Pathology of inflammatory bowel disease

Correspondence: Dr. Shiva Raj K.C.,MBBS, MD Associate Professor, Pathology Department Kist Medical College and Teaching Hospital, Imadole, Lalitpur, Nepal Email: shiva_kc_123@yahoo.com Inflammatory bowel disease is a group of inflammatory disorders of unknown etiology. Various genetic factors, mucosal immune response, inappropriate activation of immune system driven by the presence of various luminal flora and epithelial defects have been postulated. Crohn disease and Ulcerative colitis are the two most common inflammatory bowel diseases. Since, specific clinical laboratory features are lacking which may help in establishing a diagnosis histopathological diagnosis remains the gold standard. This review highlights the known hypothesis regarding the etiopathogenesis of these two diseases and also describes pertinent histological features. ABSTRACT


Genetics
Familial aggregation has been known for more than 70 years and large concordance studies in twins in northern Europe were early indicators of a genetic component in Crohn disease.A study done in German 9 showed that 35% of monozygotic pairs, but only 3% of dizygotic pairs, were concordant for the disorder.In 70% of discordant monozygotic pairs the first-born had IBD. 9 Substantial phenotypic (location, behaviour, and age at diagnosis) concordance exists, both at diagnosis and longitudinally, in monozygotic twins. 10Familial aggregation is confirmed. 11oreover, prevalence in Ashkenazi Jews is higher than in any other ethnic group and Jewish descent is an independent risk factor for the disorder.
In recent years, genome-wide association studies (GWAS) that assess single-nucleotide polymorphisms have been used to broaden the search for IBD-associated genes. 8dvances have occurred in understanding the genetics of human IBD, from studies based onsingle nucleotide polymorphism (SNP) and candidate gene approaches, and from studies inmouse experimental colitis that used transgenic and deletion (knockout) techniques. 12,13Several genes implicated in both IBD and experimental colitis are seen in Table 1.These genes regulate immunoregulation, mucosal barrier integrity and microbial clearance and/or homeostasis. 14e first gene found to be associated with Crohn disease was CARD 15 formerly known as NOD2 (nucleotide oligomerization binding domain 2) as a susceptibility gene in Crohn disease.CARD 15 encodes a protein that binds to intracellular bacterial peptidoglycans and subsequently activates NF-κB.It has been postulated that diseaseassociated NOD2 variants are less effective at recognizing and combating luminal microbes, which are then able to enter the lamina propria and trigger inflammatory reactions.Other data suggest that NOD2 may regulate immune responses to prevent excessive activation by luminal microbes. 8There are three mutations-causing amino-acid substitutions Arg702Trp and Gly908 Arg and the frame shift 1007fs-found within the region of CARD15 that encodes a leucine-rich repeat, which is responsible for bacterial recognition.At least one of these mutations is present in 25-35% of Crohn disease patients of European ancestry, but not in Asian or African American Crohn disease patients. 12,14her genes, involved in the pathogenesis of Crohn disease, are SLC22A4 and SLC22A5 along with DLG5 gene, and PPARG genes.Mutations in the transcribed region of SLC22A4, which encodes OCTN1, and the promoter region of SLC22A5, which encodes OCTN2, affect the transcription and function of these carnitine and organiccation transporters.These variants are most actively expressed in the intestinal epithelium, macrophages and T cells, and cause decreased carnitine transport.Although many studies have associated the region of chromosome 5 that contains SLC22A4 and SLC22A5 with Crohn disease, some investigators are hesitant to identify the mutations in these genes as causative of Crohn disease because of the tight linkage disequilibrium that exists between multiple genes in this chromosomal region. 15milarly DLG5 gene encodes scaffolding protein for epithelium; its mutation leads to weakening in epithelial integrity in IBD. 16PPARG (peroxisome proliferativeactivated receptor γ) variants have been linked with susceptibility in the SAMP1/YitFc mouse model of spontaneous chronic ileitis, and rare PPARG polymorphisms were found to be associated with human Crohn disease. 17PAR γ is a nuclear receptor that inhibits NFκB activity: its expressionis decreased in patients with active ulcerative colitis and its expression is upregulated by 5-aminosalicylic acid. 18In addition to a potential role in protecting against intestinal inflammation, treatment with the PPAR γ 18,19 ligand rosiglitazone was effective in an open-label trial involving ulcerative colitis patientsas well as in mouse experimental colitis. 20,21G16L1 (autophagy-related 16-like-1) is other gene which is a part of the autophagosome pathway and is critical to host cell responses to intracellular bacteria.Similarly, IRGM (immunity-related GTPase M), is also involved in autophagy and clearance of intracellular bacteria.NOD2, ATG16L1, and IRGM are expressed in multiple cell types, and their precise roles in the pathogenesis of Crohn disease have yet to be defined.Like NOD2, however, ATG16L1 and IRGM are related to recognition and response to intracellular pathogens, supporting the hypothesis that inappropriate immune reactions to luminal bacteria are important in pathogenesis of IBD. 8

Environmental factors
Apart from genetics, several alternative explanations, mostly related to lifestyle, are possible.The importance of environment is suggested by increasing incidence rates in previously less affected ethnic groups such as Asians and Hispanics 22 and in immigrants from low incidence regions moving to areas with a traditionally high incidence. 23ndustrialisation has greatly changed people's lifestyle.5][26][27][28] Though nicotine is not the cause, studies have shown that early tobacco use significantly increases the risk of developing the disorder. 29

Microbiota
Crohn disease frequently occurs after infectious gastroenteritis, 30 has a distinct mucosal flora (dysbiosis), 31 and increased numbers of intramucosal bacteria 32 often featuring adhesive species 34 and thus efforts to identify acausative infectious agent continue.Infectious granulomatous ileitis conditions including intestinal tuberculosis and Johne's disease are azoonosis caused by Mycobacterium avium paratuberculosis, which induces similar immune responses to Crohn disease. 35Controlled trials with antituberculous drugs have failed. 7Mycobacteria-related Crohn disease research frequently comes from ruminant farming areas where alternative explanations including contaminated foods and drinking water occur.However, mycobacteria still stand out from all other suspected infectious causes since genome wide association studies showed shared susceptibility loci with leprosy (ie, NOD2,LACC1) and polymorphisms in autophagy (ie, CARD9,IRGM1) required for mycobacterial clearance.Despite a growing body of data that suggest that intestinal microbiota contribute to IBD pathogenesis, their precise role remains to be defined. 7

Immune responses
Both Crohn disease and ulcerative colitis patients have activated innate (macrophage, neutrophil) and acquired (T and B cell) immune responses and loss of tolerance to enteric commensal bacteria. 36,37Tolerance, in normal hosts, is mediated by regulatory T cells, B lymphocytes, natural killer T cells and dendritic cells that secrete transforming growth factor and interleukin, interferon-α/β and prostaglandin J2.Antibody-neutralization studies have implicated tumor necrosis factor (TNF) and IL-12 p40 in the pathogenesis of Crohn disease. 14ohn disease seems to result from an impaired interaction of the intestinal commensal microbiota that is normally in a state symbiotic mutualism with the human host (immune system).Despite enormous progress in understanding the many facets of this ancient relation, distinction between primary inciting events and secondary occurrences is challenging.Although the mechanisms by which mucosal immunity contributes to the pathogenesis of ulcerative colitis and Crohn disease are still being deciphered, immunosuppressive and immunomodulatory agents remain mainstays of IBD therapy. 8e TH1 cytokine profile, which includes IFN-γ and IL-12 p40, is dominant in patients with Crohn disease.Traditional TH1 responses are mediated by IFN-γ, the production of which is stimulated by IL-12, produced by antigen-presenting cells.Most experimental colitis models also have a dominant TH1 response, although in several models TH1 responses can change into TH2 (type 2 T-helper lymphocyte) responses as the inflammatory process matures.IL-17 mediates TH17 responses.The production of this cytokine is stimulated by the production of IL-6, TGFB and IL-23 by innate immune cells and APCs, especially dendritic cells.Bacterial colonization stimulates IL-23 expression by ileal dendritic cells.The levels of both IL-23 and IL-17 are increased in Crohn disease tissues and most forms of experimental colitis.Of pathogenic importance, the IL-12-IFN-γ and IL-23-IL-17 pathways seem to be mutually exclusive, since IFN-γ suppresses IL-17, and vice versa.The levels of an IL-12-related protein, IL-27, are also increased in patients with Crohn disease.In addition, production of IL-21 is induced by IL-12 and is selectively increased in Crohn disease.Like IL-12, IL-21 stimulates T-bet, an intracellular transcription factor that is key to TH1 cell differentiation and activation. 14

Mucosal defects
The first line of defense of the mucosal immune system is a single layer of columnar epithelial cells covered by mucus produced by goblet cells with interspersed bacteria.Depletion in expression of MUC1 in the terminal ileum in patients with Crohn disease suggests that mucin cover becomes insufficient. 7Similarly defects in intestinal epithelial tight junction barrier function are present in patients with Crohn disease and a subset of their healthy first-degree relatives.
This barrier dysfunction co-segregates with specific disease associated NOD2 polymorphisms, and experimental innate and adaptive mucosal immunity and sensitize subjects to disease.Interestingly, the Paneth cell granules, which contain antimicrobial peptides that can affect composition of the luminal microbiota, are abnormal in patients with Crohn disease carrying ATG16L1 mutations, thus providing one potential mechanism where a defective feedback loop between the epithelium and microbiota could contribute to disease pathogenesis. 8e model that unifies the roles of intestinal microbiota, epithelial function, and mucosal immunity suggests a cycle by which transepithelial flux of luminal bacterial components activates innate and adaptive immune responses.In a genetically susceptible host, the subsequent release of TNF and other immune-mediated signals direct epithelia to increase tight junction permeability, which further increases the flux of luminal material.These events may establish a self-amplifying cycle in which a stimulus at any site may be sufficient to initiate IBD.Although this model is helpful in advancing the current understanding of IBD pathogenesis, a variety of factors are associated with disease for unknown reasons.For example, the risk of Crohn disease is increased by smoking, whereas that of ulcerative colitis is reduced. 8

Morphological features
Grossly, segmental distribution of the lesions (skip lesions) and preference for the right side of the colon are important diagnostic features.Other gross findings include: stricture and fissure formation, a cobblestone appearance, transmural involvement and creeping fat. 6

Inflammatory Bowel Disease
Classical microscopic features of active Crohn disease include abundant neutrophils that infiltrate and damage crypt epithelium.Crypt abscess and crypt destruction are another common findings.Ulceration is common in Crohn disease, and there may be an abrupt transition between ulcerated and normal mucosa.Mucosa has relatively normal appearance and retains most of the mucin producing goblet cells even adjacent to ulceration.The main features are presence of noncaseating granulomas, preservation of goblet cells, lymphoid aggregate etc.The absence of granulomas does not preclude a diagnosis of Crohn disease.Repeated cycles of crypt destruction and regeneration lead to distortion of mucosal architecture; the normally straight and parallel crypts take on bizarre branching shapes and unusual orientations to one another.Epithelial metaplasia (pseudopyloric metaplasia), Paneth cell metaplasia also may occur. 6,8usual Patterns of Disease in Crohn Disease Approximately 50% of Crohn Disease patients have colonic involvement and nearly 20% develop colitis without involvement of the oesophagus, stomach or small intestine.Unfortunately, many of the 'classic' features of Crohn Disease, such as transmural inflammation, strictures and fistulous tracts occur less commonly in the colon.Thus, some cases of Crohn Diseaseof the colon may mimic Ulcerative colitisby demonstrating only superficial mucosal involvement without inflammatory changes in the submucosa or muscularispropria, diffuse and continuous disease, or even pancolitis. 38In this situation, evaluation of mucosal biopsy samples of the distal ileum and colon for evidence of other 'hardcore' features of Crohn Disease [39][40][41][42][43] , combined with correlation with the clinical and endoscopic features of the patient (such as upper GI tract involvement), may help establish an accurate diagnosis.

Dysplasia and Cancer in Crohn Disease
Patients with Crohn disease are at increased risk for intestinal carcinoma.Small-bowel carcinoma in a patient with Crohn disease occurs at younger age.The carcinomas most often occur in ileum actively involved by Crohn disease.The carcinoma tends to be poorly differentiated and is associated with poor prognosis.Colon cancer; in patient with Crohn disease; occurs on average 10 years earlier.These carcinomas tend to be better differentiated than in small intestine. 44

Ulcerative colitis
Ulcerative colitis was first described in the mid-1800s, 45 When inflammatory bowel disease is identified in a new population, ulcerative colitis invariably precedes Crohn disease and has a higher incidence.The incidence of ulcerative colitis is 1.2 to 20.3 cases per 100,000 persons per year, and its prevalence is 7.6 to 246.0 cases per 100,000 per year, as compared with an incidence of 0.03 to 15.6 cases and a prevalence of 3.6 to 214.0 cases per 100,000 per year for Crohn disease. 46Ulcerative colitis is closely related to Crohn disease.However, ulcerative colitis is limited to the colon and rectum.Some extraintestinal manifestations of ulcerative colitis overlap with those of Crohn disease, including migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, skin lesions, pericholangitis, and primary sclerosing cholangitis. 8Similar to Crohn disease, etiopathology of Ulcerative colitis is largely unknown.The discovery that NOD2 variants are associated with susceptibility to Crohn disease opened a new era in the study of the genetic basis of inflammatory bowel disease. 47,48

Etiopathology of Ulcerative colitis
As Crohn disease, ulcerative colitis is believed to results from a combination of errant host interactions with intestinal microbiota, intestinal epithelial dysfunction, and aberrant mucosal immune responses.

Genetics
In studies of twins, and in genome wide association studies suggest larger number of susceptible loci for Crohn disease that genetic influences play a greater role in Crohn diseasethan in ulcerative colitis. 49Forty seven loci are confirmed till date to be associated with ulcerative colitis, of which 19 are specific for ulcerative colitis and 28 areshared with Crohn disease. 50Risk loci for ECM1, HNF4A, CDH1, and LAMB1 implicate dysfunction of the epithelial barrier;an association with DAP suggests a link to apoptosis and autophagy; and associations with PRDM1, IRF5, and NKX2-3 suggest defects in transcriptional regulation.In addition, multiple genesin the interleukin-23 signaling pathway overlap inulcerative colitis and Crohn disease (e.g., IL23R,JAK2, STAT3, IL12B, and PTPN2).HLA-DR and genes involved in helper T-cell types1 and 17 (Th1 and Th17) differentiation, such asIL10, IL7R, IL23R, and IFN-γ are risk loci linked to immune system-mediated diseases and also to ulcerative colitis.
The multidrug resistance gene MDR1 encodes P-glycoprotein 170, a transporter that governs efflux of drugs and possibly xenobiotic compounds from cells.P-glycoprotein 170 might also function as a 'flippase' that moves amphipathic substrates from the inner to the outer leaflet of the cell membrane.MDR1 variants have been associated with ulcerative colitis. 14Ulcerative colitis appears to be as genetically heterogeneous as Crohn disease, but given the large number of implicated genes and the small additive effect of each, genetic screening is not currently indicated to assess the risk of ulcerative colitis.

Microbiota
Intestine harbors a greaterand more diverse number of microorganisms thanany other organ. 51Thus intestinal health depends on a beneficial host-microbe interaction.The gut immune system is generallytolerant of this microbial load, and a breakdownin tolerance is postulated to be central tothe pathogenesis of inflammatory bowel disease. 52Although loss of tolerance to the gutmicrobiotais demonstrable in animal models of IBD, there is no evidencein with ulcerative colitis.
It has also been postulated that alterations in the composition of the gut microbiota, defects in mucosal immunity, or the both factors combined could lead to ulcerative colitis.However, supportive evidence is sparse.Thereis a consensus that the density of microbiota isgreater in patients with ulcerative colitis than in healthy control subjects, but whetherthere are reproducible, disease-specific alterationsis unclear. 2 The fact that antibiotic therapy as no clinical effect on ulcerative colitis arguesagainst an important role of bacteria in this disease. 2Although serumantibacterialantibodies are present in patientswith ulcerative colitis, they are much more commonand are found in higher titers in patientswith Crohn disease.Furthermore, the range ofantibodies against bacterial antigens (anti-I2, anti-OmpC, and anti-CBir1 antibodies) and fungalantigens (anti-Saccharomyces cerevisiaeantibodies[ASCA]) is broader in Crohn disease, whereasthe only ulcerative colitis-associated antibodyis perinuclearantineutrophil cytoplasmic antibody(pANCA), which recognizes nuclear antigens thatmay cross-react with bacterial antigens. 2

Immune Response
Intestinal homeostasis requires a controlled innate immune response to the microbiota, whichis recognized by toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors on epithelial and immune cells. 2 This recognition process contributes to tolerance,but when the process is dysregulated, inflammationensues.At present, there isno clear evidenceof specific, innate immune defects in Ulcerativecolitis.Overexpression of TLR2 and TLR4 by colonocytes 53 is probably secondary to inflammation.The production of proinflammatorycytokines, such as interleukin-1β,interleukin-6, tumor necrosis factor α (TNF-α), andtumor necrosis factor-like ligand 1 (TL1A), isuniversally increased in patients with inflammatorybowel disease but does not allow one to discriminatebetween ulcerative colitis and Crohndisease.Abnormalities in humoral and cellular adaptiveimmunity occur in ulcerative colitis.ElevatedIgM, IgA, and IgG levels are common in IBD, but there is a disproportionateincrease in IgG1 antibodies in ulcerativecolitis.[6-(31)] Abnormalities of adaptive immunity that differentiate ulcerative colitis from Crohn diseaseare defined by mucosal CD4+ T cells, whichwere initially divided into two lineages: Th1 andtype 2 helper T cells (Th2).Crohn disease is aTh1-like condition, on the basis of evidence of increased production of interferon-γ.In contrast, ulcerative colitis represents an atypical Th2 response, as indicated by the presence of nonclassical natural killer T cells in the colon that secrete abundant interleukin-13, which mediates epithelial-cell cytotoxicity, apoptosis, and epithelial barrier dysfunction.Interleukin-5-producing Th2-polarized T cells are also present in ulcerative colitis.The balance between Th1 and Th2 has been used to differentiate between ulcerativecolitis and Crohn disease.[56][57][58][59] Autoimmunity may play a role in ulcerative colitis.In addition to pANCA, this disease is characterized by circulating IgG1 antibodies against a colonic epithelial antigen that is shared with the skin, eye, joints, and biliary epithelium; since these are the sites of extraintestinal manifestations in ulcerative colitis, it is possible that crossreacting antibodies against the colon cause organ-specific damage.Tropomyosin 5, a structural protein, is the putative target autoantigenof the IgG1 antibodies, but evidence of classical antibody-mediated autoimmunity in ulcerative colitis is still lacking. 60,61

Mucosal Defects
Ulcerative colitis typically does not extend into the small intestine and occurs in proximity to the epithelium.Colonocytes are implicated in the pathogenesis of this disease.In ulcerative colitis there is an epithelial-barrier defect and impaired expression of peroxisome proliferatoractivated receptor γ (PPAR-γ), a nuclear receptor that regulates inflammatory genes.Variants of the XPB1 gene, the product of which is a component of the stress response of the endoplasmic reticulum in epithelialcells, have been linked to IBD, reinforcing the concept that colonocytes are involved in its pathogenesis. 45

Morphological features
Ulcerative colitis is characteristically a left-sided disease, which usually begins in the rectosigmoid area.In acute phase, mucosa is markedly hyperemic and petechias are seen.Longitudinal ulcers are seen in the mucosa along with several pseudopolyps in an otherwise flat surface.In chronic phase the colon is narrowed and shortened and becomes fibrotic. 2

Diffuse active colitis
Untreated ulcerative colitis in an active phase demonstrates a diffuse abnormality.The luminal border of the mucosa is irregular.In the lamina propria increased numbers of chronic inflammatory cells are present and may spill over into the superficial portion of submucosa.Goblet cell population is depleted.Cryptitis and crypt abscess are prominent.Atrophy, branching and budding of crypts are noticeable even in early stage.The most useful criteria for the diagnosis of ulcerative colitis are crypt distortion along with basal plasmacytosis. 44

Focal active colitis
Focal active colitis refers to the patchy distribution of combined architectural change and inflammation in a mucosal biopsy.Focal active colitis pattern consists of limited areas of increased inflammatory cells associated with focal architectural distortion; characteristically, some areas of the biopsy specimen maintain an essentially normal morphology.Focal active pattern is usually not seen in ulcerative colitis and presence of it suggests Crohn disease or infectious colitis.However, the focal active pattern may be present in resolving ulcerative colitis under medical treatment. 44 most instances, these two disorders may be readily distinguished from each other pathologically, particularly when each exhibits classic histological features (Table 2).However, some patients with IBD show overlapping pathological features of Corhn's disease and Ulcerative colitis, which make definite distinction between these two disorders difficult.Under these circumstances, the term "indeterminate" colitis (IC) has been used.However IC is not a disease entity and has no diagnostic criteria.Rather, it represents a provisional descriptive term to be used by pathologists' only when he or she is unable to establish a definite diagnosis given the information available at the time of surgical sign out.In fact, in up to 80% of cases, the true nature of the patient's underlying IBD usually becomes apparent within a few years. 1

Indeterminate colitis
Historically, the term 'IC' was originally used to describe the pathological findings in colectomy specimens from patients with fulminant colitis, which is a severe form of colitis associated with systemic toxicity and, occasionally, colonic dilation (toxic megacolon). 38Fulminant colitis often shows extensive transverse ulceration affecting right colon more severely than the distal colon. 62In most cases, the colitis is diffuse and continuous, but some may show complete, or relative, rectal sparing.Fissuring may also be present in some of the cases and are characterized by the presence of knife-like defects that extend into the superficial half of the muscularispropria.These ulcers are also often associated with transmural lymphoid inflammation.All these features are typically associated with Crohn disease.Some authors believe that the presence of fissuring ulcers supports a diagnosis of Crohn disease, whereas others regard them as part of the spectrum of severe Ulcerative colitis. 38However in other study superficial fissuring ulcers in their colectomy specimens were observed in 20% of cases with severe chronic active colitis. 38In another study of 67 patients with fulminant IBD, Swan et al. found that 87% could be accurately classified as either Ulcerative colitisor Crohn Disease based solely upon pathological evaluation of colectomy specimens.In that study, only the presence of granulomas and transmural inflammation in regions of intact mucosa predicted the development of Crohn Disease. 38It is well recognized that the presence of chronic active inflammation of the ileum, transmural lymphoid aggregates in areas underlying intact mucosa, deep fissuring ulcers that extend into the outer aspects of the muscularis propria, segmental involvement of the colon in a previously untreated patient, and the presence of noncaseating epithelioid granulomas unassociated with ruptured crypts, are individual features that strongly favour a diagnosis of Crohn Disease.Unfortunately, recognition of these 'hardcore' features may be difficult, particularly when the findings are limited, or masked, by extensive ulceration.Nevertheless, failure to recognize and accept any of these features as definitive evidence of Crohn Diseasemay lead to a potentially erroneous diagnosis of IC.

Morphologic variants of Ulcerative colitis
There are several circumstances in which the 'classic' morphological features of Ulcerative colitis may be altered or entirely absent.In some cases Ulcerative colitis may show discontinuous or patchy disease with rectal sparing involvement ileum, transmural inflammation or even granuloma formation.[68] In contrast to Crohn Disease, Ulcerative colitis does not typically involve non-colonic areas of the gastrointestinal tract.However, incompetence of the ileocaecal valve that result in retrograde flow of colonic contents into the distal ileum and inflammation, which is often referred to as 'backwash' ileitis. 38In most cases (88%), inflammatory changes consisted of a mild degree of neutrophilic inflammation in the lamina propria, which was often patchy in distribution and occasionally associated with focal cryptitis, crypt abscesses and a mild degree of villous atrophy and regenerative epithelial changes.Inflammation in the ileum may be considered part of the spectrum of Ulcerative colitis if the inflammatory changes are mild, superficial and confined to the distal 2-3 cm of ileum, and occur in a patient in whom all of the clinical, radiological and pathological features support a diagnosis of Ulcerative colitis. 38Transmural lymphoid aggregates are present in most cases of Crohn Disease involving the ileum, and less frequent in the colon.Occasionally, transmural mononuclear cell inflammation may be present in Ulcerative colitisas well; especially when superficial fissuring ulcers extend into the deep submucosa or superficial muscularis propria.However, in contrast to Crohn Disease, mural inflammation in Ulcerative colitisis typically not in the form of discrete lymphoid aggregates and usually underlies areas of severe ulceration. 38Thus, lymphoid aggregates in areas under intact mucosa are not a feature of Ulcerative colitis and, in fact, favour a diagnosis of Crohn Disease.
Approximately 30-40% of Crohn Disease cases contain either mucosal, or mural, non-necrotic granulomas. 383][74] The cluesto differentiate granuloma arising due to ruptured crypts are presence of neutrophils and lymphocytes along with histocytes and multinucleated giant cells.

Dysplasia and Cancer in Ulcerative Colitis
Patients with longstanding Ulcerative colitis are at increased risk for colorectal adenocarcinoma.Colitis associated carcinomas are often flat, infiltrate, and difficult to visualize by standard radiographic techniques, most gastroenterologists recommend regular surveillance for cancer or dysplasia, using colonoscopy with biopsy. 44he incidence of dysplasia in Ulcerative colitisis difficult to estimate; studies suggest a 5% incidence of dysplasia after ten years and a 25% incidence after 20 years. 1 The cumulative incidence of colorectal cancer after 25-35 years of Ulcerative colitis ranges from 3.1% to 43%.
Dysplasia, the presumed precancerous epithelial lesion, has been recognized adjacent to and distant from colitisassociated carcinoma.Furthermore, adenoma-carcinoma sequence has well been accepted.Thus identifying dysplasia and its subsequent adequate management remains vital for preventing it to transform into carcinoma.Dysplasia is recognized by well-defined criteria.However, epithelial repair may mimic as dysplasia, as both dysplasia and repair are associated with nuclear enlargement and hyperchromasia, increased mitoses and depletion of intracellular mucin.None the less, nucleus in repair are often round to oval with a smooth contour, they are evenly spaced and contain granular chromatin with single of multiple nucleoli.The nuclear-to cytoplasmic ratio is often decreased and the cell cytoplasm is eosinophilic.

Table 3 : Common conditions leading to diagnosis of Inde- terminate colitis
44wever, nearby crypt abscesses and cryptitis help to confirm the diagnosis of repair.Features that favour dysplasia over repair are shown in table4.The Inflammatory Bowel Disease-Dysplasia Morphology Study group has proposed the following three-tierd classification for biopsy interpretation in IBD: Positive, negative and indefinite for dysplasia.Positive biopsy specimens are further graded into high grade or low grade dysplasia.44