Inflammatory Disorders of the Large Intestine

Intestinal Barrier and Innate Immunity

The intestinal barrier, consisting of intestinal epithelial cells (IECs) and innate immune cells, maintains the equilibrium between luminal contents and the mucosa. Enterocytes, goblet cells, neuroendocrine cells, Paneth cells, and M cells each appear to play distinct roles in maintaining this equilibrium. Genetic deletion of Muc2 (mucin 2), a major goblet cell-derived secretory mucin, results in spontaneous colitis in murine models. Dendritic cells have been found to accumulate in the mucosa of patients with IBD. Blockage of CD40/CD40L interactions between dendritic cells and effector T-cell populations prevents experimental T-cell–mediated colitis.

Adaptive Immune Response

Both humoral and cell-mediated immunological mechanisms play major roles in the pathogenesis of UC. UC is associated with an increase in the synthesis of IgG, notably the IgG ₁ and IgG ₃ subclasses. Most patients have circulating antibodies to a variety of dietary, bacterial, and self antigens that are of the IgG ₁ subclass, and these are polyclonal in nature. Because serum antibody titers usually do not correlate with disease activity or course, it has been postulated that cross-reactivity between antibodies to bacterial antigens and colonocyte epithelial epitopes may help trigger an immunological response that leads to mucosal inflammation.

UC is associated with several autoimmune diseases such as diabetes mellitus, pernicious anemia, and thyroid disease. The possibility that UC is an autoimmune disease is supported by the fact that patients with UC have serum antibodies directed against lymphocytes, ribonucleic acid, smooth muscle, gastric parietal cells, and thyroid tissue. Patients also have antibodies to epithelial cell–associated components, notably an autoantibody against a 40-kDa epithelial antigen found in normal colonic epithelium. This IgG autoantibody was eluted specifically from colonic mucosa of patients with UC and was not found in patients with CD or other colonic inflammatory conditions. This antigen also shares epitopes with antigens found in the bile ducts, skin, eyes, and joints, sites that are commonly associated with extraintestinal manifestations of UC. The other autoantibody associated with UC is pANCA. It is found in 60% to 80% of UC patients and belongs to the IgG ₃ subclass. The exact antigen to which pANCA is directed is unknown. There is some evidence that the antigen is a 50-kDa nuclear envelope protein that is specific to myeloid cells. The pathogenic relevance of pANCA is unclear. It appears to be associated with an aggressive disease course and development of pouchitis.

Bacterial antigens also trigger innate immunity by activation of pattern-recognition receptors, which include Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Activation of TLRs and NLRs results in downstream activation of nuclear factor κB (NF-κB), which further stimulates production of various proinflammatory cytokines and chemokines. Defects in any of these pathways can result in abnormal bacterial processing and possibly IBD.

Colonic epithelial cells express class II major histocompatibility complex (MHC) antigens and can initiate an inflammatory response by acting as antigen-presenting cells. Increased turnover of colonic epithelium, reduced metabolism of short-chain fatty acids, abnormal membrane permeability, and altered composition of mucosal layers contribute to the pathogenesis of UC. ^, Animal models of colitis produced by disruption of colonic epithelium further support the role of epithelial cells in the pathogenesis of IBD.

Release of various cytokines from the T-cell inflammatory pathways may also lead to increased epithelial cell permeability and alteration of the endothelium, contributing to diarrhea and localized ischemia, respectively.

Gross Features

In untreated cases, the extent of colonic involvement depends on the clinical severity of disease. UC classically involves the rectum with variable, but continuous, involvement of the colon more proximally ( Fig. 17.7 ). According to the Montreal classification, the extent of UC is divided into ulcerative proctitis (involvement limited to the rectum), left-sided or distal UC (involvement of the rectum and sigmoid but not beyond the splenic flexure), and extensive UC or pancolitis (involvement of the rest of the colon proximal to the splenic flexure). At the initial onset of disease, pancolitis occurs in approximately 20% of patients, left-sided colitis in 50% to 60%, and proctitis or rectosigmoiditis in approximately 45% of patients. Skip lesions, in the form of appendiceal, periappendiceal, or ascending colon/cecal involvement, have been observed in as many as 80% of patients with subtotal UC (see Unusual Morphological Variants of Ulcerative Colitis). Based on a long-term follow-up study by Farmer and colleagues, pancolitis eventually develops in almost one-half (46%) of patients with proctitis or rectosigmoiditis and in more than 70% of those with left-sided colitis.

In the active phase of disease, the mucosa usually appears diffusely congested, granular, and edematous. Ulcers, when present, are usually small and oriented longitudinally in relation to the teniae coli. They often appear to undermine adjacent areas of mucosa, which leads to the formation of polypoid mucosal folds or inflammatory pseudopolyps. In such cases, the mucosa may have a cobblestone appearance, similar to that observed in CD. Rarely, an exaggerated form of pseudopolyp formation, known as filiform polyposis, may be present ( Fig. 17.8 ). It is characterized by the presence of elongated, slender, villiform, wormlike, polypoid mucosal projections and usually spares the rectum. In severe cases, ulcers may be extensive, involve large segments of bowel, and lead to near-total or total mucosal loss.

In cases of toxic megacolon, the bowel wall appears extremely thin, dilated, and congested. The serosal surface usually demonstrates fibrinous or fibrinopurulent exudate. Rarely, there is evidence of perforation. The mucosal surface in these cases is extensively denuded, hemorrhagic, ulcerated, and often covered with purulent exudates.

In the quiescent (inactive) phase of UC, the mucosa may appear completely normal, or it may show diffuse granularity, either with or without inflammatory pseudopolyps. In some cases of long-standing UC, the bowel wall is thickened and contracted (“colonic foreshortening”), and the mucosal surface may appear atrophic.

In treated UC, especially when patients have been given steroid enemas, the rectal mucosa may show minimal or no abnormalities on gross examination. Similarly, in patients who have received medical treatment before surgical resection, there may be focal, diffuse, or even widespread areas of grossly normal-appearing bowel between areas of affected bowel.

Microscopic Findings

Depending on the phase of disease and the degree of inflammatory activity, UC is categorized histologically as chronic inactive, chronic active, or active (without features of chronicity) for the purpose of diagnostic sign-out. Chronic colitis (regardless of “activity”) is defined by the presence of histological features of chronicity ( Box 17.1 ), such as crypt architectural distortion, crypt atrophy, diffuse mixed lamina propria inflammation, basal plasmacytosis, basally located lymphoid aggregates, and Paneth cell metaplasia (in the left colon). Other changes of chronicity include lamina propria fibrosis, pyloric gland metaplasia, and Paneth cell hyperplasia in the right colon. Common changes of “activity” include neutrophilic or eosinophilic cryptitis, crypt abscesses, regenerative or degenerative epithelial changes, hemorrhage, necrosis, erosions, and ulceration.

Unfortunately, there is no universally accepted method of grading histological activity in biopsy specimens from patients with UC. At least 18 different histological scoring systems have been proposed to categorize activity, but these are mainly used in research protocols and do not have much relevance to clinicians when deciding how to manage their patients. Scoring systems that have been used in clinical studies range from use of stepwise methods, in which disease activity is divided into rather subjectively assessed grades, to others that prefer use of a more quantitative methods, by using numerical scores that correspond to specific histological features. For instance, the Riley scoring system uses a four-point score ( none, mild, moderate , and severe ) to assess six histological features: presence of an acute inflammatory cell infiltrate (neutrophils in the lamina propria), crypt abscesses, mucin depletion, surface epithelial integrity, chronic inflammatory cell infiltrate (round cells in the lamina propria), and crypt architectural irregularities. This scoring system was applied in a prospective study that was aimed at predicting recurrence in 82 outpatients with asymptomatic UC in endoscopic remission. This scoring system was later modified (Modified Riley score) to rank the degree of inflammation hierarchically, and to exclude crypt architectural changes, which according to the authors, are not responsive to clinically relevant changes in inflammation. This system has never been validated but has been used in multiple randomized control trials.

Geboes et al. developed a scoring system that categorizes histological changes as grade 0 (structural change only), grade 1 (chronic inflammation), grade 2 (2a, lamina propria neutrophils and 2b, lamina propria eosinophils), grade 3 (neutrophils in the epithelium), grade 4 (crypt destruction), and grade 5 (erosions or ulcers). This system generates a score from 0 to 5.4 that increases with disease severity or activity. The Geboes scoring system has been shown to be reproducible to some degree, where the authors found moderate to good interobserver agreement among three pathologists (kappa 0.59 to 0.70).

More recently, two histological scoring methods have been developed and validated: the Nancy index and the Robarts histopathological index (RHI). ^, Both of these scoring systems demonstrate mostly a high degree of intraobserver and interobserver agreement. The RHI was developed by scoring biopsies according to the Geboes score and then determining which features were reproducible and correlated best with the pathologists’ interpretation of disease severity using a visual analog scale. Four features were found to correlate best with overall disease severity, including lamina propria chronic inflammation, lamina propria neutrophils, neutrophils in the epithelium, and the presence of ulcers and erosions. The Nancy index is a stepwise 5-item method that assesses lamina propria lymphoplasmacytic inflammation, neutrophilic inflammation, and ulcers to arrive at the final grade.

One simple and reproducible type of grading system that is commonly used in clinical practice by the authors of this chapter is as follows. The degree of activity is graded as mild if less than 50% of the mucosa shows evidence of activity, and the lamina propria is only mildly expanded by inflammatory cells. It is graded as moderate if more than 50% of the mucosa shows activity and/or if the lamina propria inflammatory component is moderately or severely dense, but there are no surface erosions or ulcers. It is graded as severe if surface erosion or ulceration is present, regardless of the density of inflammation in the lamina propria or epithelium. In this simple classification, “activity” includes any of the features outlined earlier in this chapter, and in this manner, it takes into account the fact that patients who are in an active phase of disease clinically may not necessarily show peak neutrophil influx at that point in time (see Figs. 17.10 to 17.12 ).

Chronic Active Colitis

Histologically, previously untreated UC in adults typically involves the colon in a diffuse and continuous manner, always beginning at the distalmost portion of the rectum and extending proximally to the point at which inflammation stops, which in most cases is rather abrupt ( Table 17.2 ). Typically, specimens from involved regions of the colon have a similar appearance. Usually, each biopsy fragment shows a homogeneous and diffuse pattern of injury, although the severity of inflammation may vary from region to region in the bowel (usually worse distally) or between individual biopsy fragments from one area of the colon, especially posttreatment (see discussion on posttreatment features later in this chapter).

TABLE 17.2

Features of Untreated Ulcerative Colitis and Crohn’s Disease

Untreated Ulcerative Colitis	Crohn’s Disease
Diffuse, continuous disease	Segmental disease
Rectal involvement	Variable rectal involvement
Disease worse distally	Disease severity is variable from segment to segment
No fissures (except in fulminant colitis)	Fissures, sinuses, fistulous tracts common
No transmural aggregates	Transmural lymphoid aggregates
Either no or only mild distal ileal involvement (less than 5 cm in general)	Often moderate to severe ileal involvement, either segmental or diffuse and usually more than 5 cm
Upper GI tract involvement (stomach, duodenum) less common	Upper GI tract involvement (esophagus, stomach duodenum, jejunum) much more common
Anal disease less common	Anal tags, fissures and fistulae are more common
Granulomas are less common, and when present are crypt-rupture (mucin) associated	Epithelioid granulomas unrelated to ruptured crypts common
Appendiceal involvement is more common and resembles chronic active colitis seen in the rest of the colon	Appendiceal involvement is less common

UC characteristically involves the mucosa and sometimes involves the superficial submucosa as well ( Fig. 17.9 ). The histological findings vary depending on the clinical phase of disease. Ultimately, in periods of clinical activity, UC is predominantly a lymphoplasmacytic inflammatory process with superimposed neutrophils, hemorrhage, and epithelial degeneration and regeneration. A dense, homogeneous lymphoplasmacytic infiltrate typically expands the lamina propria ( Fig. 17.10 ). The density of plasma cells is usually greatest in the basal region of the lamina propria (termed basal plasmacytosis ). Basally located lymphoid aggregates (situated between the bases of the crypts and the muscularis mucosae) are also common. They may show germinal centers. Expansion of the lamina propria and the presence of basal lymphoid aggregates contribute to irregular spacing of the crypts.

One characteristic and frequent morphological feature of UC is crypt architectural distortion, which is characterized by irregularly arranged, branched, dilated, and/or shortened crypts. In some circumstances, branching and shortening of crypts represents morphological manifestations of crypt regeneration. Most patients with new-onset (pretreatment) UC have experienced several weeks to months of subclinical or minimal inflammation, during which time the lamina propria has been inflamed, plasma cells have congregated in the basilar region of the lamina propria, and significant crypt injury with regeneration has occurred. Crypt architectural distortion is considered a hallmark of chronic injury. However, it may develop in any inflammatory disease of the colon that manifests as periods of repeated bouts of injury and repair before full mucosal healing. Thus when the inflamed mucosa is repeatedly exposed to bouts of injury followed by repair, the epithelium does not always heal with perfectly well-formed and aligned crypts. Crypt distortion is therefore not a specific feature of UC (or CD). It occurs in many other types of disorders, such as chronic recurrent ischemia, persistent or recurrent infections (e.g., C. difficile ), radiation colitis, drug-induced colitis, graft-versus-host disease (GVHD), and even microscopic colitis. Furthermore, not all patients with UC, even in an active phase of disease, reveal crypt distortion in every portion of the colonic mucosa. For this reason, absence of crypt distortion does not necessarily rule out a diagnosis of UC.

Depending on the severity of active disease, a neutrophilic inflammatory cell infiltrate (with or without eosinophils) may be seen within the lamina propria and/or in the surface and crypt epithelium (cryptitis); it may be minimal, focal and patchy, or diffuse and severe. Similarly, aggregates of neutrophils within the crypt lumina (crypt abscesses) may be focal or diffuse ( Figs. 17.11 and 17.12 ). Rupture of crypts caused by inflammation can lead to the development of aggregates of histiocytes, foreign-body giant cells, and even well-developed granulomas as a response to extravasated mucin ( Fig. 17.13 ). These mucin granulomas (crypt rupture–associated granulomas) are usually present in the deeper portions of the mucosa, where crypts tend to rupture more often compared with the superficial mucosa. Often, deeper cuts through tissue blocks are necessary to determine whether or not a granuloma is related to a ruptured crypt. Some patients show a marked foreign-body–type giant cell response or even a fully developed granulomatous response, which can be seen at the base of the mucosa. Distinguishing granulomas in UC from those in CD can be challenging, but the latter are more often randomly located in the mucosa, are more often superficial in location, and are typically unrelated to injured crypts (see Crohn’s Colitis). When a mucosal granuloma is identified, serial sections should be evaluated to determine whether it is located immediately adjacent to a ruptured crypt.

In areas of activity, the surface and crypt epithelium always shows regenerative and/or degenerative changes. Features of regenerative changes include loss of mucin, enlarged and variably sized nuclei either with or without nuclear stratification, hyperchromasia, prominent nucleoli, and increased mitotic activity. Features of degenerative changes include cytoplasmic vacuolization and heterogeneity, nuclear fragmentation and pyknosis, and lack of mitotic activity. In addition, the crypts may show increased apoptotic activity. In areas adjacent to erosions and ulcers, degenerative cells may acquire a syncytial appearance, with abundant and prominent eosinophilic cytoplasm ( Fig. 17.14 ). In some instances, the syncytial epithelium overlies stroma that is devoid of crypts and contains actively inflamed granulation tissue. Regenerating surface epithelial cells, which are cuboidal initially and then columnar with maturation, acquire a slightly more basophilic cytoplasm. On occasion, the surface epithelium may be villiform in appearance, resembling small-intestinal mucosa. Regenerative changes may mimic dysplasia (see Dysplasia in Ulcerative Colitis and Crohn’s Disease). Mucin reappears slowly, first in cuboidal cells and later in goblet cells. With time, goblet cells may become numerous.

Paneth cell metaplasia in the left colon and pyloric gland metaplasia are reliable histological indicators of chronic injury. In active disease, even the ascending colon, cecum, and transverse colon may show irregularity in the distribution and increased numbers of Paneth cells ( Fig. 17.15 ). Pyloric gland metaplasia is less common in UC than in CD. It is more commonly observed in samples from the proximal colon and is often seen in close proximity to ulcerated mucosa.

Occasionally, the rectum is completely free from inflammatory disease (absolute rectal sparing) or shows less activity than in the proximal colon (relative rectal sparing). This phenomenon is usually caused by the effects of prior medical treatment, either orally or, more commonly, with enemas (e.g., steroid enemas). However, on careful inspection, one often finds one or more subtle features of chronicity, which is evidence of prior inflammation and injury.

Grossly normal–appearing colonic mucosa proximal to regions of active colitis may also reveal a spectrum of abnormalities. Most commonly, there is a mild lymphoplasmacytic infiltrate within the lamina propria. However, the crypts are usually more evenly arranged and lack distortion. A few neutrophils may be present in the lamina propria or occasionally within a crypt, but neutrophilic crypt abscesses are rare. Eosinophils may also be increased and may produce small eosinophilic crypt abscesses on occasion. In the context of a patient with classic UC in the more distal colon, these changes in the proximal bowel are a reflection of the underlying inflammatory disorder.

Most patients with UC eventually enter a resolving, or healing, phase of disease, characterized by decreasing activity (and symptoms) after an active colitis episode. This phase of disease is characterized morphologically by less activity and less crypt injury, but higher levels of crypt regeneration and remodeling ( Fig. 17.16 ). Injured crypts typically heal from the base of the mucosa progressively upward toward the luminal surface. Neutrophils and other active components of crypt injury decrease first, followed by a reduction in lamina propria lymphocytes and plasma cells. During this initial healing phase, there is often much variability in the type and degree of mucosal inflammatory changes within biopsy fragments from different regions of the colon and even within individual fragments of mucosa from a single site. Neuroendocrine cell hyperplasia occurs in some patients, whereas others develop prominent lymphoid follicles that are more common in the distal colon and rectum (follicular proctitis). Follicular proctitis appears to identify a subgroup of patients who have a less favorable response to medical therapy. ^,

Chronic Inactive (Quiescent) Colitis

The resolution period of UC, characterized by decreasing activity and increasing repair, may last for several weeks or months. Thereafter, UC patients may be symptom free for variable but often long periods. This is the “inactive” or “quiescent” period of disease. During this time, the mucosa may be completely normal, or it may show various degrees of chronic inactive disease (mainly crypt distortion), either with or without mild patchy activity ( Fig. 17.17 ). Architecturally distorted crypts represent a” biomarker” of prior bouts of colitis. Alternatively, the colon may heal completely and thus appear normal histologically. The rate at which this occurs is variable among patients. For instance, patients with only mild active colitis of short duration can show complete restitution of architecturally normal mucosa within several months after the initial active episode. The pace of crypt remodeling is usually slow in most patients; such remodeling occurs typically over many weeks to months.

Unusual Morphological Variants of Ulcerative Colitis

A summary of the causes of unusual morphological patterns of disease in UC is provided in Box 17.2 . It is important that pathologists recognize these variants so they can avoid falling into diagnostic traps and misdiagnosing UC as CD. This section provides a summary of many of the causes of Crohn’s-like changes that may occur in UC as a result of a variety of factors such as treatment effect, age of the patient, systemic manifestations of disease, or simply a result of long-term waxing and waning of inflammatory activity. These include most commonly segmental or patchy involvement of the colon, rectal sparing, skip lesions, ileal or upper GI tract inflammation, aphthous ulceration, and granulomas, among others.

Ascending Colon, Cecum, and Appendiceal Involvement as “Skip Lesions” in Ulcerative Colitis

Some UC patients with either subtotal or limited left-sided colitis may show patchy, mild, chronic, or active inflammation in the cecum or ascending colon that may be falsely interpreted as CD because of the impression of segmental involvement of the colon, which is a classic manifestation of CD in the colon. Up to 65% of patients with UC have limited left-sided involvement initially. However, proximal extension occurs in 29% to 58% of such patients. ^{, ,} For instance, in one study by D’Haens and colleagues of 20 patients with established left-sided UC, 6 showed a sharp demarcation between affected and unaffected portions of colon, whereas 14 showed a more gradual transition. The area of transition in such cases may appear somewhat patchy, giving a false impression of skip lesions. Seventy-five percent of this latter group of patients showed an area of inflammation in the cecum, primarily in the periappendiceal mucosa, that was separate from the distal inflamed segment. In a study by Mutinga et al., 14 patients with both left-sided UC and pathologically confirmed patchy right-sided chronic inflammation were compared with 35 control patients who had limited left-sided UC only. The two groups had similar demographic features, extraintestinal manifestations, severity of disease, prevalence of progression to pancolitis, and natural history, which suggests that patchy right-sided inflammation in patients with left-sided colitis has little clinical significance. This phenomenon should be recognized by pathologists so a false diagnosis of CD can be prevented when there is an initial suspicion for segmental disease in the colon.

In a prospective study of 271 patients with UC, including 63 with inactive left-sided or subtotal colitis, periappendiceal cecal mucosal involvement was identified in 32% of patients. Similarly, since the original description by Davison and Dixon in 1990 of “discontinuous involvement” wherein the appendix was found to be inflamed in 21% of 62 cases of patients with only distal colonic UC, several other studies have shown that the appendix may be involved as a “skip lesion” in this disease, ^, although at least one other study failed to confirm this finding. In another study by Groisman et al., ulcerative appendicitis was present in 86% and 87% of patients with “nonuniversal” and “universal” UC, respectively. Their study included two cases with limited left-sided involvement combined with appendiceal involvement. Overall, the role of the appendix in UC is poorly understood. Patients with prior appendectomy have been shown to have a lower risk for UC. ^, In one study, the severity of appendiceal inflammation (ulceration) in patients with UC was a strong predictor of the development of pouchitis after a total proctocolectomy and ileoanal pouch procedure. In summary, involvement of both the appendix and the cecal or ascending colon can occur in patients with subtotal colitis. This phenomenon should be recognized by pathologists as an acceptable potential skip lesion in UC.

Ulcerative Colitis in Pediatric Patients

Several studies have shown that pediatric patients with untreated UC at initial clinical presentation may show evidence of relative, or even complete, rectal sparing or even patchy colonic disease on biopsy studies. Markowitz et al. reported 12 pediatric patients with untreated UC, 5 (42%) of whom showed patchy, mild active inflammation and mild crypt changes in the rectum, but diffuse involvement in the more proximal regions of the colon. In fact, one patient had a completely normal rectal biopsy specimen. A study by Glickman et al. compared the rectal mucosal biopsy appearance of 70 pediatric patients who had UC with that of 44 adult patients, all at initial presentation before medical treatment. Compared with adults, the pediatric patients showed significantly fewer cases of chronic active disease and a greater number of patients with microscopic skip areas and relative rectal sparing. In this study, 2 of the 70 pediatric patients had completely normal rectal biopsy specimens at initial clinical presentation, in contrast with none of the adult patients. Thus an absence of features of chronicity or the presence of mild active disease and microscopic skip areas at initial presentation in pediatric patients should not exclude a diagnosis of UC. In adults, relative (but not absolute) rectal sparing (i.e., less severe inflammation in the rectum compared with the proximal colon) may be seen, rarely, at initial presentation before treatment as well. ^, In one study, a 31% prevalence rate of relative rectal sparing was noted in a series of 46 adult patients with UC at initial presentation, but even in those cases, histological features of chronicity were almost always present in the rectal mucosa at the time of initial diagnosis.

Ileitis in Ulcerative Colitis

Patients with UC, and particularly those with involvement of the cecum and ileocecal valve, may also show active inflammation in the distal few centimeters of the terminal ileum; a condition that has been historically termed backwash ileitis (BWI). The hypothetical mechanism for this phenomenon is that when inflammation of the proximal cecum/ileocecal mucosa is severe enough, it may cause malfunction of the ileocecal junction (ICJ), retrograde flow of colonic contents into the distal terminal ileum, and secondary inflammation of the terminal ileum as a result of a “toxic” reaction to the luminal refluxate. ^, This theory was originally proposed in the early 20th century by Crohn and Rosenak in an effort to explain the observation that some patients had a previously undescribed “combined form of ileitis and colitis,” a constellation of findings that was unusual in “regional enteritis” or “ulcerative colitis.” In a more contemporary study of the ileum in UC patients, Haskell et al. reviewed 200 UC resection specimens and found active ileitis in 17% of cases; in most cases, the inflammation was confined to the distal 1 cm of the ileum. Ninety percent of cases consisted of mild, patchy neutrophilic inflammation in the lamina propria, focal cryptitis or crypt abscesses, and patchy villous atrophy and regenerative changes ( Fig. 17.18A ). In rare instances, surface ulceration or even pyloric (mucous gland) metaplasia was present as well (see Fig 17.18B ). Most interestingly, in their study, a “backwash” mechanism for ileitis in UC was questioned because some patients showed a conspicuous lack of cecal involvement. The authors of that study suggested that ileitis may have developed as a result of drug toxicity (such as NSAIDS) or perhaps as a result of the bowel preparation procedure, rather as a result of backwash. More recently, in a critical evaluation of the literature on BWI by Patil et al., the concept of BWI was discarded in favor of a theory that ileitis in UC patients may more likely be related to primary involvement of the underlying disease, rather than as a result of mechanical backwash of colonic contents into the ileum. The originally proposed backwash theory has never been proven experimentally and, in fact, was postulated during a time when little was known regarding the broad pathological manifestations of CD in the GI tract, including the colon, or the variability of involvement of the upper GI tract in either CD or UC. Regardless, most cases of ileitis in UC, regardless of the precise etiology, show only mild inflammation. Thus when a patient with presumed UC shows more severe ileal findings, such as deep or even fissuring ulceration, abundant submucosal inflammation, non–crypt-rupture related granulomas, or long lengths of ileal involvement (generally >5 cm), a strong suspicion for CD should always be entertained, particularly when the patient does not have inflammation of the proximal cecum and ileocecal valve.

Gastric and Duodenal Involvement in Ulcerative Colitis

Gastric and/or duodenal involvement may rarely occur in patients with clinically and pathologically confirmed UC. For instance, Valdez et al. described four patients with chronic active inflammation in the duodenum similar in appearance to the patients’ colonic disease. In another study, five patients had chronic active gastritis, and four had chronic active duodenitis; in these cases, the upper GI findings resolved after colectomy. Several similar cases have been reported in the Japanese literature. In a study by Lin and colleagues, esophageal, gastric, and duodenal biopsies from 69 patients with proven UC were compared with those of 97 control subjects. The most common pattern of inflammation in the upper GI tract was “focal gastritis,” followed by the presence of mixed inflammation in the basal aspect of gastric mucosa, and superficial plasmacytosis ( Fig. 17.19 ). Diffuse chronic duodenitis was observed in 10% of UC patients, and these changes persisted after colectomy. The authors did not find specific mucosal changes in esophageal biopsy specimens from patients with UC. Until such cases have been followed for longer periods, it is difficult to know with certainty whether the finding of upper GI inflammation in UC represents a primary manifestation of UC or simply an unrelated, coincidental inflammatory disorder. Ultimately, more precise characterization of these types of UC cases will likely require long-term follow-up to help establish specific criteria of upper GI involvement in patients with UC.

Aphthous Ulcers in Ulcerative Colitis

Although aphthous type ulcers are common in CD, they may occur in other types of colitides and even in UC, as well. For instance, they have been reported in infectious colitis, diverticular disease–associated colitis, and diversion colitis, among other conditions. In one study, aphthous-type ulcers were present in 17% of UC resection specimens. In this study, manifestations of CD did not develop in any of the patients, nor was the presence of aphthous ulcers associated with the subsequent development of pouchitis on follow-up.

Granulomas in Ulcerative Colitis

Some cases of active UC, particularly the more severe ones, may develop granulomas in the deep mucosa, and these are most often associated with ruptured crypts (see Fig. 17.13 ). This finding may be prominent in some UC patients and may, in fact involve several contiguous crypts in the deep mucosa. Granulomas may also develop in UC from degenerated collagen, particulate matter, superimposed infections, or as a result of a drug reaction, therefore not all are related to ruptured crypts. In equivocal cases, “mucin granulomas” related to ruptured crypts may be distinguished from primary granulomas in CD by the use of histochemical stains or by evaluation of multiple deep tissue sections to find the ruptured crypts. In general, granulomas located in the superficial aspects of the mucosa (and certainly in the submucosa) are more likely to be CD-related compared with basally located mucosal granulomas, which are more often crypt rupture–related in etiology.

Medical Therapy

Current therapeutic strategies for UC are separated into those that treat active disease (induction therapy) and those that prevent disease recurrence once remission has been achieved (maintenance therapy). Medical therapy focuses on agents that alter the host’s immune response in an effort to decrease mucosal inflammation. First-line therapy consists of oral 5-ASA preparations such as sulfasalazine, Pentasa, Asacol, and balsalazide. Sulfasalazine induces remission in 39% to 62% of patients with mild to moderate UC. Topical 5-ASA enemas can be used to treat disease located as much as 20 cm from the anal verge. Moderate to severe flares of UC are treated with systemic glucocorticosteroids. Azathioprine and 6-mercaptopurine are two purine analogue immunomodulators that interfere with nucleic acid metabolism and exert a cytotoxic effect on lymphocytes. Cyclosporine A, another potent inhibitor of cell-mediated immunity, is primarily indicated in patients with severe steroid-refractory disease.

Several recent advanced biological therapies and small molecules have shown clinical efficacy in patients with moderate to severe colitis who have previously failed to improve with corticosteroids and/or thiopurines. These therapies include anti–TNF agents like infliximab, adalimumab, and golimumab, anti-α ₄ β ₇ -integrin antibody (vedolizumab), anti-IL-12/IL-23p40 antibody (ustekinumab), and small-molecule antibody preferentially targeting JAK1 and JAK3 (tofacitinib).

Evaluation of Medical Therapy

The goal of medical therapy is to achieve clinical remission. In current clinical practice, disease activity is monitored by assessing patients’ clinical symptoms and severity of colonic inflammation by colonoscopy. However, there is evidence to suggest that endoscopic findings do not necessarily correlate with histological disease, especially after treatment. ^,

Effects of Prior Treatment on the Histology of Ulcerative Colitis

In patients who have received medical therapy (oral or enema), mucosal histological changes can vary considerably. Portions of mucosa may heal completely, whereas others may still be active. Healing occurs in a segmental or patchy fashion. This pattern of healing gives an impression of segmental or patchy disease (skip lesions), which may be mistaken for CD. In this circumstance, exceptions to the classic principles of UC pathology may lead to diagnostic confusion.

Classic teaching emphasizes that UC is characterized morphologically by the presence of diffuse fixed architectural or cellular mucosal changes (or both) that categorize the process as chronic. However, in 1993, Odze and colleagues prospectively evaluated 123 rectal mucosal biopsy specimens from 14 patients with pathologically confirmed UC treated with either 5-aminosalicylic acid (5-ASA) or placebo enemas. During the course of treatment, 29% of rectal biopsies from 64% of patients were histologically normal, showing no evidence of chronic or active disease. Patients treated with 5-ASA showed a significantly higher percentage of normal biopsy specimens (obtained from areas of mucosa previously shown to be involved with chronic active disease) than did the placebo group. This was the first report to demonstrate that “fixed” chronic features in UC may revert to normal in the natural course of the patient’s illness and that topical therapy may enhance this phenomenon. Subsequent studies by Kleer and Appelman, Bernstein and colleagues, and Kim and colleagues, all of whom evaluated patchiness of disease and patterns of involvement in UC colorectal biopsy specimens with time, confirmed and expanded the initial findings of Odze’s group.

In these studies, 30% to 59% of patients, some of whom were treated with oral sulfasalazine or steroids (or both), showed either patchiness of disease or rectal sparing on follow-up surveillance biopsies. Awareness of these data should prevent misinterpretation of the findings of a normal rectal biopsy specimen or patchiness of disease in medically treated patients with UC as evidence against this diagnosis or as representing skip areas characteristic of CD. In addition, patients with low-grade indolent disease, particularly those in clinical and pathological remission, may show minimal architectural features of chronicity or perhaps even a completely normal-appearing biopsy specimen during the natural waxing and waning course of their illness. However, it must be emphasized that these data relate primarily to biopsy material from treated patients. They do not apply to patients whose UC has not yet been treated or in whom a diagnosis is being considered on the basis of the evaluation of a resection specimen. Evaluation of disease “continuity” by analysis of mucosal biopsies is not useful to distinguish UC from CD of the colon in previously treated IBD patients. In contrast, large portions of mucosa from a resection specimen with a normal histological appearance are an indication of true segmental disease and normally provide reliable evidence in support of an alternative diagnosis such as CD.

Histology of Patients in Clinical Remission

The European Crohn’s and Colitis Organization and the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) define remission as complete resolution of clinical symptoms and endoscopic mucosal healing. Endoscopic mucosal healing in UC is defined by resolution of visible mucosal inflammation and ulceration, often assessed by using the Mayo endoscopic scoring method. As discussed earlier Chronic Inactive (Quiescent) Colitis, as mucosal healing occurs, there is quite a lot of variability in the type and degree of inflammatory changes such that at any given point of time, mucosal biopsies may show changes ranging from active colitis, chronic active colitis, chronic inactive colitis, or completely normal mucosa on histological examination. In fact, in a prospective observational study of 103 patients with UC in clinical remission, histological inflammation was found in 54% of patients receiving maintenance therapy, and 37% had at least moderate inflammation based on histology scores. Of the 52 patients with endoscopic evidence of left-sided colitis, 34% had histological inflammation in the proximal colon.

Deep remission is a more recent concept in IBD management. It is currently defined as the combination of clinical remission and mucosal healing. In a large retrospective study consisting of 252 IBD patients who were treated with anti–TNF-α therapy for ≥11 months, 122 patients achieved deep remission. The majority of patients in deep remission (81%) had “inactive disease,” while 19% had active disease histologically.

Histological Features Predictive of Clinical Outcome and Disease Recurrence

Much emphasis has recently been placed on the importance of mucosal healing as an outcome for therapies in patients with IBD. Few studies in UC have shown that despite endoscopic mucosal healing, active histological disease is associated with poor long-term outcomes. ^{, ,} In two studies by Bitton et al. and Bessissow et al. in which biopsies from UC patients with endoscopically inactive disease (defined as a Mayo endoscopic score of 0) and a follow-up period of 12 months were evaluated, basal plasmacytosis, whether present in a focal or diffuse pattern, was found to be an independent predictor of clinical relapse in UC patients with mucosal healing. In a more recent study of 646 UC patients, 60% had endoscopic mucosal healing, 40% had histological quiescence, and 10% had histological normalization on follow-up colonoscopy. Of the 310 patients who were in clinical remission, histological normalization was independently associated with increased odds of relapse-free survival compared with histological quiescence (hazard ratio [HR], 4.31; 95% CI, 1.48 to 12.46; P = 0 .007) and histological activity (HR, 6.69; 95% CI, 2.16 to 20.62; p = 0.001). Another study by Zezos and colleagues found increased numbers of lamina propria eosinophils in patients with active UC, and severe eosinophilic infiltration was the most significant predictor of treatment failure in these patients. In a recent study consisting of 281 UC patients, histological features of UC activity were associated with increased rates of systemic corticosteroid use, colectomy, and hospitalization in the entire cohort (P <0.05 for all) and with increased rates of systemic corticosteroid use in an analysis limited to patients in endoscopic remission (p <0 .001); in patients in endoscopic remission, only histological activity was independently associated with use of systemic corticosteroids (multivariate OR, 6.34; 95% CI, 2.20–18.28; p <0 .001). Compared with patients without histological evidence of UC activity, patients with only a small number of mucosal neutrophils still had higher rates of systemic corticosteroid use (p <0.001). Interestingly, in contrast with the aforementioned studies, this study did not find any association between basal lymphoplasmacytosis or intramucosal eosinophilia and poor clinical outcome.

Lastly, in a large meta-analysis that included 28 studies contributing 2677 UC patients, histologically active disease was associated with an overall increased risk of relapse (OR 2.41, 95% CI, 1.91 to 3.04), with a similar effect noted in the subgroup with an endoscopic Mayo score of 0 versus 0 or 1. More rigorous Geboes cutoffs demonstrated numerically stronger impact on relapse rates: Geboes <3.1 (OR 2.40, 95% CI 1.57–3.65), Geboes <2.1 (OR 3.91, 95% CI 2.21–6.91), and Geboes 0 (OR 7.40, 95% CI 2.00–18.27). Among individual histological features, basal plasmacytosis (OR 1.94), neutrophilic infiltrations (OR 2.30), mucin depletion (OR 2.05), and crypt architectural irregularities (OR 2.22) predicted relapse.

Histological Inflammation as a Predictor of Colorectal Neoplasia

Persistent histological inflammation has been associated with an increased risk for development of colorectal neoplasia in patients with UC. In a case control study of 204 patients with UC, histological and endoscopic activity predicted the development of neoplasia during the 14-year study period on univariate analysis. However, only histological inflammation was predictive on multivariate analysis (OR, 4.69; 95% CI, 2.10 to 10.48; p <0.001). In another cohort study of 418 UC patients, 15 developed advanced neoplasia during a median follow-up period of 6.7 years. In this study, the average histological inflammation score correlated with neoplasia development on multivariate analysis (HR, 3.8; 95% CI, 1.7 to 8.6). In a more recent meta-analysis of 1443 patients, Flores et al. showed that the pooled odds ratio for colorectal neoplasia was 3.5 (95% CI, 2.6 to 4.8; p <.001) in those with any mucosal inflammation and 2.6 (95% CI, 1.5 to 4.5; P = 0.01) in those with histological inflammation, when compared with those with mucosal healing. These findings could have implications on surveillance for CRC screening in patients with long-standing UC where clinicians may consider adjusting screening intervals in individuals who lack mucosal healing at surveillance colonoscopy.

Surgical Therapy

Surgical therapy is indicated in cases of medically refractory disease, recurrent systemic complications, unacceptable side effects of medical therapy, colonic perforation, colonic dysplasia, or carcinoma. Surgical choices include subtotal colectomy with ileostomy, colectomy with ileorectal anastomosis, and proctocolectomy with ileal pouch–anal anastomosis (IPAA). A variety of configurations of the ileal pouch have been designed, with J- pouch, S- pouch, and K- pouch being the most common. The J- pouch procedure is commonly performed in patients with refractory UC or UC-associated neoplasia. In patients with UC-associated dysplasia of the rectum or sigmoid colon, mucosectomy of the rectal cuff is often performed during the pouch construction.

Clinical Course

The typical course of UC consists of periods of remission interrupted by flares of activity. In approximately 5% of patients, the course is complicated by toxic megacolon, defined as acute colonic dilation (with a transverse colon diameter >6 cm radiologically) with loss of haustration in a patient with a severe attack of colitis. It is usually encountered early in the course of disease and in some cases may be the initial presentation of UC. Approximately 50% of patients respond to medical therapy alone. Perforation is the most important predictor of mortality. Surgery is recommended for patients with perforation or clinical deterioration after 48 to 72 hours of medical therapy.

Colonic strictures develop in almost 5% of UC patients. Their presence should always prompt a high index of suspicion for malignancy, especially if the stricture is located proximal to the splenic flexure. In a retrospective study comprising 1156 patients, 24% of strictures were found to be malignant. Most of the malignant strictures were located proximal to the splenic flexure, were clinically symptomatic, and developed late in the course of disease (after 20 years). Cancers associated with strictures tend to be more advanced than those not associated with a stricture.

Patients with UC have an increased risk for CRC, and the primary risk factor is the duration and extent of the disease (see Dysplasia in Ulcerative Colitis and Crohn’s Disease).

Genetic Factors

The relative risk (RR) for development of IBD among first-degree relatives of patients with CD is 14 to 15 times higher than in the general population. Ethnicity also appears to play a significant role. Eastern European (Ashkenazi) Jews have a two-fold to four-fold higher risk for CD than non-Jews from the same geographic location. Further support for a genetic predisposition is provided by data on monozygotic and dizygotic twins. ^, The concordance rate for CD is 67% among monozygotic twins and 8% among dizygotic twins, suggesting a strong genetic influence. Although results are inconsistent and vary with the population being studied, numerous studies have found both positive and negative associations between HLA antigens and the development of CD. ^,

Genome-wide association studies and computerized meta-analyses have identified 71 susceptibility loci for CD on 17 chromosomes thus far. Three important pathways have been highlighted by these studies. The first susceptibility locus was identified in 2001 as nucleotide-binding oligodimerization domain 2 (NOD2) or caspase-recruitment domain 15 (CARD15). A homozygous carrier of disease-specific allelic variants has a 17.1-fold increased risk for CD, whereas the OR for a heterozygous carrier is 2.5. Genetic polymorphisms in NOD2/CARD15 are present in 20% to 30% of patients with CD, and the abnormalities correlate with younger age at onset, ileal location of disease, and an increased likelihood of stricture formation. ^, NOD2/CARD15 mutations are more common in white patients with CD but are rare in Asians and Africans. The NOD2/CARD15 gene product binds to muramyl dipeptide, a component of bacterial peptidoglycan found in both gram-positive and gram-negative bacteria. ^, NOD2/CARD1 is expressed in Paneth cells that produce endogenous antimicrobial peptides known as defensins. NOD2/CARD15 gene variants interfere with binding to muramyl peptide, resulting in decreased antibacterial defense.

The second important pathway implicated in CD pathogenesis is related to autophagy, a unique process by which cytoplasmic constituents are isolated within a membrane-bound vesicle and then delivered to lysosomes for elimination. Misfolded or misaggregated proteins are eliminated via this pathway without inciting an inflammatory or autoimmune response. Variants in at least two autophagy-related genes have been associated with CD, namely, the autophagy-related 16-like 1 (ATG16L1) gene and the immunity-related guanosine triphosphatase family member M (IRGM) gene on chromosome 5.

The third pathway associated with CD is related to IL-23. IL-23 is a cytokine produced by dendritic cells and macrophages in response to various antigenic signals. In response to IL-6 and transforming growth factor-β (TGF-β), naïve CD4+ T cells upregulate the IL-23 receptor (IL-23R), which results in autocrine generation of effector T cells that produce IL-17. Although most common single nucleotide polymorphisms (SNPs) in the IL23R gene are associated with an increased risk for CD and UC, rare variants appear to be protective against the development of CD. ^,

Environmental Factors

The gradually increasing incidence of CD has also been attributed to a variety of environmental factors. Higher socioeconomic status, use of oral contraceptives, NSAID use, increased intake of refined sugars, and decreased intake of dietary fiber have all been implicated as risk factors for CD. Zinc deficiency is associated with immunological dysfunction in patients with CD, and some data suggest that an elemental diet may improve CD by reducing intestinal permeability.

In contrast with UC, CD is more prevalent among smokers. Smoking is an independent risk factor for clinical, surgical, and endoscopic recurrences in CD and also appears to influence disease activity after surgery. Although the pathogenesis is unclear, it is believed that smoking causes alteration of intestinal permeability, induces cytokine production, and promotes production of microvascular thrombi. ^,

Immune Factors

Similar to UC, disturbance of the intestinal epithelial barrier and innate immunity also plays a role in the pathogenesis of CD. Analysis of intestinal biopsies from patients with CD shows downregulation of the junctional protein epithelial cadherin, which composes the tight junctions of this physical barrier.

Interaction of effector T cells and antigen-presenting cells is vital to the pathogenesis of CD. Processing of luminal antigens by dendritic cells located within the lamina propria and the subsequent interaction between MHC class II molecules and T-cell receptors leads to activation and differentiation of T cells. The helper T-cell Th1 and Th17 responses that characterize CD are influenced by cytokines IL-23, IL-6, and TGF-β. Within mononuclear cells, NF-κB plays a key role in regulating transcription of IL-1, IL-6, IL-8, TNF, and other peptides that generate an inflammatory response. TNF is not only essential in formation of granulomas, but also causes neutrophil activation and, along with interferon-γ, induces expression of MHC class II molecules on IECs.

TNF and other proinflammatory cytokines also promote expression of adhesion molecules on endothelial cells, which leads to trafficking of inflammatory cells into mucosa. Integrins α ₄ β ₇ and α _E β ₇ have ligands (mucosal addressin cellular adhesion molecule and E-cadherin, respectively) that are specific to the intestinal environment. Antibodies to the α ₄ subunit of integrin have a therapeutic role in the management of CD.

Tissue destruction (especially penetrating ulcers, fistulas, and sinuses) ultimately results when proinflammatory substances such as prostaglandins and matrix metalloproteinases are elaborated by mononuclear cells and granulocytes. Mural fibrosis, another characteristic finding of CD, is a result of TGF-β that is released in the presence of inflammation. It stimulates production of type III collagen, which not only promotes healing of ulcers but also contributes to the formation of strictures. Fat wrapping (“creeping fat”) is an indicator of transmural disease that is often identified intraoperatively. It results from upregulation of peroxisome proliferator–activated receptor-γ (PPAR-γ), which regulates homeostasis of adipose tissue. Histologically, the finding of pyloric gland metaplasia in the lower GI tract indicates chronic mucosal injury. Pyloric glands are a form of ulcer-associated cell lineage (UACL); they represent budlike glandular structures that develop from the base of intestinal crypts at sites of chronic ulceration. The UACL expresses a variety of peptides implicated in the repair of damaged GI mucosa, notably epidermal growth factor and members of the trefoil peptide family, which restores epithelium in areas of mucosal ulceration.

The pathophysiology of diarrhea in CD is related to multiple factors. Increased mucosal permeability caused by inflammation and production of prostaglandins, biogenic amines, neuropeptides, and reactive oxygen metabolites results in exudation of proteins and fluids. Bacterial overgrowth and altered colonic mobility in areas of strictured bowel also contribute to diarrhea.

Gross Features

CD is classically characterized by segmental involvement of the affected areas of bowel, although pancolitis, and even proctitis as the only manifestation of colonic involvement may occur in a small proportion of cases ( Fig. 17.20A ). The serosal surface often appears congested and may be covered with a fibrinous exudate. Fat wrapping (creeping fat) along the antimesenteric border is a common finding in CD. In contrast with UC, the bowel wall in CD is typically thickened. It does not lie flat on opening. Mucosal aphthous ulcers overlying lymphoid aggregates are an early feature of CD. A zone of hyperemia often surrounds larger ulcers. As the disease progresses, ulcers enlarge to form discontinuous, serpiginous, or bear claw–type longitudinal furrows (see Fig. 17.20B ). Areas of edematous, mildly inflamed, or even normal mucosa are located between areas of longitudinal ulcers; this results in the development of a cobblestone appearance of the mucosa. Inflammatory pseudopolyps are most commonly encountered in the transverse colon and splenic flexure. In segments of bowel involved by disease, the wall of the bowel is usually thick and fibrotic. Fissures, sinuses and fistulous tracts, and mural or pericolonic abscesses may be present in complicated cases.

Strictures are more common with long-standing disease. Depending on the degree of obstruction, the bowel wall proximal to the stricture may be secondarily dilated and congested ( Fig. 17.21 ). Perforations are uncommon in CD, occurring only in 1% to 3% of cases. ^, They occur as a result of superimposed ischemia or infection or as a complication of fissures, sinus tracts, or fistulas. Fibrous adhesions may seal off sites of perforation, so they may not be visible on gross examination of the bowel.

Microscopic Features

Mucosal Changes

Similar to UC, and depending on the phase of disease, the mucosa may show a wide spectrum of changes ranging from completely normal to diffuse and severe chronic active inflammation with ulceration. In biopsies, mucosal disease is categorized similar to UC: chronic inactive, chronic active, or active (see earlier discussion). Histological features of chronicity include crypt architectural distortion, crypt atrophy, diffuse mixed lamina propria inflammation, basal plasmacytosis, basally located lymphoid aggregates, pyloric gland metaplasia, and Paneth cell metaplasia (in the left colon). Other changes of chronicity include lamina propria fibrosis and Paneth cell hyperplasia in the right colon. “Activity” is characterized by the presence of neutrophilic or eosinophilic cryptitis, crypt abscesses, regenerative and/or degenerative epithelial changes, necrosis, erosions, and ulceration. Grading of the degree of inflammation in patients with CD is difficult and has not been standardized. This is also because some areas of the bowel may show severe ulcerating disease, and others adjacent to it may be completely normal. However, in individual biopsies, grading the degree of activity can be done similar to the system proposed by the authors in the Ulcerative Colitis section earlier in this chapter.

In active CD, the disease may be patchy, with foci of injured and inflamed crypts situated adjacent to completely normal crypts. Two types of ulcers are characteristic of active CD: aphthous and fissuring ulcers. Aphthous ulcers arise in focal, mildly active CD. They are well-delineated, small, superficial lesions that overlie lymphoid aggregates. They usually involve a portion of mucosa occupied by about two to four crypts in length. The earliest stage is a mild neutrophilic infiltrate in the superficial half of the lymphoid aggregate. Neutrophils infiltrate the crypts and form small basilar crypt abscesses, producing epithelial necrosis and an intraluminal exudate ( Fig. 17.22 ). Concomitant neutrophilic infiltration and erosion of the superficial epithelium develops into a small microabscess that covers the lymphoid aggregate as the ulcer expands. Irregularly shaped crypts with regenerative epithelial changes are typically found at the edges of older (healing) ulcers. Aphthous ulcers can continue to expand and connect to form serpiginous or longitudinally oriented ulcers.

Crypt disarray is a feature of mucosal involvement in CD, similar to UC. There is significant variation in the size and shape of crypts. Features such as crypt branching and shortening are most easily appreciated at medium or low magnification ( Fig. 17.23 ). Heterogeneity in the density and distribution of lymphoplasmacytic inflammation within the lamina propria is a common finding in CD, as it is in UC. Well-circumscribed, focal collections of lymphocytes that surround several crypts (lymphoid aggregates) simulate normal lymphoid follicles. However, lymphoid aggregates in CD may reveal crypts within their center, whereas in normal lymphoid follicles, the crypts are pushed toward the periphery.

Although nonnecrotizing epithelioid granulomas are characteristic of CD, they are neither specific nor sensitive for this diagnosis. ^{, ,} The prevalence of granulomas in endoscopic biopsy samples ranges from 13% to 50%; in resections, it ranges from 40% to 60%. Granulomas are more frequently encountered early in the course of disease. They are typically sarcoid-like and composed of aggregates of epithelioid histiocytes admixed with lymphocytes and neutrophils ( Fig. 17.24 ). Occasionally, giant cells are present. In some cases, they may be very sparse and poorly formed, consisting only of small, pericryptal collections of closely arranged histiocytes, referred to as pericryptal microgranulomas . Serial step sections enhance the likelihood of detecting pericryptal microgranulomas. They may be present in involved as well as in uninvolved segments of colon. They may be present in any layer of the bowel wall or within pericolonic lymph nodes ( Fig. 17.25 ).

Granulomas in CD should be distinguished from mucin granulomas that form around ruptured crypts, which is common in UC (see Pathological Features in the Ulcerative Colitis section earlier in this chapter). Macrophages within mucin granulomas usually have a greater amount of bubbly or clear cytoplasm, which is caused by phagocytosis of mucin and crypt contents. Foreign-body giant cells usually are not a component of CD-related granulomas, but they may be found in mucin granulomas. Mucin stains are not always helpful because a small amount of mucin may also be present in the cytoplasm of macrophages in CD-related granulomas. Thick-walled capillaries, pericryptal fibroblastic sheaths, and tangential sections of germinal centers may mimic the well-formed granulomas of CD. The presence of necrotizing granulomas or a large number of granulomas should prompt a workup for an infectious etiology such as tuberculosis, histoplasmosis, yersiniosis, or sarcoidosis.

Pyloric gland metaplasia is far more common in CD than in UC, and it is frequently present in the small bowel. In colonic CD, pyloric gland metaplasia is more common in the cecum and right colon ( Fig. 17.26 ).

Mural Changes

Among the common mural changes of CD are knifelike fissuring ulcers and sinus tracts, which typically occur at right angles to the longitudinal axis of the bowel. They may extend through the bowel wall and may develop into a fistula or result in pericolonic abscess formation ( Fig. 17.27 ). They are usually lined by acute inflammatory cells, necrotic and granulation tissue, and loose aggregates of epithelioid histiocytes resembling early granulomas. Multinucleate giant cells may be present as well. Dense lymphoid aggregates, with or without germinal centers, are usually found at the mucosal-submucosal junction. However, transmural lymphoid aggregates that are located in the deeper aspects of the bowel wall, including the subserosal adipose tissue (“Crohn’s rosary”), are characteristic of CD ( Figs. 17.28 and 17.29 ). These are defined as collections of predominantly small, mature-appearing lymphocytes of variable size that are distributed throughout the bowel wall. Some cases of CD show prominent perivascular lymphoid aggregates, which may or may not be associated with granulomas, particularly in the submucosa. This feature has led some authorities to postulate that CD may represent a vascular disorder.

Abnormalities in smooth muscle, such as splaying and hypertrophy of the muscularis mucosae and distortion (and hypertrophy) of the muscularis propria, are common in long-standing CD. Proliferation of smooth muscle that obliterates the submucosa (“muscularization of submucosa”) occurs more commonly in stricturing CD. CD also affects the neural tissue. There is both hypertrophy of nerve trunks and an increase in the number of ganglion cells. ^, Large, abnormal fusiform nerve bundles may be seen throughout the affected bowel wall. Additionally, the myenteric plexuses may show infiltration by lymphocytes (myenteric plexitis) ( Fig. 17.30 ). Some studies have shown that myenteric plexitis in the proximal margins of an ileocolonic resection is more likely to be present in resection specimens of patients with a previous surgery for CD and of those with a shorter duration of disease before surgery. The severity of inflammation also appears to correlate with severity of endoscopic recurrence.

Some studies suggest that colonic CD less frequently shows major pathological features than does ileal CD. A study by Soucy and colleagues showed that patients with isolated CD had significantly fewer major pathological features of CD, such as strictures/stenosis, pericolonic adhesions, segmental disease, the finding of proximal disease worse than distal disease, perivascular lymphoid aggregates, and pyloric gland metaplasia, compared with those with ileal CD. A small proportion of patients from both groups showed inflammatory changes limited to the mucosa, similar to what is seen in UC (see later discussion).

Perianal Crohn’s Disease

Perianal involvement occurs in approximately 74% of CD patients, typically within 10 years of the initial diagnosis, and it generally increases in frequency in patients with more distal colonic disease. In 20% to 36% of patients with CD, the patients’ perianal disease actually precedes the intestinal disease. Skin tags or fibroepithelial polyps are the most common type of perianal lesion in CD, being present in 40% to 70% of cases. Histologically, they resemble fibroepithelial polyps that occur in non-CD patients. Other manifestations of anal CD include anal fissures, stenosis, and anorectal abscesses and fistulas, the latter comprising 18% of all CD-related perianal lesions. The histological features of perianal CD are similar to CD elsewhere in the GI tract in that the specimens from excisional biopsies, limited resections during fistula repair, or proctocolectomy for severe or medically refractory perianal disease show mucosal ulceration accompanied by transmural lymphoid aggregates and mural fibrosis. One note of caution is that the fistulae may be associated with a foreign-body–type giant cell reaction, and this should be distinguished from true granulomas when evaluating whether the patient has CD. Medical management remains the main type of therapy for most patients with perianal CD.

Superficial (Ulcerative Colitis–Like) Crohn’s Colitis

As mentioned previously, the colon is involved in almost 50% of CD cases, either alone or in combination with the small intestine. However, in some studies, up to 20% of CD patients have disease limited to the colon. Although some cases of Crohn’s colitis show classic features of CD (e.g., fissuring ulcers, sinus tracts, transmural lymphoid aggregates, submucosal fibrosis, granulomas), others show few or none of these features and resemble UC, both clinically and, particularly, histologically. These cases have been termed superficial Crohn’s disease or UC-like Crohn’s disease because the inflammatory changes are limited to the mucosa and, in some cases, the superficial submucosa, similar to UC ( Fig. 17.31 ). In these cases, a diagnosis of CD may be established by noting the presence of typical CD in other regions of the GI tract, such as the distal small intestine or the perianal region, or by showing other cardinal features of CD such as granulomas unrelated to ruptured crypts, segmental involvement of the colon with skip areas unrelated to treatment effect, or absolute rectal sparing from the initial onset of disease. In addition, CD also should be suspected in patients who have UC-like features in the colon and severe anal or perianal disease (e.g., fissures, fistulas). UC-like CD is rare. In one of the earlier studies that evaluated 10 patients with “superficial” CD, the diagnosis of CD was rendered based on the association with classic CD in other segments of the same resection specimens, a previous history of resection for CD, small bowel involvement, segmental or irregular disease distribution, and presence of granulomas.

In a comprehensive case-control study by Soucy et al. comprising 73 patients with isolated colonic CD and 45 patients with ileocolonic CD, all of whom had detailed pathological evaluation of a wide variety of UC and CD features, the incidence of UC-like CD was 14% and 13%, respectively, in the two groups. Patients with UC-like CD were younger than those who had classic CD with mural involvement. In this study, 50% of patients with superficial UC-like CD had only left-sided colitis, whereas 19%, 13%, and 6% showed right-sided, total, and subtotal colitis, respectively. Granulomas were observed in 44% of cases. Of the four UC-like CD patients who underwent an IPAA procedure, none showed an anastomosis breakdown. When the UC-like colonic CD cohort was compared with patients with non–UC-like colonic CD, the mean age at diagnosis was significantly younger in the former group (25 vs. 35 years; P = 0.02). However, there were no differences in the pathological (nonmural) features or in overall outcome between these two groups.

In another study consisting of 21 CD patients with UC-like pancolitis at presentation who underwent a pouch procedure, only 14% had pouch complications that necessitated pouch resection. Furthermore, recurrent CD in the small intestine developed in only 5%. Therefore it appears that many patients with UC-like colonic CD have good success after a pouch procedure, and this approach may be a viable option in affected patients who are either resistant to permanent ileostomy or prefer a pouch procedure.

Resection Specimens

UC characteristically involves the mucosa in a diffuse and continuous manner. It almost always affects the rectum. The terminal ileum may be affected to a lesser degree and exclusively in patients with pancolitis (i.e., BWI). Infections, drug or medication-related injury (e.g., NSAIDs), and bowel preparation agents can also result in inflammation of the terminal ileum. In contrast, CD shows segmental or patchy involvement of the bowel and often affects longer lengths of terminal ileum, both actively as well as chronically. In a resection specimen, a diagnosis of UC is usually established by the presence of diffuse chronic active colitis or chronic inactive colitis involving the mucosa in the absence of mural changes typical of CD, such as fissuring ulcers, transmural lymphoid aggregates, non–mucin-related granulomas, mural fibrosis, and fistulas or sinus tracts. Neural hyperplasia, hyperplasia of muscularis mucosae, and submucosal fibrosis are also less common in UC than in CD. In addition, involvement of other regions of the GI tract, especially perianal disease, is a sign of CD. Upper GI involvement in UC has been described, but it is unclear whether these changes are specific to UC or represent a nonspecific systemic immune response to a generalized inflammatory condition. A summary of the classic microscopic features of UC and CD is provided in Table 17.2 .

Because most resections are performed for medically refractory disease or disease-related complications and therefore have been treated medically, both UC and CD may show patchy, or segmental, histological changes. One may also see a reduction in the amount of transmural inflammation in CD. Granulomas are also far less common after treatment.

Biopsy Specimens—Before Medical (Drug) Treatment

UC and CD demonstrate considerable overlap in morphological features in biopsy samples with chronic and/or active disease. Furthermore, because the characteristic features of CD are typically found deeper in the bowel wall, it is difficult or impossible to distinguish UC from CD based solely on analysis of mucosal biopsy specimens. However, in untreated cases, features in favor of CD are granulomas not associated with crypt rupture, long or multiple segments of small bowel involvement, clear evidence of upper GI involvement (esophagus, stomach, duodenum, jejunum), rectal sparing at disease onset, particularly in adults, fistulas, and CD-like perianal disease, such as recurrent and severe or unremitting fissures, fistulas, anal tags, ulcers, and hemorrhoidal disease. Patchy disease in the same segment before treatment and evidence of deep and prominent submucosal involvement in a patient without fulminant colitis are additional features that favor CD over UC.

Biopsy Specimens: Post–Medical (Drug) Treatment

After medical therapy, either orally, intravenously, or by enema, an uneven pattern of healing caused by the therapeutic effects of drugs used for the disease often cause the histological features of UC to become patchy in distribution, mimicking the pattern of CD in the colon (see Unusual Morphological Variants of Ulcerative Colitis). Thus in the posttreatment setting, pathologists cannot consider “patchiness” of disease or “rectal sparing” as features necessarily indicative of CD. In medically treated patients, unless there is confirmed radiological evidence of CD-like anal or perianal disease, granulomas unrelated to ruptured crypts, or definite CD-like ileal or upper GI involvement, it is almost impossible to distinguish UC from CD in this setting.

Grading of Dysplasia

According to the grading system proposed by Riddell and colleagues in 1983, dysplastic changes in UC and CD are separated into three distinct categories: negative for dysplasia, indefinite for dysplasia, and positive for dysplasia (low and high grade). The Vienna grading system, which denotes five diagnostic categories, is used by many pathologists in Japan and Europe. A comparison of the two systems is outlined in Table 17.4 . Both visible and invisible dysplastic lesions are graded in the same manner.

The grade of dysplasia is determined by evaluating a combination of cytological and architectural alterations of the epithelium. A diagnosis of “negative” is reserved for nondysplastic or regenerating epithelium ( Fig. 17.35 ).

Cases are considered “indefinite for dysplasia” when the features of the atypical epithelium resemble dysplasia, but because of other factors such as inflammation, ulceration, or technical artifact, a definite diagnosis cannot be established with complete certainty ( Fig. 17.36 ). Inflammation and ulceration make interpretation of atypical changes difficult (i.e., reactive vs. neoplastic). Regenerating epithelium often shows enlarged and variably sized nuclei, nuclear stratification, prominent nucleoli, and increased mitoses. These changes overlap with those observed in true dysplasia. In some cases, tangential sectioning of the tissue or severe cautery or processing artifact may also render an atypical focus difficult to interpret. In general, the presence of surface maturation is usually (but not always) indicative of a regenerative process. Thus the presence of this feature should always evoke great caution in diagnosing true dysplasia ( Table 17.5 ).

In low-grade dysplasia, the crypts show a tubular and/or villous configuration and may also demonstrate focal or mild crypt budding and crowding. Cytologically, dysplastic crypts are lined by cells that show nuclear enlargement, elongation (often referred to as pencillate ), increased nucleus-to-cytoplasm (N:C) ratio, hyperchromasia, stratification, a clumped chromatin pattern, single or multiple nucleoli, and hypereosinophilic, mucin-depleted cytoplasm ( Fig. 17.37 ). Dysplastic epithelium normally involves both the crypt and surface epithelium, but early cases may show involvement of the crypts only ( crypt dysplasia; see later discussion). Mitotic figures are often plentiful, but atypical mitotic figures are less common than in high-grade dysplasia. In low-grade dysplasia, the nuclei are usually limited to the basal half of the cell cytoplasm, and there are no significant architectural abnormalities such as glandular crowding, cribriforming, or a back-to-back gland pattern. Other, less common features of low-grade dysplasia include dystrophic goblet cells and endocrine and Paneth cell metaplasia.

With progression from low- to high-grade dysplasia, the cells acquire more cytological atypia, characterized by even more pronounced nuclear enlargement, pleomorphism, hyperchromasia and, in particular, loss of nuclear polarity ( Fig. 17.38 ). The nuclei may show a more “open” chromatin pattern and contain prominent and enlarged nucleoli. Full-thickness nuclear stratification is characteristic when the nuclei are pencil shaped. However, many high-grade lesions show enlarged, but irregular, round nuclei rather than pencil-shaped nuclei. In these cases, nuclear stratification may not be present. Architecturally, back-to-back glands or cribriforming may be present, and this is always considered a high-grade feature, especially when it is prominent and even if the nuclei appear more low-grade cytologically. Mitotic figures, both typical and atypical, are more frequent than in low-grade lesions and are usually present in both the upper and lower portions of the crypts and in the surface epithelium. In general, the features of the most atypical portion of dysplastic mucosa determine the overall grade of dysplasia in any particular biopsy sample. However, there is no uniform agreement regarding the proportion of high-grade dysplastic crypts that is necessary to upgrade a biopsy from low to high grade. A simple rule of thumb is that there should be more than one or two (i.e., more than rare) high-grade crypts present to designate a biopsy as high-grade, but admittingly, this number varies among expert pathologists.

Intramucosal carcinoma is defined by the presence of cells or glands that have penetrated into, but not beyond, the lamina propria or muscularis mucosae. Common patterns of early invasion include single-cell or small-gland infiltration, glands with irregular jagged contours, and extensive cribriforming with pushing borders. Desmoplasia is absent when the carcinoma is limited to the mucosa. Thus its presence is normally diagnostic of submucosal invasion ( Fig. 17.39 ).

Morphological Types of Dysplasia

Historically, intestinal (“adenomatous”), hypermucinous/villous, and serrated dysplasia were considered the predominant morphological subtypes of dysplasia in IBD. In one study of IBD cancers, 52% of dysplastic lesions were villous, 29% were serrated, 5% were tubular (adenomatous), and 13% showed mixed features. However, more recently, an international group of IBD pathology experts proposed a novel histological classification system of IBD-associated dysplastic lesions that serves to recognize several additional variants that are rare and often difficult to recognize ( Table 17.6 ). This new classification includes four general categories: intestinal, gastric, mixed intestinal and gastric, and unclassifiable . The intestinal type of dysplasia is further separated into tubular/villous (adenoma-like), goblet cell–deficient, crypt cell, sessile serrated lesion (SSL)-like, traditional serrated adenoma (TSA)-like, and serrated, not otherwise specified (NOS) subcategories. The tubular/villous (adenoma-like) intestinal-type of dysplasia remains the most common and most well-characterized type, both histologically and clinically, However, there is emerging data with regard to the other subtypes, and this is discussed in more detail later. Unfortunately, much of the prior dysplasia literature either does not specify clearly the type of dysplasia under study or refers specifically to the intestinal type. As a result, the following discussion applies mainly to the tubular/villous intestinal type of dysplasia, unless otherwise specified.

Intestinal Dysplasia

Tubular/Villous “Adenoma-like” Dysplasia

This type of dysplasia is by far the most common type of dysplasia encountered in patients with IBD. Morphologically, it resembles conventional colorectal adenomas. The growth pattern is tubular and/or villous, and the crypts are often crowded. The nuclei are enlarged, elongated, hyperchromatic, and stratified. The density of goblet cells is variable. The intervening columnar cells are enterocyte-like but may contain a small amount of microvesicular mucin. Some lesions contain prominent Paneth cells or endocrine cells. Surface maturation is minimal or absent except near villous tips (see Fig. 17.37 ).

Goblet Cell–Deficient Dysplasia

This form of dysplasia is characterized by crypts that either lack completely, or show only rare, goblet cells. The cells show nuclear hyperchromasia and stratification and elongation of nuclei, and it involves the crypts as well as the surface epithelium ( Fig. 17.40 ). In the original study that described this morphological variant of dysplasia, it was associated with the highest interobserver agreement (95% agreement) among all GI IBD pathology experts.

Crypt Cell Dysplasia

Crypt cell dysplasia is characterized by a noncrowded, uniform flat tubular growth pattern of the epithelium. The crypts are lined by “terminally differentiated” enterocytes interspersed with goblet cells, basally located Paneth cells, and scattered endocrine cells ( Fig. 17.41 ). The nuclei are typically round or oval-shaped, enlarged, hyperchromatic, or vesicular. As opposed to normal or reactive epithelium, crypt cell dysplasia shows lack of maturation to the surface with the nuclei showing either very little or no reduction in overall size. Paneth and endocrine cells may be sparse or completely absent in some cases. The term crypt cell dysplasia is a consensus-based revision of the original term dysplasia with terminal epithelial differentiation in the prior study that described the rare morphological subtypes of dysplasia.

Serrated Dysplasia (Sessile Serrated Lesion–like Dysplasia, Traditional Serrated Adenoma–like Dysplasia, and Serrated Dysplasia Not Otherwise Specified)

It has been known for quite some time that serrated lesions, both visible and invisible, may develop in IBD patients. In fact, some early studies had suggested that serrated dysplasia is quite common, and in some studies, even more common than the intestinal type. Unfortunately, early studies did not differentiate the various subtypes of serrated dysplasia or recognize that even IBD patients may develop sporadic serrated lesions. Thus the old literature is now difficult to interpret. Serrated lesions may be visible or invisible. Visible lesions are often polypoid, and these range from those that resemble conventional hyperplastic polyps ( Fig. 17.42A ) at one end of the cytological atypia scale to SSLs and TSAs at the other end of the scale. In some cases, serrated lesions may not quite fit nicely into any of these categories, and in these cases the term serrated dysplasia NOS may be used. Invisible (randomly sampled) and nonpolypoid colonic mucosa may also reveal dysplastic lesions with a serrated pattern of growth and even some with cytological and architectural features identical to that of an SSL or TSA.

Sessile serrated lesion–like dysplasia is similar to SSLs seen in the sporadic setting and is characterized by crypts with serrated architecture wherein the serrations may involve the basal or superficial crypts, or both. The crypts show dilation, with or without lateral extension, resulting in L- or T- shaped configurations (see Fig. 17.42B ). However, unlike sporadic SSL, flat crypt bases are not a required feature. The cells have microvesicular cytoplasm and are interspersed with smaller numbers of goblet cells. The nuclei are round to oval or slightly elongated, hyperchromatic, and may contain inconspicuous nucleoli. They are basally located and may be slightly stratified at the crypt base, and there may be maturation at the surface. This category excludes lesions that resemble conventional SSLs without cytological dysplasia.

Traditional serrated adenoma-like dysplasia resembles a sporadic TSA in which the lesion is composed of villiform epithelial proliferation containing slitlike epithelial serrations along with ectopic crypts or aberrant crypt foci. The individual cells show pencillate nuclei with fine chromatin and prominent eosinophilic cytoplasm (see Fig. 17.42C ). In a recent study that evaluated 52 TSA-like lesions in 30 IBD patients, the prevalence of TSA-like lesions in IBD patients was found to be 0.4%. In this series, 23/27 TSA-like lesions identified in colectomy specimens presented as ill-defined plaquelike areas of the mucosa with a granular appearance, and low-grade and high-grade serrated dysplasia was found in 15 of 27 and 10 of 27 cases, respectively.

Little is known regarding the biological characteristics and natural history of serrated lesions in IBD. However, there are some data on hyperplastic changes and hyperplastic-type polyps. In a large clinicopathological and outcome study published in abstract form, 188 polyps from 161 IBD patients with at least 1 serrated polyp were analyzed. Most were hyperplastic polyps (97%) that were detected microscopically, not endoscopically. Adenocarcinoma, adenoma, or flat or elevated dysplasia did not develop in any of the patients, but additional hyperplastic or inflammatory polyps developed in 33% of the patients. In a retrospective study consisting of 94 patients with “hyperplastic polyp-like changes” in biopsies of flat mucosa obtained during routine surveillance (“flat serrated change”), the authors found that 12.8% of these patients had subsequent visible dysplasia on follow-up. However, a multivariate analysis did not show a statistically significant difference in the risk between patients with and without these lesions. Based on these results, the authors suggested that there should be no change in routine surveillance protocols for patients with invisible hyperplastic polyp–like serrated change. One study evaluated serrated lesions in 78 IBD patients and classified them as SSA/P-like (negative for dysplasia), TSA-like (positive for low-grade dysplasia), and cytologically atypical hyperplasia–like (indefinite for dysplasia). The authors found that SSA/P-like visible lesions in IBD occurred preferentially in females and in the right colon, similar to sporadic polyps. Nearly 11% of these nondysplastic SSA/Ps were associated with synchronous or metachronous neoplasia over a follow-up period of 103 months. In contrast, TSA-like and cytologically atypical hyperplasia–like polyps were significantly associated with synchronous or metachronous neoplasia (low-grade dysplasia in 17, high-grade dysplasia in 6, and invasive adenocarcinoma in 3).

Gastric Type Dysplasia

Rarely, dysplastic lesions in either UC or CD are composed nearly exclusively of cells with mucinous cytoplasm, similar in appearance to gastric foveolar cells. These cases typically show either no or only a few goblet cells within the dysplastic epithelium. The predominant growth pattern of these lesions may be tubular/villous, completely villous, or even serrated.

Gastric dysplasia has been termed mucinous, hypermucinous, or hypermucinous villous in prior studies. It is a rare form of dysplasia, and when present, it may show such minimal cytological atypia that it may be difficult to recognize it as unequivocally neoplastic. In general, the dysplastic epithelium shows relatively small, hyperchromatic, basally oriented nuclei with minimal, or in some cases, no cytological atypia. ^, ( Fig. 17.43 ). However, more traditional dysplastic changes may be present in higher-grade lesions. These features include a crowded, back-to-back arrangement of glands lined by cells with hyperchromatic and markedly enlarged nuclei. Prominent nucleoli are common. For the most part, the nuclei maintain their basal orientation or are only partially stratified. In general, the colonic epithelium is rather resistant to mucinous metaplasia, with a few exceptions such as pyloric metaplasia, or focally within hyperplastic polyps (in a microvesicular pattern). Thus the finding of gastric-like mucinous metaplasia should always arouse strong suspicion for gastric dysplasia in an IBD patient. In three recent studies (one published in abstract form) that evaluated the different morphological subtypes of dysplasia in IBD, the prevalence of mucinous dysplasia ranged from 6.8% to 14%. Given the limited number of cases of mucinous dysplasia reported to date, the natural history and biological characteristics of this variant remain largely unknown.

Gastric serrated dysplasia is similar to tubular/villous adenoma–like dysplasia but is distinguished by a strikingly serrated growth pattern involving both the basal and superficial crypts, sometimes resulting in mucin-filled cystic glands. The nuclei are round and vesicular and show little or no reduction in size near the surface ( Fig. 17.44 ).

Early (Crypt) Dysplasia

Although better characterized in patients with Barrett’s esophagus, rarely patients with IBD may develop early dysplastic changes limited to the bases of the crypts without involvement of the surface epithelium (i.e., surface maturation is present). The lesions usually have a flat configuration, noncrowded crypts, and cytoplasmic features that simulate the repertoire of normal colonic epithelium. This is also known as crypt dysplasia ( Fig. 17.45 ). In our experience, most patients with crypt dysplasia reveal conventional dysplasia (involving both crypt and surface epithelium) elsewhere in the colon at the time of discovery of crypt dysplasia. Because crypt regeneration also shows surface maturation, a diagnosis of crypt dysplasia should not be made in biopsy specimens exhibiting inflammation or ulceration or in those that are not well oriented. At this time, the biological characteristics and natural history of crypt dysplasia in IBD are largely unknown. In a small series of 14 colon biopsies from 7 patients with IBD, aneuploidy was detected in all 14 biopsies with crypt dysplasia in IBD, and 6 patients developed HGD ( n = 5) or adenocarcinoma ( n = 1) in the same colonic segment where crypt dysplasia was diagnosed within a mean follow-up duration of 27 months.

Campylobacter jejuni

C. jejuni is one of the most frequently isolated stool pathogens in patients with ASLC. In immunocompromised patients, Campylobacter fetus is more frequently isolated. The incidence of C. jejuni –related diarrhea is 4% to 11% in the United States. Bacterial transmission usually occurs via contaminated food. In developing countries, the infection is hyperendemic in children younger than 2 years of age. The most common presenting symptoms are diarrhea (90%), fever (90%), and abdominal pain (70%). These may be accompanied by headache, myalgia, and vomiting. Stool examination typically reveals red blood cells and leukocytes. Campylobacter DNA may be isolated in as many as 19% of affected patients with acute-onset diarrhea.

Salmonella Species

At least 2000 serotypes of nontyphoid Salmonella species have been identified as potential causative agents of gastroenteritis (nontyphoid salmonellosis). Almost 45,000 cases of Salmonella gastroenteritis are reported annually. In the United States, Salmonella enteritidis and Salmonella typhimurium are the most commonly isolated species. Infection is most likely to develop in children younger than 1 year of age. In addition, patients with achlorhydria, hemolytic anemia, immunosuppression, or malignancy (e.g., disseminated carcinoma, hematolymphoid malignancies) are predisposed to Salmonella infection. Gastroenteritis develops in 75% of patients infected with this organism. Patients usually present with nausea, vomiting, fever, and bloody diarrhea.