileum in three of four cases and in the jejunum in one case. Endorectal pull-through (ERPT) procedures were performed in three of four patients and an end-to-end ileorectal anastomosis was done in one patient. Despite extensive upper gastrointestinal tract involvement, none of the patients developed postsurgical Crohn's-like complications during a follow-up period of 12 to 54 months.

This suggests that patients with pancolitis and DD do not necessarily have CD, but rather may have UC and, most importantly, that successful ERPT procedures may be performed in these patients.



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.


Anti-neutrophil cytoplasmic auto-antibodies (ANCA) in ulcerative colitis (UC): no relationship with disease activity.

Reumaux D, Colombel JF, Masy E, Duclos B, Heresbach D, Belaiche J, Cortot A, Duthilleul P;

GETAID. Groupe d'Etude des Affections Inflammatoires du Tube Digestif. Departement d'Hematologie-Immunologie-Cytogenetique, Centre Hospitalier de Valenciennes, France.

Inflamm Bowel Dis 2000 Nov;6(4):270-4 Abstract quote

The relationship between anti-neutrophil cytoplasmic auto-antibodies (ANCA) and disease activity in inflammatory bowel diseases remains controversial.

The aim of this study was to highlight the relationship between ANCA presence or titers and disease activity in ulcerative colitis (UC). Three groups of patients with UC were studied: 1) group A included 39 patients who had not undergone colectomy, 2) group B, 43 patients with subtotal colectomy and ileo-rectal anastomosis, 3) group C, 98 patients with proctocolectomy and ileo-anal anastomosis, including 88% with pouchitis and 12% without pouchitis at the time of the study. Determination of ANCA was performed using the standardized indirect immunofluorescence assay. ANCA were positive in 59%, 65%, and 54% of patients from groups A, B, and C, respectively (NS). No relationship between ANCA presence or titers and UC activity could be detected within groups A and B. In group C, 45 of 86 patients (52%) without pouchitis and 8 of 12 patients (67%) with pouchitis, were ANCA positive (NS).

These results do not support a relationship between ANCA and UC activity in this cohort of 180 patients.


Classic presentation

Involves the rectum and extends proximally up the bowel to involve the entire bowel without evidence of skip lesions

Islands of regenerating mucosa forms pseudopolyps

Serosal surface is usually normal

Toxic megacolon Sudden cessation of bowel function leads to toxic dilatation which can potentially perforate

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.

Clinical Presentations-Extragastrointestinal  
Migratory polyarthritis  
Ankylosing spondylitis  
Erythema nodosum  
Clubbing of the fingertips  
Hepatic sclerosing cholangitis  


Classic Presentation

Mucosal inflammation with chronic mucosal damage located predominately within the lamina propria

Scattered crypt abscesses with ulceration

Continuous damage from the rectum to proximal colon

Patterns of Colonic Involvement at Initial Presentation in Ulcerative Colitis
A Retrospective Study of 46 Newly Diagnosed Cases

Marie E. Robert, MD, Mark Skacel, MD, etal.
Am J Clin Pathol 2004;122:94-99 Abstract quote

Studies have shown that rectal sparing and patchiness develop in treated and longstanding ulcerative colitis (UC), making the distinction from Crohn colitis increasingly difficult after treatment is initiated. However, no histologic studies of the incidence of rectal sparing in adults at UC onset have been performed.

Colectomy specimens from 46 patients with classic UC histologic features and no Crohn disease features were identified. Biopsy specimens obtained before medical therapy were retrieved and examined blindly by 2 pathologists, along with appropriate control samples. Slides were scored for chronicity (crypt branching, subcryptal plasma cells, lamina propria plasma cells) and activity (cryptitis, crypt abscesses, epithelial injury). In 28 cases, only rectal biopsy specimens were taken; for 16, rectal and at least 1 proximal biopsy specimen were taken.

All cases showed rectal involvement; none had rectal sparing at initial biopsy. Of 16 cases with rectal and more proximal biopsy specimens, 5 (31%) showed relative rectal sparing (lower scores in rectum than in more proximal sites). In 16 cases with rectal and more proximal biopsy specimens, chronicity and activity scores were higher in the rectum than in more proximal sites (P = .01; chronicity and activity). The mean overall chronicity score decreased in a linear manner from rectum to cecum. The rectum is involved and shows evidence of chronicity and activity at disease onset in UC, using colectomy as the gold standard for diagnosis.

Because rectal sparing at UC onset has been reported, a prospective study using uniform biopsy protocols is needed to establish the true incidence of rectal sparing at presentation.

Histopathology of Ulcerative Colitis in Initial Rectal Biopsy in Children

Kay Washington, M.D., Ph.D.; Joel K. Greenson, M.D.; Elizabeth Montgomery, M.D.; Yu Shyr, Ph.D.; Karen D. Crissinger, M.D., Ph.D.; D. Brent Polk, M.D.; John Barnard, M.D., Ph.D.; Gregory Y. Lauwers, M.D.

Am J Surg Pathol 2002; 26(11):1441-1449 Abstract quote

Definitive histologic diagnosis of ulcerative colitis relies upon mucosal architectural distortion and inflammation in the appropriate clinical setting. Although crypt branching, atrophy, and loss are usually present in first biopsies from adults with ulcerative colitis, it has been our impression that features of chronicity are often lacking in first biopsies from children.

To test this hypothesis, initial rectal biopsies and follow-up biopsies and/or colonic resections from 53 children (age 15 months to 17 years) and 38 adults (age 21-76 years) with ulcerative colitis were examined in a blinded fashion for villiform surface, crypt atrophy, branching crypts, lamina propria inflammation, crypt abscesses, cryptitis, and basal plasma cells. Mucosal architecture was classified as normal, focally abnormal, or diffusely abnormal. Medical records were reviewed for confirmatory evidence of ulcerative colitis and for duration of symptoms before biopsy. In 87 of 91 biopsies, the lamina propria contained a mixed inflammatory infiltrate. Crypt abscesses and cryptitis were common in both groups. Initial biopsies from children were less likely to show diffuse architectural abnormalities (17 of 53, 32.1%) compared with biopsies from adults (22 of 38, 57.9% p <0.05). Duration of symptoms before diagnosis was significantly shorter in children (mean 17.5 weeks) compared with adults (mean 54.9 weeks).

In summary, initial rectal biopsies from children with ulcerative colitis are less likely to show diagnostic mucosal architectural distortion than biopsies from adults. This difference may be related to a shorter duration of symptoms before biopsy.

BACKWASH ILEITIS 10% of severe pancolitis may involve the ileum and appendix
Contemporary morphologic definition of backwash ileitis in ulcerative colitis and features that distinguish it from Crohn disease.

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.
Pathologic Features and Clinical Significance of "Backwash" Ileitis in Ulcerative Colitis.

Haskell H, Andrews CW Jr, Reddy SI, Dendrinos K, Farraye FA, Stucchi AF, Becker JM, Odze RD.

From the Departments of *Pathology and daggerMedicine, Brigham and Women's Hospital, and the Departments of double daggerPathology, section signMedicine, and parallelSurgery, Boston Medical Center, Boston, MA.

Am J Surg Pathol. 2005 Nov;29(11):1472-1481. Abstract quote  

Patients with ulcerative colitis (UC) may develop inflammation in the distal ileum thought to be due to "backwash" of cecal contents ("backwash ileitis"). However, a systematic analysis of ileal changes in UC has never been performed, and the prevalence and criteria for "backwash" ileitis have not been defined.

The aim of this study was to evaluate the prevalence and spectrum of inflammatory changes in the ileum in patients with UC and to correlate ileal changes with outcome after total proctocolectomy and ileal pouch-anal anastomosis. Routinely processed ileocolonic resection specimens from 200 consecutive patients with clinically and pathologically confirmed UC were evaluated for a wide variety of pathologic features in the ileum and colon. The ileal data were correlated with both the clinical features and the pathologic findings in the colon. Follow-up data were obtained to confirm absence of Crohn's disease and to evaluate outcome of ileo-anal pouches.

Overall, 34 of 200 (17%) UC patients had inflammatory changes in the ileum (male/female ratio, 16/18; mean age, 42 years); 32 of 34 (94%) had pancolitis, which was significantly higher than the rate of pancolitis (39%) in patients without ileal disease (N = 166) (P < 0.001), but there were no other differences between patients with or without ileal pathology. In the colon, 22 of 34 (65%) patients had severe activity. Ileal changes included villous atrophy and crypt regeneration without increased inflammation (N = 3), increased neutrophilic and mononuclear inflammation in the lamina propria (N = 6), patchy cryptitis and crypt abscesses (N = 21) and focal superficial surface erosions (N = 4), some with pyloric metaplasia (N = 2 of 4). In general, the severity of ileal changes paralleled the severity of colonic activity. However, 2 of 4 (50%) patients with superficial erosions in the ileum had subtotal or left-sided colitis only, and had only mild colonic activity. Other cases showed only mild to moderate colonic activity and patchy or discontinuous involvement of the distal ileum.

Upon follow-up of patients with erosions (mean, 48.5 months; range, 26-102 months), none developed manifestations of Crohn's disease anywhere in the gastrointestinal tract. The presence of inflammatory changes in the ileum had no effect on the prevalence of pouch complications or on the occurrence of dysplasia or cancer.

Ileal changes in UC are not uncommon (prevalence, 17%), are generally mild in nature (villous atrophy, increased inflammation, scattered crypt abscesses), and are not associated with an increased rate of ileo-anal pouch complications, dysplasia, or carcinoma. In some cases, our findings are consistent with a backwash etiology. However, rarely, ileal erosions may occur in patients without cecal involvement, which may indicate that other pathogenetic mechanisms should be considered in the etiology of ileitis in UC patients.
DYSPLASIA Nuclear atypia and loss of cytoplasmic differentiation
Currently divided into low and high grade

Observer variation in the assessment of dysplasia in ulcerative colitis.

Dixon MF, Brown LJ, Gilmour HM, Price AB, Smeeton NC, Talbot IC, Williams GT.

Department of Pathology, University of Leeds, UK.


Histopathology 1988 Oct;13(4):385-97 Abstract quote

Six histopathologists allocated 100 sections from patients with long-standing ulcerative colitis into four diagnostic categories, regular hyperplasia, reactive atypia, low-grade and high-grade dysplasia. Their allocations were analysed using kappa statistics, including Fleiss's multiple kappa for groups of observers, and agreement on specific diagnoses was explored by constructing a conditional probability matrix. The nature of their disagreements was investigated using coefficients for systematic and haphazard errors.

Over the four diagnostic categories there was a wide range of pairwise agreement from a low of 49% up to 72% and kappa values were only 'fair' or 'moderate'. As expected, agreement over the two categories 'dysplasia' vs 'no dysplasia' was better, ranging from 68% to 84%, and for 'atypia present' (reactive atypia, low- and high-grade dysplasia) vs "no atypia' two pairings achieved over 90% and 11 pairings over 80% agreement. In view of its clinical importance, conditional agreement on high-grade dysplasia, pairwise agreement on this diagnosis ranged from 100% down to as low as 33%. However, most of these disagreements fell into the low-grade dysplasia category so that closer follow-up and further biopsies would still have been indicated. It is a truism that the basis for safe management is careful co-operation between clinicians and pathologists who have all the relevant facts and who know and trust one another's judgement.

Thus, several aspects of the ideal diagnostic process cannot be evaluated in inter-observer studies and the element of artificiality should be borne in mind when applying the findings to diagnostic practice. Nevertheless, the low level of agreement on the diagnosis of high-grade dysplasia achieved by certain pairings of specialist pathologists is a disturbing outcome of this study.

Inaccuracies should be minimized by a concensus approach and we therefore recommend referral of putative cases of dysplasia to interested pathologists for further opinions. We would also advocate that pathologists faced with appearances which are indefinite between reactive atypia and dysplasia, would do better to describe them in terms of "atypia, significance uncertain', so that closer surveillance is undertaken, rather than force them into more precise diagnostic categories which may be incorrect.

Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome.

Melville DM, Jass JR, Morson BC, Pollock DJ, Richman PI, Shepherd NA, Ritchie JK, Love SB, Lennard-Jones JE.

Imperial Cancer Research Fund Colorectal Cancer Unit, St Mark's Hospital, London, England.

Hum Pathol 1989 Oct;20(10):1008-14 Abstract quote

Patients with extensive ulcerative colitis are entered into surveillance programs that aim to detect premalignant changes. Biopsy specimens have been collected in the St Mark's Hospital (London) surveillance program over a 22-year-period. Specimens from patients reported as having dysplasia were reexamined.

A total of 207 biopsy specimens from 86 patients were graded by five experienced pathologists according to the severity of the dysplasia. The overall agreement between the pathologists grading the specimens was poor; each pair agreed on between 42% and 65% of the slides. The best agreement was for slides that were said to show no dysplasia. Comparison with clinical outcome indicated that the pathologists most likely to diagnose dysplasia in patients with carcinoma were also likely to diagnose dysplasia in patients who did not go on to develop carcinoma. Calculating an average grade of dysplasia did not significantly improve diagnostic accuracy. Despite the findings of this interobserver study, dysplasia has been a successful marker in clinical practice.

Pathologists should ensure that they have access to previous slides from the same patient and adequate clinical information before reporting biopsies as positive for dysplasia. An additional biopsy should usually be undertaken before surgery is considered.

Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis.

Eaden J, Abrams K, McKay H, Denley H, Mayberry J.

Gastrointestinal Research Unit and Department of Pathology, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK.

J Pathol 2001 Jun;194(2):152-7 Abstract quote

Histological dysplasia is the cornerstone of colorectal cancer surveillance in ulcerative colitis (UC). Recently, pathologists have received unfavourable media attention concerning other cancer screening programmes.

The aim of this study was to determine whether colonic biopsy specimens should be examined by gastrointestinal pathologists as opposed to generalists, by examining inter-observer variation between the two groups. Fifty-one coded slides showing varying degrees of dysplasia were mailed to seven gastrointestinal and six general histopathologists. Pathologists allocated each biopsy into one of four categories without the benefit of a clinical history or an opportunity to use the 'indefinite' category that is included in the Riddell classification. The responses were analysed using kappa statistics. The overall kappa statistic for gastrointestinal pathologists was 0.30 [95% confidence interval (CI)=0.26-0.34] and for general pathologists 0.28 (95% CI=0.23-0.32). Agreement was best for high-grade dysplasia (kappa of 0.54 and 0.61 for GI and general pathologists, respectively). There was total concordance of the 13 pathologists in only four of the 51 slides (7.8%) (95% CI=0.4-15.2%).

It is concluded from these results that gastrointestinal pathologists are no better than generalists when grading dysplasia in UC and that agreement is poor in both groups. There is therefore no evidence that there would be any benefit in having specialist histopathology centres concentrating specifically on the interpretation of all surveillance colonoscopy biopsies from around the UK. It must be made clear to the public that surveillance and screening programmes carry a significant rate of histological error and that perfection cannot be expected or achieved with present methods.

Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology.

Odze RD, Goldblum J, Noffsinger A, Alsaigh N, Rybicki LA, Fogt F.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Mod Pathol 2002 Apr;15(4):379-86 Abstract quote

Telepathology (TP) is the practice of remote diagnostic consultation of electronically transmitted, static, digitalized images. The diagnostic efficacy of TP-based consultation services has not been widely tested. Dysplasia that arises in association with chronic ulcerative colitis (CUC) is, at present, the most important marker of an increased risk of malignancy in patients with this disease. Unfortunately, dysplasia is difficult to diagnose histologically and, as a result, suffers from a significant degree of intra- and interobserver variability. Furthermore, it is often necessary to obtain expert consultation of potential CUC-associated dysplasia cases before treatment.

Therefore, the aim of this study was to evaluate the utility and interobserver variability of diagnosing dysplasia in CUC with the use of TP. Static, electronically transmitted, digitalized images of 38 CUC cases with areas considered negative, indefinite, or positive for dysplasia (low or high grade) were evaluated independently by four gastrointestinal pathologists. All cases were then graded by each of the pathologists by light-microscopic examination of the hematoxylin and eosin-stained glass slides. The degree of interobserver variability was determined by kappa statistics. Overall, there was a fair degree of agreement (kappa = 0.4) among the four reviewing pathologists after analysis of the digitalized images. The poorest level of agreement was in the indefinite and low-grade dysplasia categories. Grouping together several diagnostic categories (for instance, indefinite and low-grade dysplasia, or low-grade dysplasia and high-grade dysplasia) had no effect on the overall level of agreement. The degree of variability in interpretation of glass slides was slightly better (kappa = 0.43) but still remained fair. After reviewing all cases by glass slide analysis, the diagnosis was changed in 38% of the slides; in the majority of these, the grade of dysplasia was increased.

Use of TP for consultation in CUC-associated dysplasia has a moderate level of interobserver agreement. Because of a variety of technical reasons, diagnoses rendered by evaluation of digitalized images tended to be of a lower grade than that observed after a review of the glass slides.


Am J Surg Pathol 2000;24:1407-1413
Rare cases of diffuse duodenitis have been speculated to be Crohn's disease-histology identical to UC observed in the rest of the colon

In a follow-up of 4 cases, ranging from 12-54 months, none of these patients developed Crohn's like complications

Successful endorectal pull-through procedures (ERPT) were performed


Pediatric Patients With Untreated Ulcerative Colitis May Present Initially With Unusual Morphologic Findings

Glickman, Jonathan N MD, PHD*‡; Bousvaros, Athos MD†; Farraye, Francis A MD, MSC¶; Zholudev, Anna BA†; Friedman, Sonia MD‡; Wang, Helen H MD§; Leichtner, Alan M MD†; Odze, Robert D MD, FRCPC‡

From the Departments of *Pathology and †Gastroenterology and Nutrition, Children's Hospital; ‡Department of Pathology, Brigham and Women's Hospital and §Beth Israel Deaconess Medical Center, all Harvard Medical School; ¶Gastroenterology Section, Boston Medical Center, Boston University Medical School; Boston, MA.

The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 190-197 Abstract quote

Background: Anecdotal observations by the authors of this study, together with the results of a few previous smaller studies, suggest that children with new-onset (previously untreated) ulcerative colitis (UC) may occasionally present with discontinuous disease, relative or absolute rectal sparing, and may lack histologic features of chronicity. Therefore, the objectives of this study were to determine the clinical and pathologic features of new-onset UC in children and to compare the initial presentation of UC in this group with a control group of adults.

Design: Routinely processed rectal and colonic mucosal biopsies from 73 pediatric (male/female ratio 33/40, mean age 11.5 years, range 2.5-18 years) and 38 adult patients (male/female ratio 15/23, mean age 41.5 years, range 27-64 years) who presented with new-onset UC were evaluated for a variety of clinical and pathologic features, including duration of symptoms prior to presentation, crypt architectural (e.g., atrophy, branching) and nonarchitectural (e.g., basal plasmacytosis, Paneth cell metaplasia) features of chronicity, degree of active inflammation, and distribution and extent of disease.

Results: A significant proportion of children with new-onset UC had patchiness of microscopic features of chronicity (21% of patients), relative (23%), or absolute (3%), rectal sparing, and had little or no crypt architectural distortion in their rectal biopsies (8%). These features were not observed in adult patients with UC. In addition, a higher proportion of children with UC initially presented with subtotal or with pancolitis compared with the adults (42% vs. 11%; P < 0.002).

Conclusions: A significant proportion of children with new-onset UC may show unusual patterns of disease. Pathologists should be aware of these findings since they have significant implications for the differential diagnosis of pediatric inflammatory bowel disease.

Patterns of Inflammation in Mucosal Biopsies of Ulcerative Colitis: Perceived Differences in Pediatric Populations Are Limited to Children Younger Than 10 Years

Robert, ME; Tang, L; Hao, LM; Reyes-Mugica, M

From the Department of Pathology, Yale University School of Medicine, New Haven, CT.

The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 183-189 Abstract quote

The histologic criteria used to diagnose ulcerative colitis in colonic mucosal biopsies have been established for many years and include crypt architectural distortion, plasmacellular infiltrates, and neutrophils in the crypt epithelium and lumen. In several recent studies, it has been noted that colonic mucosal biopsies from children presenting with ulcerative colitis show fewer histologic abnormalities at initial presentation, especially less architectural distortion, than do biopsies from adults.

In this study, colonic mucosal biopsies taken at the time of presentation of ulcerative colitis in 15 adults and 25 children were examined blindly by two pathologists. All biopsies were taken prior to the initiation of therapy. Twelve children were between 1 and 10 years of age, and 13 children were between the ages of 11 and 17 years. All patients had at least 1 year of follow-up, with clinical and pathologic confirmation of the diagnosis of ulcerative colitis.

Five separate histologic features that are characteristic of ulcerative colitis were scored on mucosal biopsies. Children =10 years of age had significantly less crypt branching, plasma cells in the lamina propria, cryptitis, crypt abscesses, and epithelial injury than adults ( P values ranging from <0.0001 to 0.0032). Children between the ages of 11 and 17 years had less cryptitis, crypt abscesses, and epithelial injury than adults ( P values ranging from 0.0001 to 0.007) but similar degrees of crypt architectural distortion and plasma cell infiltrates. For all histologic features examined except epithelial injury, the significant findings were due to differences in biopsies taken proximal to the rectum. No significant differences in histology scores were found in rectal biopsies between any age group, except for epithelial injury, which was significantly less in children =10 years.

The findings show for the first time that the perceived differences between adults and children with ulcerative colitis are largely due to a decrease in histologic features of colitis in children less than 10 years of age.

As children approach adulthood, the degree of inflammation and architectural distortion seen is similar to that found in adults. However, rectal biopsies show similar degrees of colitis in all age groups.

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.



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.


PROGNOSIS Cancer may supervene in long-standing cases, risk is greatest in cases >10 years
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.

Infliximab for patients with refractory ulcerative colitis.

Chey WY.

Rochester Institute for Digestive Disease and Sciences, New York 14607, USA.

Inflamm Bowel Dis 2001 May;7 Suppl 1:S30-3 Abstract quote

Conventional treatment options for patients with severe corticosteroid-refractory ulcerative colitis (UC) include intravenous cyclosporine, which is frequently limited by toxicity, or colectomy.

The efficacy of infliximab was investigated in the treatment of 16 patients with severely active UC refractory to conventional therapy; 7 of these patients were considered for colectomy pending medical failure. All patients received a single infusion of infliximab, 5 mg/kg; 6 of 16 patients (38%) received a second infusion approximately 5 months later. Efficacy was assessed by clinical response (defined as the lack of symptoms) as well as endoscopic and histologic outcomes. Clinical, endoscopic, and histologic improvement was observed in 14 of 16 patients (88%) after treatment with infliximab. Surgery was avoided in six of seven surgical candidates (86%). Clinical remission was maintained in 14 of 16 patients (88%) for > or = 4 months, and 4 of 16 patients (25%) for 7-10 months. Most of the treated patients were completely withdrawn from corticosteroid therapy. Treatment with infliximab induced endoscopic remission at 30 days and a significant improvement from baseline in mean histologic score (p < 0.001).

In conclusion, infliximab improved clinical, endoscopic, and histologic outcomes in patients with severely active UC refractory to conventional therapy, allowing corticosteroid sparing and reducing the need for colectomy.

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