Inflammatory Bowel Disease

Ilyssa O. Gordon

Chronic idiopathic inflammatory bowel disease (IBD) includes two chronic gastrointestinal (GI) disorders of unknown etiology: ulcerative colitis (UC) and Crohn disease (CD). The natural history of IBD differs from patient to patient. Disease severity at its onset, disease extent, and patient age at the time of diagnosis, along with other variables, determine overall disease severity and the likelihood of subsequent morbidity and mortality. Once established, IBD patients suffer episodic acute attacks that become superimposed on chronic disease. As a result, the patient is likely to suffer from disabling disease for decades.

▪ EPIDEMIOLOGY, RISK FACTORS, AND PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

Epidemiology

The annual incidence of IBD in North America is 19.2 cases per 100,000 person-years for UC and 20.2 cases per 100,000 person-years for CD, and the overall incidence and prevalence of IBD have been increasing (1). Both CD and UC are predominantly diseases of young adults, with a peak incidence occurring between 10 and 39 years of age, with no significant gender difference. At age 10, both diseases rapidly increase in incidence. Overall, both UC and CD show the highest incidence in 20- to 29-year-olds (1). A second peak of IBD occurs in the United States in the sixth and seventh decades, especially in females (2), although many epidemiologic studies have not found a second peak (3).

Epidemiologic studies show that the incidence and prevalence of IBD vary significantly depending on geographic location and patients’ racial or ethnic backgrounds. IBD occurs worldwide and exhibits a relatively low but increasing incidence in Asian, Mediterranean, and Middle Eastern countries and a higher incidence in European countries, the United States, Canada, Australia, and New Zealand (4). This may reflect racial, ethnic, and genetic factors, as well as socioeconomic, health care availability, and data collection and reporting factors. Prevalence rates for IBD among non-Caucasians in the United States are lower than rates for Caucasians, although IBD-associated hospitalizations and mortality were both disproportionately highest among African Americans (5). Jewish families, particularly those of Ashkenazi origin, have a high incidence of IBD, likely associated with genetic factors. Migration studies have confirmed that cohorts, which often correspond to ethnic groups that move to more industrialized countries, have an increased incidence of IBD, although rates often remain lower than in natives of the industrialized country (6).

Risk Factors

Tobacco Use and Exposure

The association between tobacco use and development of IBD is well established. Smoking decreases the risk for the development of UC but exacerbates and aggravates Crohn disease (7,8). Former smokers have a lower risk of UC than do those who never smoked. In addition, exposure to passive smoke also appears to confer a lessened risk of developing UC relative to nonexposed nonsmokers (9). Overall, the effect of smoking appears to be dose dependent (10). Tobacco use is also associated with protection against sclerosing cholangitis and pouchitis in UC patients (10,11). Although the specific mechanism by which the effects of tobacco impact IBD are not known, likely pathways include the toxic effects of cigarette smoke components on the gut microflora, on intestinal permeability, on the gut and systemic immune system, and on epigenetic events (12). Nicotine itself is thought to be beneficial in IBD through anti-inflammatory mechanisms, and nontoxic nicotinergic agents are being investigated as a therapeutic option (13).

Appendectomy

Appendectomy early in life (before the age of 20) has been shown in several studies to decrease the risk of developing UC (14,15), while the data on risk for Crohn disease are conflicting. Interestingly, the risk for UC is reduced only in patients who undergo appendectomy for acute appendicitis and not in those whose appendices are removed because of nonspecific abdominal pain or incidentally during surgery for other causes. This finding suggests that the appendicitis itself or the combination of appendicitis followed by appendectomy, rather than appendectomy alone, is protective. Alternatively, there may be other factors among patients destined to develop UC that prevent those individuals from developing appendicitis. Studies have suggested that the distinct appendiceal microbiome associated with appendicitis may be protective against UC (16). A series of studies on a mouse model of acute appendicitis followed by appendectomy have elucidated several mechanisms for the protective effect, including autophagy suppression, T helper type 17 (Th17) pathway suppression, and modulation of vascular remodeling by suppressing endothelin pathways (17,18,19).

Dietary Factors

The relationship of dietary factors on the development of IBD is difficult to study in populations, although it is generally accepted that dietary factors do play a role in the development and course of disease. Studies showing a protective effect of breast-feeding on development of IBD have not been reproducible (6). Long-term dietary fiber intake is associated with decreased risk of Crohn disease but not UC (20). Fatty acids, carbohydrates, and refined sugars have also been studied (16,21). Studies on long-term diet and childhood diet have shown associations with gut microflora (22,23), and this likely is a mechanism for the effects of diet on the development of IBD.

Stress, Hormones, and Inflammatory State

Stress, anxiety, and depression have been associated with increased risk of Crohn disease, as well as increased rates of flares and need for surgery in IBD in general (16). Studies of microbiota-gut-brain interactions have elucidated complex interactive networks whereby microbiota influences gut function and immunoregulation; inflammation, immune factors, and nutrition contribute to psychological dysfunction; and psychological stress affects gut inflammation and microbiota (24,25). Impaired function of glucocorticoid receptors resulting in glucocorticoid resistance may be enhanced by persistent inflammation, and nuclear factor kappa beta (NFkB) and corticotropin-releasing hormone may also play a role (24). Oral contraceptive use is associated with an independent risk of developing Crohn disease and with risk of developing UC in women with history of smoking (26). An earlier metaanalysis found oral contraceptive use to be associated with an increased risk of Crohn disease and UC, with dose-response relationship in Crohn disease, and a reduced risk of IBD with discontinuation of use (27). Postmenopausal hormone replacement therapy is associated with increased risk of UC, possibly related to effects of estrogen on gut inflammation (28).

The effects of exercise and sleep are likely related, at least in part, to stress and hormones in general. Regular exercise is known to have anti-inflammatory effects (29) and a prospective study from the Nurses’ Health Study cohorts has shown that the risk of Crohn disease was inversely associated with physical activity, although physical activity had no effect on the risk of UC (30). The relationship between sleep and IBD risk has also been studied (16).

Epidemiologic data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) can exacerbate existing UC and may even induce it de novo (31). This effect was initially attributed to the cyclooxygenase (COX)-1 inhibitory effect of the drugs, but recent reports suggest that even COX-2-specific inhibitors also demonstrate this effect (32). Possible mechanisms by which NSAIDs exert these effects include inhibition of protective mucosal prostaglandin production and increased leukocyte migration and adherence. It has been estimated that NSAID use increases the risk of IBD exacerbation by as much as 30%.

Infections and Antibiotics

Enteric infections, especially with Clostridium difficile, are associated with IBD flares, and Salmonella and Campylobacter infections have been associated with increased risk of developing IBD (16). In addition, exposure to antibiotics, especially during early childhood, is associated with increased risk of developing IBD (16). As an inflammatory disorder with increasing incidence, IBD has been studied in relation to the hygiene hypothesis, the concept that early childhood immune development depends on microbial exposures (24).

Pathogenesis

The intrinsic complexity of IBD and its variable manifestations hampers progress in understanding its pathogenesis. However, it is generally accepted that there are immunologically mediated mechanisms of injury, related to gut microbial factors, with multifactorial genetic influence. The fundamental pathogenic question could be: Does the chronic recurring inflammatory activity in IBD reflect an appropriate response to a persistently abnormal stimulus (a structural alteration of the intestine or causative agent in the environment) or an abnormally prolonged response to a normal stimulus (aberrant regulation of immune responses) (Fig. 11.1)? It is conceivable that some factors initiate the disease, whereas others sustain the inflammatory process or possibly even reactivate it.

Immunologic Factors

CD and UC are both associated with abnormal immune responses to nonpathogenic commensal bacteria within the gut. Both the innate (neutrophil, macrophage, dendritic cell) and adaptive (T cell, B cell, plasma cell) immune systems are involved in the pathogenesis of IBD. The physical barrier
of the intestinal epithelium and its covering mucous layer are also recognized as being important components in IBD pathogenesis.

FIG. 11.1 Inflammatory bowel disease (IBD) likely results from a combination of genetic predisposition, cellular alterations, and up-regulated immunity. The genetic influences affect both the predisposition to injury and the nature of the response to the injury.

Innate Immunity

The role of the innate immune system in IBD pathogenesis has mostly been derived from cell culture and murine studies (33). Innate immune cells in the gut mucosa are among the first line of defense in recognizing and responding to gut microorganisms, and additionally, they directly activate the adaptive immune response against microbial invasion. Pathogen-associated molecular patterns, or PAMPs, on microorganisms are recognized by various pattern recognition receptors, or PRRs, including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) on innate immune cells resulting in proinflammatory cytokine production through a nuclear factor (NF)-kB pathway (34).

NF-kB is activated in the tissues of IBD patients and stimulates expression of many molecules that likely play a role in IBD including IL-1&bgr;, TNF, IL-6, IL-8 and other chemokines, ICAM-1 and other adhesion molecules, CD40, CD80, CD86, and the T-cell stimulator ICOS (35). NF-kB also stimulates expression of protective molecules including TNF-induced protein 3, CARD15, cyclooxygenase 2, &bgr;-defensins, and peroxisome proliferator-activated receptor (PPAR)-&ggr; (35).

Another important component of the innate immune pathway with a role in IBD are the members of the inhibitor of apoptosis (IAP) family, especially cIAP1, cIAP2, and XIAP. These proteins mediate NOD2 signaling by their ubiquitin ligase activity and are involved in receptor-mediated signaling through TNF receptors, TLR receptors, and NOD receptors (36). Interestingly, cIAPs are also involved in regulating NF-kB, resulting in proinflammatory cytokine production, including TNF-&agr; (36). Deficiency of XIAP is associated with bowel inflammation and has been found in 4% of patients with pediatric-onset CD (36).

Innate lymphoid cells, including natural killer (NK) cells, also likely play a role as they produce cytokines similar to those produced by T helper (T_H) cells (37,38). Defects in innate immune cell recognition and/or response to microbial invasion likely play a role in IBD pathogenesis (39).

Adaptive Immunity

The contribution of the adaptive immune system to IBD pathogenesis has been more thoroughly studied. Additionally, elucidation of specific T_H subsets beyond the traditionally described T_H1 and T_H2 cells has helped to further our understanding of the role of T cells in IBD. Generally, CD is considered to be a T_H1-driven disease, while UC is T_H2 driven, although with less certainty (34). T_H1 cells interact with antigen-presenting cells that have been in contact with microbes, including macrophages, and are induced by IL-12, leading to the production of proinflammatory molecules, such as interferon (IFN)-&ggr;, tumor necrosis factor (TNF)-&agr;, interleukin (IL)-2, and IL-12. TH2 cells interact with B cells that have been exposed to microbes, leading to the secretion of IL-4, IL-5, and IL-13, among others. More recently, the contribution of T_H17 cells in neutrophil recruitment via secretion of IL-17
and in extracellular matrix (ECM) degradation via secretion of IL-21, which induces matrix metalloproteinases (MMPs), has been highlighted (37). T_H17 cells are induced in response to IL-23 production by macrophages and dendritic cells.

Anti-TNF-&agr; antibodies have become a mainstay therapy for refractory IBD. TNF-&agr;, produced by both TH1 cells and by macrophages, is a major contributor to MMP production and ECM degradation, affecting the intestinal wall and secondarily leading to enterocyte apoptosis by damaging the basement membrane (34). Also, monoclonal antibodies directed at the shared p40 subunit of IL-12 and IL-23 have demonstrated early success in CD treatment (40).

Regulatory T cells (Tregs) maintain homeostasis of gut inflammation by secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor (TGF) &bgr;. Altered levels of Tregs and impairment of TGF&bgr; signaling, leading to loss of this anti-inflammatory regulation, have been described in IBD (37). Table 11.1 summarizes important cytokines in IBD, their actions, and whether they are currently being developed as therapeutic targets.

Cytokine release by activated effector cytotoxic T cells, along with altered Treg activity, results in generation of activated MMPs, enzymes that mediate tissue destruction. In addition, cytokines act directly on the microvasculature, up-regulate adhesion molecules, and enhance recruitment of additional effector cells including neutrophils and macrophages, which amplify and perpetuate the inflammatory response and contribute to additional tissue injury. Finally, alterations in T-cell apoptosis have been described in IBD, contributing to T-cell accumulation and persistence of the inflammatory response (41).

TABLE 11.1 IMPORTANT CYTOKINES IN INFLAMMATORY BOWEL DISEASE

Cytokine	Action	Therapeutic Target
Innate immune response
IL-1&bgr;	Proinflammatory; neutrophil and T-cell recruitment	Yes
TNF-&agr;	Proinflammatory; promotes epithelial cell death; ECM degradation	Yes
IL-2	Proinflammatory; epithelial cell apoptosis and proliferation	No
IL-6	Proinflammatory; prevents epithelial cell apoptosis; stimulates epithelial proliferation after injury	Yes
IL-8	Neutrophil recruitment and activation	No
IL-12	Proinflammatory	Yes
IL-18	Epithelial damage and goblet cell dysfunction (myeloid production); epithelial repair (epithelial production)	No
IL-22	Antibacterial defense; tissue repair; tumorigenic	Yes
IL-23	Induces T_H17 cells	Yes
IL-27	Anti-inflammatory; epithelial repair	Yes
IL-33	Proinflammatory	No
Adaptive immune response
IFN-&ggr;	Proinflammatory; epithelial damage; antiangiogenic	Yes
IL-4	Anti-inflammatory; antiangiogenic	No
IL-5	Eosinophil recruitment and proliferation	No
IL-10	Anti-inflammatory; inhibits naive T-cell proliferation	No
TGF&bgr;	Anti-inflammatory; prevents T-cell activation; fibrogenic	Yes
IL-13	Increases epithelial apoptosis; slows regrowth of damaged epithelium; stimulates goblet cell mucus production; eosinophil recruitment	Yes
IL-17	Proinflammatory; neutrophil recruitment	No
IL-21	Proinflammatory; ECM degradation	Yes
IL-35	anti-inflammatory; down-regulates T_H17 cells	Yes
ECM, extracellular matrix; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

As a result of these immunologic events, the mucosa becomes heavily infiltrated by inflammatory cells. Soluble inflammatory mediators produced by neutrophils, lymphocytes, monocytes, fibroblasts, mast cells, neuroendocrine cells, and nerves generate many of the functional and histologic changes that characterize the disease (Fig. 11.2).

Autoantibodies

Populations of mucosal B cells and plasma cells increase in UC, a finding that initially suggested that the disease was antibody mediated and complement dependent. While there are relatively few studies on the role of complement in IBD, complement components are considered as potential therapeutic targets (42). Also, the concept of antibodies mediating IBD has not been born out. Instead, antibodies, including autoantibodies such as atypical perinuclear antineutrophil
cytoplasmic antibody (atypical p-ANCA) and antimicrobial antibodies such as anti-Saccharomyces cerevisiae (ASCA) antibody, among others, have a demonstrated role in distinguishing IBD from non-IBD; UC from CD; disease onset, duration, location, and behavior in CD; and disease progression, severity, and pouchitis in UC (43,44).

FIG. 11.2 Immune reactions in inflammatory bowel disease (IBD). Immune reactivity is generally upregulated in many immune cellular subsets, leading to the synthesis and release of cytokines, reactive oxygen molecules, and immunoglobulins. The release of these products and interactions between the various cell types eventually result in the phenotypes that we recognize clinically and pathologically as IBD. CD, Crohn disease.

Epithelial Cells

The intestinal epithelium is well known as a structure to be the first layer of defense against microbial invasion; however, the specific details of how the epithelium interacts with the immune system and bacteria and how it is affected by the recurrent damage and repair in IBD are now becoming clearer.

Intestinal epithelial cells secrete mucin, and this mucin has been shown to be altered in its composition and to contain more bacteria in IBD patients (34,45,46,47). Both depletion and overproduction of mucus cause damage to the gut epithelium (48). Intestinal permeability is also increased in IBD, and murine studies have shown that impairment of intestinal tight junction proteins are associated with intestinal inflammation (48,49). Protein kinases involved in maintaining both the mucin layer and epithelial junctions are a potential therapeutic target in IBD (50).

One of the most interesting roles of intestinal epithelial cells is their ability to function similarly to innate immune cells, expressing the same PRRs leading to microbial detection and cytokine release (37). Paneth cells in particular have been a focus of study, as their numbers and distribution are altered in IBD, and they exhibit decreased expression of bactericidal defensins (34). Paneth cells also express NOD2, alterations in which lead to defects in cellular clearing of bacteria, a process known as autophagy (34). NOD2 has known genetic defects in IBD patients as discussed below.

Once damaged, the intestinal microbiome can interact directly with intestinal immune and stromal cells. Repair of damaged epithelium in IBD is necessary to prevent this interaction. IL-6, a proinflammatory cytokine, has been shown to prevent epithelial apoptosis in the setting of chronic inflammation and is necessary to stimulate epithelial proliferation following injury (51). A complex array of molecules involved in cellular migration (e.g., villin), cell growth (e.g., epidermal growth factor [EGF]), and immune regulation (e.g., TGF&bgr;), as well as signals from stromal cells (e.g., PGE2) and from microbial sensors (e.g., TLRs and NLRs), all work together to repair damaged intestinal epithelium and can lead to impaired epithelial healing when altered, such as in IBD (52).

Microbial Factors

The normally harmless and beneficial commensal microbes colonizing the intestine play a central role in IBD pathogenesis. Loss of tolerance toward these microbes in IBD and altered microbial composition, also called dysbiosis, both affect inflammatory responses (53,54). Alterations in particular bacterial phyla, Bacteroidetes and Firmicutes in CD and Proteobacteria, Actinobacteria, and Bacteroidetes in UC, have been demonstrated (52). Probiotic bacteria are thought to have a protective role in IBD (55). In an attempt to reinstate a normal gut microbiome, fecal microbiota transplantation therapy has been performed in IBD with some success (56).

Specific bacterial DNA sequences have been found in colonic tissue from some CD patients (57), and antibodies to these and other bacterial components have been shown to correlate with CD phenotype (58). The general role of microbial interaction with the intestinal epithelium and immune system is reviewed above.

Genetic Factors

Development of both CD and UC is determined, at least in part, by genetic factors. Overwhelming evidence exists that both ulcerative colitis and Crohn disease cluster within families, and having a family member with IBD represents the greatest risk factor for developing the disease. Overall, 5% to 23% of IBD patients have an affected first-degree relative (59). The clinically relevant question of absolute risk for first-degree relatives of IBD patients to develop the disease ranges from 4.8% to 7.8% for CD (0% to 15.8% for offspring) and 1.6% to 5.2% for UC (2.9% to 11% for offspring), with Jewish ancestry imparting a higher risk (59). The majority of families with multiple affected members show concordance for disease type (i.e., all affected family members have CD disease or all have UC) and even for disease location, behavior, and age at diagnosis for CD. Twin studies show that monozygotic twin concordance is higher than dizygotic twin concordance, and the effects are more often seen for CD (range, 38.5% to 63.6% monozygotic and 0% to 6.7% dizygotic) than for UC (range, 6.6% to 27.9% monozygotic and 0% to 8% dizygotic) (59). These findings suggest that although there is a strong genetic component that determines susceptibility to IBD, environmental factors also play an important role in disease development.

Susceptibility Loci

The most significant breakthrough in elucidating the genetic factors involved in the development of IBD occurred in 2012 with a meta-analysis of genome-wide association data resulting in the identification of 71 new associations, bringing the total number of significant IBD susceptibility loci to 163, of which 23 are UC specific, 30 are CD specific, and 110 are common to IBD (60). Overall, these genes are involved in innate and adaptive immunity, microbial response, autophagy, and epithelial and mesenchymal repair and remodeling.

The first CD susceptibility gene to be identified was NOD2, which is located within the IBD1 locus in the pericentromeric region of chromosome 16. NOD2 is part of the innate immune system, expressed in monocytes, intestinal epithelial cells, and Paneth cells. This protein recognizes and binds muramyl dipeptide, the biologically active moiety of bacterial peptidoglycan, resulting in activation of the proinflammatory cytokine NF-kB (9). The C-terminal leucine-rich repeat (LRR) region of the protein functions in peptidoglycan recognition. Three single nucleotide polymorphisms (SNPs) have been found in NOD2 in CD patients, and these occur in or near the LRR region and show a gene dosage effect (59).

Many of the IBD susceptibility genes are associated with the adaptive immune system, specifically, T-cell differentiation. Interestingly, IL-23R, a gene on chromosome 1 involved in IL-23 signaling and T_H17 cell differentiation, has been identified as a susceptibility locus in both UC and CD, although with different degrees of effect (60). Genetic defects related to IL-10 receptor signaling and XIAP mutations, among others, have been categorized as monogenic IBD, with very early age at onset, poor response to standard therapies, high morbidity and mortality, and some success with hematopoietic stem cell transplantation (61).

The IBD susceptibility locus on chromosome 6, IBD3, contains both major histocompatibility complex (MHC) genes and the TNF-&agr; gene. Polymorphisms in TNF-&agr; have been found in UC in different ethnic populations and may be implicated in response to anti-TNF therapy (62). Specific human leukocyte antigen (HLA) loci have been demonstrated to have a role in IBD susceptibility and pattern of disease (63). For example, HLA-DRB1^*01:03 is associated with both UC and CD (64), while HLA-DRB1^*15 is negatively associated with CD (62). As with TNF-&agr; genes, numerous studies report ethnic similarities and differences in HLA associations with IBD.

Epigenetics

Building on the GWAS studies, epigenetic modifiers of gene expression, part of the transcriptome, have also been studied in relation to IBD (65). MicroRNAs (miRNAs), which are posttranscriptional regulators of gene expression, interact with genes involved in the innate and adaptive immune system, specifically, miR-192 interacting with NOD2 and miR-155 regulating T_H17 cell differentiation (66). IBD susceptibility loci have also been found to be associated with certain long noncoding RNAs (lncRNAs), which may regulate gene expression (67).

Genotype-Phenotype Correlation

Numerous studies have described certain IBD phenotypes related to specific genetic alterations, for example, NOD2 variants associated with stricturing or fibrostenosing CD. Recognition of these correlations can aid in disease management, therapy, and improved design of future clinical trials (68).

▪ CROHN DISEASE

Incidence

As noted previously, there has been a steady rise in the incidence and prevalence of CD worldwide over the past several decades. The incidence of CD ranges from 5.0 to 20.2 per 100,000 persons in different geographic areas of the world (1). CD affects all ages and both sexes, but its incidence peaks in the second and third decades of life.
A second minor peak in incidence occurs in patients aged 50 to 70 years.

Clinical Features

The signs and symptoms of CD are often subtle, frequently resulting in a delay in diagnosis until months, or sometimes years, after symptom onset. However, the diagnosis can usually be made on the basis of a careful clinical history, physical examination, and diagnostic testing. The presentation of a patient with CD depends in large part on the location, extent, and severity of gastrointestinal involvement. CD most frequently affects the small bowel, specifically the terminal ileum, and about half of patients have both small bowel and large bowel involvement. Large bowel involvement alone affects the minority of patients, and often, there is rectal sparing. Perianal disease is relatively common, while oral, esophageal, and gastric involvement alone are quite uncommon. Because the clinical manifestations of CD are very diverse, both in the sites of tissue involvement and in the severity of the inflammation, a wide spectrum of clinical manifestations results (Table 11.2).

Patients with ileocolonic disease experience intermittent episodes of crampy, often postprandial, abdominal pain. Pain may be referred to the periumbilical region, especially in children (69). The abdominal discomfort may be accompanied by diarrhea. Stools are small, frequent at night, loose to watery, and may or may not be bloody. Such symptoms are often attributed to dietary factors or irritable bowel disease. The past history may include perirectal or perianal abscesses and fistulae. Physical examination may localize tenderness to the right lower quadrant. Occasionally, an inflammatory mass may be palpable. Patients with diffuse small intestinal CD present with diffuse abdominal pain, diarrhea, anorexia, and weight loss. Malabsorption may also occur. These patients demonstrate diffuse abdominal tenderness on physical examination. Colonic CD may mimic ulcerative colitis. Patients complain of diarrhea often containing blood and/or mucus and crampy lower abdominal pain that may be relieved with defecation. Crohn colitis is characterized by more extensive bleeding, more perianal disease, and less pain than Crohn ileitis.

Growth retardation occurs in many pediatric patients with CD and may occur before other disease signs or symptoms develop. The growth failure and malnutrition result from inadequate dietary intake, malabsorption, and increased nutritional requirements and, in treated patients, from drug therapy, particularly corticosteroids.

Progressive transmural inflammation, fibrosis, and deep ulceration may ultimately lead to symptoms associated with intestinal obstruction, perforation, bleeding, or fistula formation. When obstruction develops, it usually does so in the distal ileum. Extensive mucosal ulceration predisposes the patient to bacterial translocation with all of its complications, including a predisposition to bacterial endocarditis (70). Patients also demonstrate altered small intestinal motility with abnormal receptor-mediated small intestinal contraction (71). Deep linear ulcers or fistulae may sometimes give rise to profound lower GI bleeding.

TABLE 11.2 CLINICAL FEATURES OF CROHN DISEASE RELATED TO SITE OF BOWEL INVOLVEMENT

Isolated small intestinal involvement
	Anorexia
	Weight loss
	Early satiety
	Abdominal pain
	Postprandial cramping
	Variable diarrhea
	Lactase deficiency
	Zinc deficiency
Ileal disease (or resection)
	Vitamin B₁₂ malabsorption
	Fat-soluble vitamin malabsorption
Colonic involvement
	Diarrhea
	Cramping
	Urgency
	Bleeding
Ileocecal involvement
	Presentation mimicking appendicitis
	Obstruction, especially with transmural inflammation

A sudden worsening of clinical symptoms and/or an unusual disease presentation should alert one to the possibility of ischemia or viral infection superimposed on preexisting CD. Ischemia may develop secondary to vasculitis or may occur because of endothelialitis resulting from infection with cytomegalovirus (CMV), particularly if immunosuppressive therapy has been utilized.

Disease Classification

The Vienna classification is a commonly used clinical classification scheme describing the behavior of CD as inflammatory (nonstricturing nonpenetrating), stricturing, and penetrating (i.e., fistula forming) as well as the location of CD as terminal ileal, colonic, ileocolonic, and upper gastrointestinal (72). About half of CD patients have inflammatory disease, a quarter have stricturing disease, and a quarter have penetrating disease. Patients generally present with inflammatory disease, and over time, 60% develop stricturing or penetrating disease (73). Disease location remains stable over the patient’s lifetime, and those with ileal location of disease are more likely to develop stricturing disease, while those with colonic or ileocolonic location are more likely to develop penetrating disease (74).

Perianal Disease

Perianal involvement is common in patients with CD. Patients with colorectal involvement are more likely to also have perianal disease (75). Perianal involvement may predate, postdate, or develop concurrently with primary intestinal CD. Perianal disease includes skin tags, scarring, erosions or superficial ulcers, cavitating ulcers, fissures, sinus tracts, fistulae, and abscesses.

Jejunal Disease

Diffuse jejunoileitis is a rare, possibly underreported, clinical phenotype of CD that is thought to be more prevalent in pediatric and adolescent CD patients. This is considered a severe phenotype due to late presentation, late diagnosis, and common complications from strictures and fistulas, leading to morbidity associated with malnutrition and surgical intervention (76).

Appendiceal Disease

Sometimes, CD initially presents in the appendix (Fig. 11.3), making it very difficult to differentiate from ordinary appendicitis because of the similarity of the clinical symptoms. The distinction between these two entities is most easily made if granulomas are found in the appendix, although interval appendectomy may also harbor granulomas.

Esophageal Disease

Esophageal CD occurs, although it is rarer than oral, pharyngeal, or laryngeal involvement. Esophageal disease affects 6% of CD patients (77). Esophageal lesions include aphthous ulcers measuring 2 to 3 mm in size, strictures, esophagitis, esophageal ulcers, and granulomas. The diagnosis should not be made unless typical lesions are found elsewhere in the gut.

FIG. 11.3 Granulomatous appendicitis. Numerous compact granulomas lie in the submucosa of the appendix of a child with symptoms of acute appendicitis. This finding sometimes represents the initial presentation of a child with Crohn disease.

Gastric Disease

Gastric CD typically involves the distal stomach producing thickening and granulomatous inflammation of the gastric wall, which results in pyloric obstruction and vomiting. Patients often have concomitant duodenal disease. Gastric CD may antedate small bowel involvement, and some of the reported cases of isolated granulomatous gastritis may actually represent early gastric CD. The diagnosis can only be made with certainty if there is associated CD in the small bowel or colon.

Endoscopy exhibits antral stenosis and rigidity, aphthous ulcers, nodules, thickening and blunting of the gastric folds associated with mucosal cobblestoning and denudation, fibrosis, and ultimately stricture formation. Antral stenosis is the most characteristic feature of gastric involvement. Gastric fistulae usually originate from the intestine with direct extension to the stomach (78). Features of gastric CD grossly and radiologically mimic gastric carcinoma or other inflammatory conditions.

Duodenal Disease

CD produces pathologically and radiologically typical lesions in the duodenum in approximately 0.5% to 4% of patients (78). Duodenocolic or duodenoileal fistulae develop, originating in the diseased duodenum or from previous ileocolic anastomoses. Duodenal-enteric fistulae also complicate CD arising in other parts of the GI tract. Usually, but not invariably, duodenal CD coexists with ileal involvement, and the duodenal lesions frequently extend proximally to involve the gastric antrum or distally into the jejunum (Fig. 11.4). The clinical features include symptoms of duodenal obstruction and/or ulceration. Duodenal CD predisposes patients to develop pancreatitis. Rare patients with duodenal disease develop massive upper GI hemorrhage.

Crohn Disease in the Elderly

Patients greater than 60 years old represent about 10% to 30% of the population with IBD and about 10% to 15% of newly diagnosed cases (3,79). CD is more likely to be localized to the colon and have an uncomplicated course (79). The role of genetics is thought to be less important in elderly disease pathogenesis, while dysbiosis and immune dysregulation are thought to be more involved (80). Multiple other common diseases, such as diverticular disease or ischemia, can coexist with CD or can mimic the clinical presentation. Older individuals may have more distal Crohn colitis (Fig. 11.5) than younger patients, who tend to have more extensive colonic involvement (3). The most reliable hallmarks of CD in older persons include the presence of perianal disease, rectal bleeding, and fistulae. The anal area may show edematous skin tags, ulcers, fissures, and fistulae. Elderly CD patients require total colectomy more frequently than those in younger age groups (81).

FIG. 11.4 Crohn disease. A: Single-contrast examination of duodenal bulb demonstrates numerous aphthous ulcerations. B: Double-contrast enema of the left colon demonstrates tiny discrete aphthous ulcerations with intervening normal mucosa. C: Upper gastrointestinal series demonstrates duodenal ulcer (smaller arrow). There is also thickening of the mucosal folds in the remainder of the duodenum and proximal jejunum in this patient with Crohn disease (larger arrow).

Pediatric Crohn Disease

Multiple studies have shown that pediatric-onset CD is a distinct entity. About 5% to 25% of IBD cases are diagnosed during childhood, and many countries have an increasing incidence of pediatric-onset CD (3). Very early-onset CD, in those less than 6 years old, tends to be localized to the colon, while older children more often have ileocolonic disease (3). Monogenic early-onset IBD is an important diagnostic consideration in very young patients (61). Perianal disease is more common in pediatric CD patients. Interestingly, however, despite the longer length of time with disease, pediatric-onset CD patients generally have a stable disease course with a complication rate similar to patients with adult-onset CD (3).

FIG. 11.5 Proctocolectomy specimen in an elderly individual with Crohn disease. A: The sigmoid has become relatively featureless and atrophic, as indicated by the star. The most distal portion of the rectosigmoid is involved by active disease. B: Higher magnification showing the prominent severe distal disease. The arrows indicate the boundary of the normal and the involved portion by active disease, as verified by histologic examination. Significant anorectal disease is present.

Patient Misdiagnosis

Some patients are diagnosed with CD who do not have the disease. Two major reasons account for such a mistaken diagnosis: (a) diseases in organs adjacent to the ileocecum produce a clinical syndrome of acute right lower quadrant pain and inflammation, which could suggest the diagnosis, and (b) neoplastic, vascular, infectious, or other small intestinal diseases mimic CD. Table 11.3 lists diseases that can mimic CD clinically.

TABLE 11.3 DISEASES CLINICALLY MIMICKING CROHN DISEASE

Ulcerative colitis

Yersinia infections of the ileum, appendix, and cecum

Tuberculous infections of the ileum, appendix, and cecum

Acute appendicitis

Appendiceal abscess

Appendiceal mucinous lesion

Meckel diverticulitis

Pelvic inflammatory disease

Ectopic pregnancy

Ovarian cysts and tumors

Cecal or sigmoid diverticulitis

Carcinoma of the cecum spreading to the ileum

Ileal carcinoid

Ileal lymphomas, plasmacytoma, and Hodgkin disease

Metastatic carcinoma

Acute terminal ileitis

Ischemic ileitis

Systemic vasculitis

Radiation enteritis

Amebiasis

Association with Other Diseases

CD associates with extraintestinal diseases that represent part of the inherent disease process (see Extraintestinal Manifestations section). Additionally, CD associates with other diseases as listed in Table 11.4.

Extraintestinal Manifestations

Approximately 25% of patients with known CD have a history of at least one extraintestinal manifestation. Multiple extraintestinal manifestations occur in the same patient more frequently than would be expected by chance. Large bowel involvement and longer disease duration predispose the patient to extraintestinal manifestations.

TABLE 11.4 CROHN DISEASE: ASSOCIATIONS

Turner syndrome
Autosomal recessive Hermansky-Pudlak syndrome
Cystic fibrosis
Hereditary neutrophilic defects
Glycogen storage type IB
Autoimmune diseases
	Ankylosing spondylitis
	Behçet disease
	Sclerosing cholangitis
	Psoriasis
	Thrombocytopenic purpura
	Systemic lupus erythematosus
	Autoimmune thyroiditis
	Pernicious anemia
	Insulin-dependent diabetes mellitus
	Alopecia areata
	Multiple sclerosis
	Myasthenia gravis
	Scleroderma

Need for Surgical Intervention

The majority of patients with CD undergo surgery at some time during their lives. Approximately 42% of children with CD require surgical intervention as compared with only 5% of those with UC (82), and approximately 20% require surgical intervention within the first year of diagnosis (83). The remainder undergoes surgery at a rate of 5% per year (84). CD patients typically require repeated operations, with 63% of patients undergoing a repeat operation by the 15th postoperative year.

In general, radical resection does not decrease the recurrence rate of the disease, and repeated resections place patients at risk for the development of short-bowel syndrome. Therefore, conservative surgical techniques have evolved to treat patients with CD-associated complications not amenable or responsive to medical therapy. Surgery in CD patients is indicated for treatment of abdominal abscesses, internal or external fistulae, bleeding, and bowel obstruction secondary to strictures and in patients with medically intractable disease. Many patients experience recurrence of their disease, but many also report an overall improvement in their quality of life following surgery.

Recurrence of Crohn Disease

CD is a recurring chronic illness, with 94% of patients experiencing recurrent disease. Nearly all patients have a recurrence within 10 years of their initial diagnosis. Recurrence occurs most commonly in patients with ileocecal disease (53%) compared with isolated colonic disease (45%) or isolated small bowel disease (44%) (85). Patients who have undergone surgical procedures are particularly prone to recurrent disease. Ileal recurrence is determined in part by the retrograde reflux of the colonic fecal stream, microvascular injury, and ischemia (86,87). Additionally, increased use of acetaminophen and other nonnarcotic analgesics and increased consumption of simple sugars sometimes heralds the development of recurrent disease. For patients whose original disease was ileitis, recurrent disease almost invariably appears just proximal to the ileocolonic anastomosis. For those with an initial colitis or ileocolitis, recurrence develops on either side or both sides of the anastomosis.

Patient Survival

Patients with CD develop a large number of complications, some of which impact patient survival. Patient survival is not influenced by disease extent at the time of diagnosis. Patients die both from their underlying IBD as well as from associated diseases, including GI cancer, respiratory diseases, and other GI diseases.

Gross Features

The gross features of the bowel reflect the stage of the disease, with the most severe lesions being seen in advanced transmural disease. Patients with severe disease are those most likely to come to resection. Thus, the pathologist is only likely to see the gross pathology of advanced disease.

Lesion Distribution

CD classically involves the distal 15 to 25 cm of the terminal ileum, often in association with disease involving the right colon, but any part of the GI tract may become involved (Table 11.5). Thus, CD can involve the mouth, esophagus, stomach, duodenum, proximal jejunum, ileum, large intestine, and anus. Ileal disease occurs in 26% of patients, colonic disease in 36%, ileocolonic in 23%, and upper GI in 15% (72). Transition from involved to uninvolved areas is usually abrupt in the small bowel but is less well defined in the large intestine.

Grossly, colonic CD shows three major patterns: (a) diffuse (almost total involvement), (b) stricture formation, and (c) disease mainly confined to the rectum. Any of these forms can exist in isolation or can coexist with other gastrointestinal lesions, especially those involving the terminal ileum. In the colon, diffuse mucosal disease with relatively less involvement of deeper structures can produce an inflammatory mucosal pattern resembling UC, which has been referred to in the literature as superficial Crohn colitis or as UC-like CD (88,89).

FIG. 11.6 Crohn disease. A: Serosal surface of Crohn disease demonstrating the presence of numerous fine adhesions and erythema on the entire serosal aspect. A portion of a fistulous tract was transected in the removal of the specimen from the patient (arrows). B: Unopened ileocolectomy specimen in patient with Crohn disease. The colon lies to the left and shows prominent taeniae coli. The appendix coils around the specimen. The distal ileum is covered with shaggy exudates and portions of transected adhesions (arrows). This process extends into the cecum. In the area of the ileocecal valve, there is an abscess. C: The specimen shown in (B) has been opened, and the ileocecal valve is cut in cross section (arrows). The cecum and ascending colon are present on the left-hand side of the photograph, and the terminal ileum is on the right. The portion immediately adjacent to the cecum is markedly stenotic, and the terminal ileum lumen is almost completely occluded by the disease (star).

TABLE 11.5 GASTROINTESTINAL FORMS OF CROHN DISEASE

Acute ileitis

Chronic regional ileitis

Localized disease of the small bowel, not in terminal ileum

Extensive small intestinal disease

Ileocolitis with skip lesions

Crohn colitis

Anorectal Crohn disease

Gastric, esophageal, and duodenal Crohn disease

External Gross Features

The external surface of the bowel appears reddened, hyperemic, and covered with serosal exudates producing serositis (Fig. 11.6). Areas of serositis appear rough and nodular, often coexisting with dense fibrous adhesions between bowel loops or fixation of the bowel to other abdominal organs, pelvic organs, or the abdominal wall. Fat encircles the antimesenteric serosal surface, producing a pattern known as “creeping fat” (Figs. 11.7 and 11.8). Miliary serosal lesions, the macroscopic equivalent of granulomas, are rarely seen. The miliary lesions appear
as multiple, minute, white nodules resembling peritoneal seeding by carcinoma or the serosal tubercles characteristic of tuberculosis. They are usually distributed along the serosal lymphatics and may be seen on the surface of the adjacent mesentery and peritoneum. These may represent an early stage of the disease. Initially, the intestinal wall remains pliable, even though it may appear slightly thickened (Figs. 11.7 and 11.8). With disease progression, the bowel becomes increasingly fibrotic and rigid (Fig. 11.8). Eventually, strictures may develop, usually in the area of the distal ileum at the area of the ileocecal valve (Fig. 11.6). Large inflammatory pseudotumors may form at this site, simulating a carcinoma. Granulomas within the lymph nodes may be grossly visible as tiny gray-white specks (Fig. 11.9).

FIG. 11.7 Crohn disease. High power of creeping fat. The figure shows the prominent creeping fat and an area of stenosis. The mucosa appears irregular with shaggy ulcerations. An area of perforation was present, as indicated by the arrow. The perforation is surrounded by numerous aphthous ulcers.

FIG. 11.8 Mucosal thickening in Crohn disease. A: Opened small bowel in a patient with Crohn disease. In the central portion of the photograph, the bowel wall is markedly thickened and edematous. Creeping fat is seen at the margin of the cut. At both the right- and left-hand margins, the bowel widens out and is more normal. B: Opened ileal segment in Crohn disease. The bowel wall is markedly thickened. The thickening predominantly is due to dense fibrous tissue. The bowel lumen is almost totally occluded by the scarring process.

The mesenteric adipose tissue should be inspected for involvement by abscesses or fistula tracts (Fig. 11.9). Interloop adhesions should also be carefully sectioned to assess for fistula tracts. Perforations should be documented, examined, and sampled. It’s important to keep in mind that enterotomies are not an uncommon surgical complication and may present grossly as a transmural defect similar to a perforation. A true perforation will have roughened, irregular, and erythematous borders; either defect may have a surgical suture placed across it to contain the luminal bowel contents. In ileocolic resections, it is important to identify the appendix, which may be involved by adhesions or incorporated into an inflammatory mass.

Internal Gross Features

The earliest grossly visible mucosal change consists of the formation of an aphthous ulcer overlying lymphoid tissue. As these ulcers enlarge, they may develop a hemorrhagic rim that makes them visible. In their early stages, aphthous ulcers are most easily seen in the colon (Fig. 11.10) because villi tend to obscure their presence in the small intestine. It is important to note that aphthous ulcers are not specific for CD, but may also occur in infectious enterocolitis (see Chapters 6 and 13). In some patients, these tiny ulcers are the only or predominant sign of the disease, whereas in other patients, they associate with more severe changes elsewhere in the bowel. Recognition
of discrete ulcers in areas of otherwise normal mucosa may precede the development of more flagrant changes of CD by weeks or years.

FIG. 11.9 Crohn disease. A: The mucosa is at the top of the photo. A fistulous track (arrowheads) extends from an abscess coursing through the mesenteric fat. B: Cross section through a fixed specimen of the ileum in Crohn disease. The loops of the bowel are adherent to one another as a result of scarring and fibrosis. C: The bowel wall appears markedly thickened with irregular linear ulcers covered by hemorrhagic exudate. Numerous pseudopolyps are present. In addition, a lymph node containing white specks corresponding to granulomas is present (arrowhead).

FIG. 11.10 Endoscopic view of aphthous ulcers. Aphthous ulcers appear as erythematous “pimplelike” mucosal lesions. The aphthous ulcers are outlined by the arrows.

The small, stellate, aphthous ulcers enlarge into discontinuous, serpiginous, or linear ulcers that then enlarge to form wide-based ulcers (Fig. 11.11). At this stage, the mucosa appears reddened and swollen. The ulcers ultimately coalesce longitudinally and transversely. Grossly, CD is classically characterized by segmentally or diffusely arranged serpiginous or longitudinal furrowed ulcers with areas of intervening normal-appearing mucosa. Islands of nonulcerated mucosa are interspersed among ulcerated areas (Fig. 11.11), producing a cobblestoned appearance. This feature is also not specific for CD because it occurs in other conditions, such as ischemia. When the linear ulcers heal, long railroad track-like scars remain (Fig. 11.12). Ulcers often lie close to the resection margins of the specimen and, if left in the patient, may form the basis of recurrent disease. Transmural inflammation predisposes the longitudinal ulcerations to become fissures or fistulae secondarily involving adjacent organs or the abdominal wall. Eventually, dense adhesions form.

With disease progression, the cut surface of the bowel demonstrates full-thickness inflammation, scarring, and fibrosis of the submucosa, muscularis propria, and serosa. The fibrosis is superimposed on other macroscopic features. Intervening normal bowel separates diseased bowel segments, creating skip areas. This patchy pattern of inflammation contrasts with the continuous pattern of inflammation and prominent rectal involvement seen in UC. The mucosa may even become atrophic in long-standing disease.

FIG. 11.11 Crohn disease. A: Large serpiginous ulcers are present. The ulcers contain granulation tissue and a fibropurulent exudate. The ulcerations extend deep into the bowel wall. The remaining mucosa appears edematous. B: Numerous geographic ulcers are present surrounded by mural edema. C: Closer magnification picture demonstrating the presence of sharp punched-out ulcers with clean, pearly bases.

FIG. 11.12 Crohn disease. The bowel is opened. Prominent linear ulcers are present. The combination of ulceration and edema produces long linear ulcers, which produce “railroad tracks” when they heal. Since both linear and transverse ulcers are present, the mucosa has a cobblestone appearance.

Abscesses, Fissures, and Fistulae

Fistulae and adhesions (see Figs. 11.9 and 11.13) occur less commonly in patients with colonic involvement than in those with small intestinal disease. Fistulae occur spontaneously and are more frequent in patients who have had previous surgery and who had residual diseased bowel. If the process remains localized, an abscess forms (Fig. 11.14). It is important to identify any prior anastomotic sites or site of prior stricturoplasty and inspect these areas for fistula tracts. Vaginal fistulae commonly occur because of the anatomic proximity of the diseased rectal mucosa to the vagina. They may also result from extension of perirectal abscesses. Intraabdominal abscesses develop in patients with CD. These abscesses may be intraperitoneal or, less commonly, retroperitoneal. Correlation with presurgical imaging at the time of gross examination is helpful to locate fistulas and abscesses. Perforation only affects 1.5% of CD patients (see Fig. 11.7) (90) because the inflammatory process penetrates the tissues slowly, causing loops of inflamed bowel to adhere to one another, thereby walling off any free perforation that might occur. Perforations result from deep penetration of fissures or fistulae through the bowel wall, from ingestion of some medicines, or from complicating ischemia (Fig. 11.15) or superimposed infection. Patients may also undergo spontaneous free rupture of an abscess into the peritoneal cavity.

Strictures

CD is characterized by strictures in the small and large intestine and in the anorectum. These strictures commonly lead to partial, intermittent obstruction. Strictures and fistulae are more common with ileitis, ileocolitis, and perianal disease than with disease predominating in the colon.
The nature of the obstructive symptoms depends on the part of the bowel that is affected. The most severe stenosis usually affects the ileocecal valve. Multiple strictures may be present (Fig. 11.16). The strictures result from transmural inflammation, fibrosis, scarring, and fibromuscular proliferation. Rectal strictures are not unique to CD because they also complicate other disorders (Table 11.6).

FIG. 11.13 Crohn disease. A: Ileum with area of stenosis (arrowheads). The proximal bowel became dilated and ruptured (arrow). B: Portion of ileocolectomy with fistula communicating between the small bowel and the colon (arrows). The colon is densely adherent to the small intestine. The small intestine lies to the right of the photograph and shows prominent thickening of the wall. The colon nearby is dilated.

FIG. 11.14 Colonic abscess in a patient with Crohn disease. A large submucosal abscess is present. It expands and occupies the majority of the submucosa on the left-hand and middle portions of the photograph.

Pseudopolyps

Pseudopolyps develop in CD. Many of these are inflammatory in nature, whereas others represent residual mucosal islands (Fig. 11.17). Giant pseudopolyps sometimes form in the colon. These large polyps measure up to 5 cm in height and 2 cm in diameter and project into the colonic lumen. The lesions have a predilection to involve the transverse colon and splenic flexure, but they occur anywhere in the large intestine. The surfaces exhibit a cribriform appearance
and may contain inspissated feces. In addition to the presence of bulky, lobulated polyps, one may also see narrow, tall, filiform polyps.

FIG. 11.15 Crohn disease complicated by ischemic colitis. The ischemic area is in the upper right-hand portion of the mucosa and is covered by a fibrinous pseudomembranous exudate.

FIG. 11.16 Strictures in Crohn disease. A: A several-inch-long strictured area is present in the ileum. The lumen immediately proximal to it is markedly dilated. B: This is the same specimen shown in (A) after fixation highlighting extension of the disease into the surrounding fat. C: Numerous strictures are present in the small intestine of this patient. The area just above the ileocecal valve shows several inches of stenosis marked by focal dilation (upper white arrow in the middle of the photograph). Immediately beneath this is another area of stricturing. The remaining arrows indicate the presence of fistulous tracts.

Histologic Features

General Comments

The ease of making the diagnosis of CD depends on whether one examines biopsy or resection specimens. Resection specimens are more likely to exhibit all of the classic changes of CD, especially those that typically affect the deeper layers of the bowel wall (Table 11.7). The features of CD were originally described in the landmark article published by Crohn and Ginsberg in 1932 (91). Irregularly distributed aphthous-type ulcers, nodular lymphoid aggregates, irregular hypertrophy of the muscularis mucosae, proliferation of submucosal nerves, and loosely organized granulomas occur in various combinations within the mucosa and the submucosa (Fig. 11.18). The biopsy diagnosis of CD remains more problematic because only the mucosa and superficial submucosa are available for examination. In addition, many of the histologic features, including the presence of granulomas, are relatively nonspecific. The pattern and distribution of changes in biopsies are frequently characteristic enough to allow one to suggest that CD is present and/or enable one to exclude other diagnoses that might be in the differential diagnosis.

TABLE 11.6 RECTAL STRICTURES: ETIOLOGY

Crohn disease

Ulcerative colitis

Ischemic colitis

Chlamydial infections

Syphilis

Status postradiotherapy

Chronic and Active Mucosal Injury

The patchy distribution of CD results in an epithelium that exhibits a range of changes, depending on whether or not the tissues are examined early or late in the course of the disease and whether the tissues come from endoscopically more normal or more diseased parts of the bowel. The epithelium ranges in appearance from completely normal, to acutely damaged, to regenerative (Fig. 11.19).

FIG. 11.17 Mucosal polyposis. Irregularly sized cobblestone-like structures are present. They represent residual islands of mucosa. The clefts between them represent linear ulcers.

TABLE 11.7 RESECTION FEATURES THAT SUGGEST A DIAGNOSIS OF CROHN DISEASE

Transmural inflammation

Focal or segmental ulceration

Deep fissures with knifelike clefts passing into the bowel wall

Fistula tracts that extend through the muscularis propria

Focal lymphocyte collections (lymphoid aggregates) in all bowel layers, including the serosal fat

Submucosal widening associated with increased adipocytes

Lymphangiectasia, especially in submucosa

Confluent linear ulcers

Perivascular inflammation along the perforating vessels (vascular tracking)

Intestinal wall thickening secondary to fibrosis

Inflammation of the superficial muscularis propria

Neuronal hyperplasia

Serosal inflammation (sometimes including granulomas and lymphoid aggregates)

Absence of known etiology (i.e., infection or ischemia)

FIG. 11.18 Whole mount sections of Crohn disease. The mucosal surface demonstrates thickening with areas of ulceration. The submucosa is considerably thickened and contains numerous prominent lymphoid aggregates as evidenced by the darker circular areas. The muscularis propria appears hypertrophic. There is a prominent serosal exudate. Lymphoid aggregates are also seen in the serosa, demonstrating transmural inflammation.

FIG. 11.19 Variable histologic features of Crohn disease (CD). A: This resection specimen shows prominent mucosal and submucosal inflammation with marked lymphangiectasia. Areas of re-epithelializing ulceration are present at the right-hand portion of the photograph. B: Portion of colonic mucosa in a patient with CD showing essentially normal histologic features. C: Portion of the small bowel showing marked regenerative changes at the bases of the crypt and extension of the proliferative zone up along the sides of the crypt. Focal chronic inflammation is present, particularly at the right-hand side of the photograph. The villi are fused, hyperplastic, and irregularly shaped.

FIG. 11.20 Histologic features of Crohn disease. A: A portion of the small intestine from a resection specimen showing the focality of the changes. The epithelium on the right-hand side of the photograph is greatly simplified and edematous. On the left-hand side of the photograph, one sees an expansion of the mucosal thickness due to large numbers of pyloric glands. The villi are atrophic, and the lamina propria is infiltrated with mononuclear cells. The underlying muscularis mucosa is hyperplastic and splayed. B: Crohn colitis from a resection specimen. The mucosa demonstrates variable inflammation. The epithelium appears markedly regenerative and mucin depleted. The underlying muscularis mucosae obliterates the submucosa.

In long-standing CD, the crypts and villi show marked distortion of the normal architecture. Distorted glandular architecture is characterized by areas of glandular branching, irregular size and shape, elongation of crypts (crypt hyperplasia) with shortening of villi in the small bowel, and the appearance of villiform gland structures in the colon (Figs. 11.20 and 11.21). Distorted gland architecture is best appreciated in sections of crypts cut in a plane perpendicular to the muscularis mucosae. In sections cut parallel to the muscularis mucosae, regenerative crypt branching can be recognized by the presence of cross sections of glands that show variable diameters and uneven spacing (Fig. 11.22). Mucosa involved by chronic injury may show epithelial hyperplasia (Fig. 11.23). Abnormal gland architecture is a chronic feature of CD and can be present with or without neutrophilic inflammation.

Neutrophilic inflammation is the hallmark of active mucosal injury. Neutrophils may be present in the lamina propria, among the crypt epithelium (cryptitis), or within the crypt lumen (crypt abscess). Severe inflammation leads to surface epithelial damage and loss, which characterizes an erosion. An aphthous ulcer or aphthous erosion refers to neutrophilic damage to and loss of the superficial epithelium overlying a lymphoid aggregate (Fig. 11.24). Epithelium on either side of the erosion appears regenerative, with cuboidal shape, eosinophilic cytoplasm, and loss of goblet cells; intraepithelial
lial neutrophils are also present (Fig. 11.24). Further extension of an erosion leads to an ulcer (Fig. 11.25).

FIG. 11.21 Crohn disease. Portion of colonic mucosa showing marked glandular distortion with relative preservation of the mucinous content within the glands.

FIG. 11.22 Diagrammatic representation of the appearance of regenerative crypts. A: Regenerative branched crypts are relatively easy to recognize when they are cut in a plane perpendicular to the muscularis mucosae. One sees crypt after crypt demonstrating irregular branching often with other features of chronicity, such as Paneth cell metaplasia or pyloric metaplasia. One must be careful in making the diagnosis of regeneration based on the finding of a single “branched crypt,” since the edges of mucosal territories may appear branched. For this reason, one would like to see several branched crypts in a row to make the diagnosis. B: Crypts cut in cross section are more difficult to recognize as being regenerative. Clues to their regenerative nature include variability in crypt diameter when one measures each through an equatorial plane. Additionally, the presence of back-to-back glands in the absence of significant cytologic atypia also suggests regeneration.

FIG. 11.23 Mucosal hyperplasia in Crohn disease. A: Low-power magnification photograph of a portion of the terminal ileum showing complex glandular structures cut in cross section. These represent sections through villi. The villi are lined by cells containing hyperplastic goblet cells. The cores of the villi contain dense mononuclear cell infiltrates. B: Higher magnification in an area of hyperplastic goblet cells (left) and epithelial cells with altered mucin content, giving them a foveolar appearance (right).

In the small intestine, especially in the ileum, one commonly sees pyloric gland metaplasia. Pyloric gland metaplasia can be present at the edges of an active ulcer or may be present in areas with intact but architecturally distorted crypts and villi, where they are thought to represent an area of prior ulceration and hence are considered part of the spectrum of chronic mucosal injury seen in CD. The presence of distorted villi and/or crypts and areas of pyloric gland metaplasia or increased numbers of Paneth cells, especially in the left colon, indicates that the disease is chronic in nature. It should be noted that both pyloric gland metaplasia and Paneth cell hyperplasia/metaplasia are nonspecific indicators of chronic mucosal injury and are not diagnostic of IBD.

Aphthous and Other Ulcers

Two distinctive types of ulceration affect both the small and large intestines. The first is the histologic equivalent of the grossly evident aphthous ulcer (Fig. 11.26). This lesion develops even before inflammatory cells diffusely infiltrate the lamina propria.

Antigen entry into M cells might lead to the proliferation of antigen-sensitized cells and granuloma formation. The underlying lymphoid nodule may contain giant cells or granulomas. As the lesion progresses, it superficially ulcerates, obliterating its associated lymphoid follicle (Figs. 11.24 and 11.25).
A thin stream of mucus, neutrophils, and inflammatory debris exudes from the ulcer mouth and empties into the bowel lumen (Figs. 11.24 and 11.25). The ulcers progressively enlarge, forming a continuum with the deeper ulcers normally seen in CD. Larger ulcers may eventually become lined by a reparative single layer of atrophic cuboidal epithelial cells. There is an associated loss of villi and reduction in the number of crypts in previously ulcerated areas. Edges of an ulcer are likely locations for findings pyloric gland metaplasia, especially in the small bowel (Fig. 11.27).

FIG. 11.24 Progression of aphthous ulcers in Crohn disease. A: The colonic mucosa and submucosa contain prominent lymphoid aggregates. The lamina propria is infiltrated with mononuclear cells. Mild regenerative features are present. The goblet cell population is still intact. B: Wider-based aphthous ulcer (arrow). C: Aphthous ulcer. An area of ulceration is noted over a lymphoid aggregate. Inflammatory debris is present in the ulcer tract overlying the lymphoid aggregate (upper arrow). The epithelium on both sides of the ulceration is regenerative (lower arrow). D: High-power view of epithelial changes associated with an erosion. In the center, the epithelium is detached in an area of erosion, and regenerative cuboidal and mucin-depleted epithelium can be seen on the right.

The second type of ulcer is the knifelike fissure, which occurs at right angles to the long axis of the bowel (Fig. 11.28). These may extend through the bowel wall and are likely the basis for fistula formation. Fissures
branch and penetrate deeply into the underlying bowel wall, producing adhesions, fistulae, abscesses, and peri-intestinal inflammatory pseudotumors (Fig. 11.29). Fistulae contain acute inflammatory cells and a granulation tissue lining with conspicuous pale, plump histiocytic cells. Giant cells may also be present. Occasionally, reparative intestinal epithelium may be seen lining a fissure or fistula tract.

FIG. 11.25 Crohn disease. Further extension of the aphthous ulcer. There is more extensive inflammation and wider area of ulceration extending from the aphthous ulcer than one sees in Figure 11.24.

FIG. 11.26 Diagrammatic summary of the development of aphthous ulcers. A: Neutrophils infiltrate the epithelium at the base of the crypt. B: Larger numbers of neutrophils accumulate. C: The proteolytic enzymes released by the neutrophilic infiltrate destroy the epithelium in the crypt overlying the lymphoid follicle. D: Areas of microulceration develop, eventually destroying the crypt.

Healed ulcers result in architectural distortion, pyloric gland metaplasia (Fig. 11.30), and a thickened or duplicated muscularis mucosae often associated with a marked dense submucosal fibrosis. As a result, in affected areas, it can be difficult to distinguish the muscularis mucosae from the submucosa or underlying muscularis propria. These areas often correlate with grossly described stricture, wall thickening, or stenosis and must be distinguished from sites of prior anastomosis or stricturoplasty. Fibroblasts and myofibroblasts proliferate in these areas of fibrosis, usually with accompanying chronic inflammatory cells. Fibrosis extends from the bowel wall to involve adjacent structures and traps within it lobules of fat that may demonstrate variable degrees of fat necrosis.

FIG. 11.27 Pyloric gland metaplasia (arrow) is often present at the edges of an ulcer in Crohn disease.

Mucosal Metaplasia

Patients with chronic disease often develop pyloric gland metaplasia (Fig. 11.30), especially in the ileum. The distal colon and rectum often develop Paneth cell metaplasia (Fig. 11.31). In the small bowel and right colon, Paneth cells are normally present but their number may increase (Paneth cell hyperplasia).

The cells in pyloric gland metaplasia have been described as ulcer-associated cell lineage (UACL) cells (92). This distinctive cell lineage typically arises in sites of enteric ulceration, most notably in the ulcerated gut in CD, but also in other ulcerating conditions. The pyloric glands usually occur singly or in clusters in the mucosa adjacent to ulcer margins. They are also found near single discrete ulcers in the edematous segments away from involved mucosal areas.

FIG. 11.28 Ulceration in Crohn disease. A deep knifelike ulcer is present.

These cells share many features of pyloric and Brunner glands, although they do not extend deeper than the muscularis mucosae, a feature that distinguishes them from Brunner glands. The regular acinar glands have a coiled tubular neck, and therefore, the entire neck is rarely seen
in a single section. They extend down to, but usually not through, the muscularis mucosae and have a number of terminal branches that are given off at right angles to the neck, so that they are usually seen in cross section. The glands are lined by clear or pale-staining columnar cells containing indistinct neutral mucin granules. The nuclei appear oval or round and are located near the base of the cell. The glandular structures have a looser architectural pattern than either pyloric or Brunner glands (92).

FIG. 11.29 Fissures, fistulae, and adhesions in Crohn disease. A: A fistula is present in the center between these two adherent loops of the small bowel. B: A fissuring ulcer extends from the mucosal surface at the top right, through the muscularis propria and into the mesenteric adipose tissue. There is mesenteric fibrosis associated with this process, as well as a site of adhesion, seen at the bottom left. C: In this cross section through an inflammatory mass, the appendix (right) was identified and found to be involved by a fistula tract (center) from a segment of terminal ileum (left) involved by Crohn disease. D: At higher magnification, one can see the dense fibrosis and muscularization associated with the fistula.

Lymphatic Dilation (Lymphangiectasia)

Another notable feature of CD is submucosal lymphatic dilation (Fig. 11.32), which commonly coexists with edema and lymphoid hyperplasia. Plasma cells, eosinophils, and
neutrophils may infiltrate along the dilated vessels. In more advanced stages of the disease, fibrous tissue replaces the edema.

FIG. 11.30 Ileal pyloric gland metaplasia. A: Low power of the basal portion of the mucosa showing expansion. Prominent pyloric glands lie beneath the intestinal epithelium and above the muscularis mucosae. B: Higher magnification of pyloric gland metaplasia in a different case. In the center of the photograph, it connects with an actively regenerating crypt.

Nature of the Inflammatory Infiltrate

Early morphologic lesions include increased numbers of mucosal plasma cells, lymphocytes, macrophages, mast cells, eosinophils, and neutrophils in all layers of the bowel wall. A basal lymphocytic-plasmacytic infiltrate occupies the lower part of the mucosa, creating a space between the base of the crypt and the inner aspect of the muscularis mucosae (Fig. 11.33). In active IBD, one sees a constant emigration of neutrophils and monocytes from the circulation into the inflamed mucosa and through the epithelium into the intestinal lumen (Fig. 11.34). Neutrophils infiltrate the intestinal epithelium, forming the lesion known as cryptitis. Collections of granulocytes within the crypt lumens are called crypt abscesses. The inflammatory infiltrate often also surrounds submucosal and serosal lymphatics and blood vessels, where they penetrate the muscularis propria. Denser lymphocytic aggregates also lie in the submucosa away from the lymphatics or they may appear scattered throughout all layers of the bowel wall (see Fig. 11.18).

FIG. 11.31 Paneth cell metaplasia. Numerous Paneth cells with eosinophilic cytoplasmic granules are present in these rectal crypts.

An early but nonspecific finding of CD is an increased number of eosinophils and macrophages (Fig. 11.35) in the lamina propria beneath the surface epithelium. Eosinophils degranulate, leading to deposition of eosinophil cationic protein and cathepsin G. These proteins contribute to the inflammatory process (93).

FIG. 11.32 Lymphangiectasia in Crohn disease. This section from the ileum of a patient with Crohn disease shows prominent dilation of the lymphatics in the submucosa and basal mucosa.

FIG. 11.33 Basal plasmacytosis in inflammatory bowel disease. The lamina propria of the deep mucosa contains numerous plasma cells. Scattered lymphocytes and eosinophils are also present. The distance from the base of the crypt to the muscularis mucosa is expanded by the inflammation.

Mucosal and submucosal mast cell hyperplasia and degranulation also represent constant features of both UC and CD. Mucosal mast cells maintain a direct association with substance P (SP)-containing nerves, as well as with capillaries, blood vessels, Schwann cells, nerve fibers, myofibroblasts, and collagen fibers. They also lie along epithelial cells, providing an anatomic basis for communication between nerves and the immune system. Inflammatory mediators released from mast cells contribute to the pathophysiology of CD due to the release of preformed and newly generated inflammatory mediators (94). The bowel develops focal edema and inflammation in the lamina propria, submucosa, and deeper layers, even in the presence of a more or less normal-appearing mucosa.

FIG. 11.34 Diagrammatic representation of the different forms of acute inflammation takes in inflammatory bowel disease. A: When neutrophils infiltrate the epithelium without causing destruction, the lesion is termed cryptitis. B: When a large number of neutrophils infiltrate the glandular lumen, the lesion is referred to as a crypt abscess. C: Because the neutrophils contain large numbers of lysosomal enzymes, they destroy the underlying crypt and the acute inflammation extends into the surrounding lamina propria, referred to as crypt rupture. D: In time, these changes resolve with new epithelium repopulating the crypt. Epithelial cells migrate upward and again reaccumulate mucin within them. Variable numbers of neutrophils may still be present at this stage.

Dendritic cells lie adjacent to granulomas and fissures. The number of macrophages in the lamina propria increases. They are arranged in bandlike zones at the bottom of ulcers or fissures, perhaps playing a scavenging role directed against microbial agents or dietary substances penetrating the GI wall through the mucosal defects. Aggregates of macrophages lead to the formation of noncaseating granulomas.

Lymphoid Aggregates

Lymphoid aggregates, which may contain germinal centers, generally lie at the mucosal-submucosal junction, but also within the submucosa, and at the muscularis propria interface with the serosal fat. Lymphoid aggregates form even in the absence of granulomas, and they may be more helpful than granulomas in establishing the diagnosis of CD (Figs. 11.18 and 11.36). Transmural lymphoid aggregates favor a diagnosis of CD over UC; however, they are nonspecific in the setting of deep ulcers of any etiology or diverticular disease. Finally, the lymphoid tissue of the terminal ileum may become hyperplastic, forming numerous grossly visible small sessile lymphoid polypoid lesions.

Granulomas

Compact epithelioid granulomas are the sine qua non for the diagnosis of CD (Figs. 11.37 and 11.38) and, when present, are a reliable histopathologic criterion for differentiating CD from UC or other histologic mimics. Granulomas assume particular diagnostic significance when seen in tissues remote from areas of ulceration in situations where foreign body granulomas are unlikely,
such as lymph nodes sampled from a resection specimen. Although the presence of granulomas represents a useful diagnostic feature for CD, they can be seen in various other conditions (see Table 11.8).

FIG. 11.35 Inflammation in Crohn disease. A: Prominent mononuclear cell infiltrate consisting mainly of lymphocytes and plasma cells. There is a mild increase in intraepithelial lymphocytes. B: The lamina propria contains a large number of eosinophils and mast cells recognizable by their prominent reddish granules. These cells are actively degranulating. C: Localized histiocytic collection surrounded by lymphocytes, plasma cells, and eosinophils.

FIG. 11.36 Crohn disease. Inflammation extends through the full thickness of the bowel wall. Prominent lymphoid aggregates are present within the submucosa and muscularis propria.

Pathologists should be cautious when diagnosing a granuloma in biopsy material. Ruptured crypts release mucin into the lamina propria, stimulating the formation of mucin granulomas (Fig. 11.39). Such mucin granulomas may include mature macrophages and foreign body-type giant cells. They can be recognized because of the predominance of giant cells, their association with and orientation around perforated crypts (Fig. 11.39), and their positivity for mucin stains. Mucin granulomas are not specific for CD because they occur in any situation that results in crypt destruction with epithelial cell loss, including UC. Examination of serial sections is often helpful to identify the edge of the ruptured crypt when an intramucosal granuloma is identified.

The reported frequency with which granulomas are identified in CD varies markedly between studies. Possible explanations for this include the criteria used to diagnose granulomas, whether or not isolated giant cells are included among granulomas, the number of biopsies obtained, and the number of sections examined. Granulomas are found in the bowel wall in 50% to 87% of colectomy specimens, in 15% to 36% of colonoscopic biopsies, and in 20% to 38% of regional lymph nodes (84,95,96). CD granulomas do not usually affect the regional lymph nodes when they are absent in the bowel wall.

Sometimes, the granulomas are quite small (microgranulomas). Microgranulomas consist of only a few histiocytes and are easily overlooked (Fig. 11.38). In one study, 16% of granulomas were so small as to be seen in only 6 of 90 serial sections. Isolated mucosal or submucosal giant cells are seen in 13% of patients (95).

Fewer granulomas occur in the ileum than in the colon. Granulomas progressively increase in number from the

ileum to a maximum number in the rectum (97). The granulomas also occur in various other tissues and organs, including the lymph nodes, pancreas, mesentery, peritoneum, liver, lung, kidney, and, occasionally, bones, joints, and skeletal muscle. The presence of granulomas does not indicate disease activity, nor does it affect the postoperative recurrence rate. Granulomas are more often found in pediatric CD biopsies and, although documented on biopsy, can be absent in 36% of adult resections and 50% of pediatric resections (98).

FIG. 11.37 Granulomas in mucosal biopsy specimens from Crohn disease patients. (A) and (B) are from the terminal ileum and show the presence of a prominent granuloma just beneath the muscularis mucosae. Figure (A) provides a low-power magnification overview showing the prominence and nodular arrangement of the granuloma (arrows). The lower left-hand corner of the specimen is more intensely infiltrated with mononuclear cells when compared with the rest of the specimen. B: Higher magnification of the granuloma in the basal epithelium. (C) and (D) represent a colonic mucosal biopsy showing a prominent granuloma. The overlying epithelium in (C) appears regenerative. The granuloma is surrounded by a dense cuff of lymphocytes (arrows). D: Higher magnification of the granuloma.

FIG. 11.38 Microgranuloma in a colonic biopsy from a patient with Crohn disease. Note the presence of a compact histiocytic granuloma in the basal portion of the mucosa. The glands surrounding the lesion lack neutrophilic inflammation.

FIG. 11.39 Early mucin granuloma in a mucosal biopsy from a patient with ulcerative colitis. This specimen shows evidence of basal plasmacytosis, which is most evident in (B). A: One sees several crypt abscesses. The right one has ruptured and herniated with extension into the surrounding lamina propria. Histiocytic cells collect at the area of herniation. B: A crypt that has ruptured and is associated with two giant cells intermingling with apoptotic cell fragments and with extravasating inflammatory cells. These lesions have a completely different appearance than the microgranulomas associated with Crohn disease. Compare this photograph with Figure 11.38.

TABLE 11.8 DIFFERENTIAL DIAGNOSIS OF GRANULOMAS IN THE INTESTINE

Mucin Granuloma	Fungal Infections
Bacterial infections	Chlamydial infections
Campylobacter	Sarcoid
Yersinia	Crohn disease
Salmonella	Hermansky-Pudlak syndrome
Shigella	Diverticulosis
Escherichia coli
Mycobacterium tuberculosis
Neisseria gonorrhoeae
Clostridium difficile
Treponema pallidum

The granulomas consist of small, localized, well-formed, loose, or more compact aggregates of epithelioid histiocytes
with or without Langerhans giant cells, often with a surrounding cuff of lymphocytes (Fig. 11.37). Nodal granulomas also contain centrally located T lymphocytes and dendritic cells. Older lesions may show varying degrees of hyalinization and fibrosis. The granulomas may be numerous or very difficult to find. Granulomas that have definite foci of necrosis or suppuration, or are restricted to the edges of ruptured crypts, are not specific for CD.

Granulomas may be observed anywhere within the intestinal wall and along blood vessels or nerves, especially in the mucosa, submucosa, and subserosa (Fig. 11.40), and in the regional lymph nodes (Fig. 11.41). Granulomas may lie adjacent to dilated lymphatics, causing compression of the lymphatic wall or projecting within the lumen of lymphatic spaces (Fig. 11.42). Granulomas and microgranulomas can be found in CD patients in otherwise histologically uninvolved and normal-appearing mucosa. Granulomas are not considered as part of either the active inflammation or the chronic mucosal injury in CD, but rather as a separate diagnostic entity. Granulomas identified in a patient suspected of having CD, but not previously diagnosed on biopsy, should be investigated for microorganisms, including an acid-fast bacillus stain and a silver stain, to exclude mycobacterial or fungal infectious mimics of CD.

FIG. 11.40 Granulomas in resections of Crohn disease. A: Several submucosal granulomas are present in this small bowel resection. Mucosal granulomas are also present at the upper right corner. B: Granulomas can involve the muscularis propria and myenteric plexus nerves. C: Granulomas in the subserosal fat often have a lymphocyte cuff and are immediately deep to the muscularis propria. D: Nonspecific intracytoplasmic inclusions, such as these calcifications (arrow) can sometimes be seen within multinucleated giant cells of a Crohn granuloma.

Vascular Lesions

Vascular lesions in CD may be seen related to transmural inflammation, but also can be secondary to ulceration, or associated with an extraintestinal manifestation. The vascular changes seen in CD must be distinguished from a primary systemic vasculitis involving the GI tract, such as Behçet disease.

FIG. 11.41 Granulomatous lymphadenitis in Crohn disease. A: Numerous compact, nonnecrotizing granulomas are present in this peri-intestinal lymph node from a patient with Crohn disease. B: Higher magnification showing the compact sarcoidlike granulomas. A multinucleated giant cell is present in the upper right.

The changes in CD appear primarily degenerative or inflammatory in nature. Obliterating endarteritis, chronic phlebitis, and other vascular lesions may rarely be seen (Figs. 11.43 and 11.44). Obliterative changes include intimal proliferation, subintimal fibrosis, medial hypertrophy, medial fibrosis, and adventitial fibrosis, all without a significant inflammatory cell component. Degenerative arterial lesions may narrow the vascular lumen due to duplication of the internal elastic lamina with medial hypertrophy. Venous lesions feature an irregular vascular sclerosis with thickening of the wall due to hyperplasia of fibrous, elastic, and muscular tissues.

FIG. 11.42 Granuloma in Crohn disease. This granuloma is arising in association with a dilated submucosal lymphatic. Granulomas in Crohn disease are commonly located adjacent to lymphatics.

The inflammatory lesions consist of perivascular inflammation and chronic inflammatory and/or granulomatous cell infiltrates associated with an obliterative vasculopathy. Lymphocytes and plasma cells infiltrate one or more layers of small arteries or arterioles, leading to interruption of the internal elastic fibers. Areas of thrombosis are rare.

Neural Changes

The autonomic neural plexuses often appear hypertrophic in CD. Large, abnormal, irregular, fusiform nerve bundles and nerve trunks are present most often in the submucosa (Figs. 11.45 and 11.46). These may contain increased numbers of ganglion cells. Occasionally, striking plexiform neuromatous proliferations associate with tortuous thick-walled arterioles. The nerve fibers contain increased amounts of vasoactive intestinal peptide (VIP) and substance P (99). They express MHC class I antigens (100) and thus, the abnormal nerves become infiltrated with mast cells, lymphocytes, and plasma cells (Fig. 11.46). The nerves also may show evidence of extensive axonal and dendritic swelling and degeneration.

FIG. 11.43 Vasculitis in Crohn disease. A: Submucosal vessel demonstrating sclerosis with mild concentric fibrosis in the submucosa of a patient with Crohn disease. A minimal infiltrate is present within the wall of the vessel (arrows). The intima is expanded. B: This small vessel shows mild sclerosis and the beginning of an organizing thrombus. C: Submucosal vessel showing prominent chronic vasculitis. The entire wall of the vessel is infiltrated by mononuclear cells.

Strictures

Stricture formation characterizes CD, especially in the small bowel and often in the terminal ileum just proximal to the ileocecal valve. These strictures result from fibroblast proliferation and increased collagen deposition in the bowel wall (Fig. 11.47), as well as hypertrophy and hyperplasia of the muscularis mucosae and muscularis propria (Fig. 11.48). The fibrosis extends along lymphatics and vascular planes and also involves the serosa and pericolonic tissues.

FIG. 11.44 Vasculitis in Crohn disease. Not all cases of vasculitis are as dramatic as those illustrated in Figure 11.40. This patient with CD had only minimal vascular inflammation. Such changes might be seen in a patient with severe ulcerative colitis, so that these features may show histologic overlap.

Rarely, CD patients develop distinctive polypoid lesions in stricturing areas. These consist of proliferations of vessels, nerves, and muscular tissue, sometimes referred to as neuromuscular hamartomas. Grossly, one sees a cluster of sessile polyps covering normal mucosa. Although the lesions have been described as hamartomas, it is more likely that they represent reparative lesions (Fig. 11.49).

Pseudopolyps

Several types of polypoid lesions develop in CD. Inflammatory polyps consist solely of inflammatory and regenerative tissues (Figs. 11.50 and 11.51). These fingerlike polyps arise in both the small and the large bowel. They contain granulation tissue and variable degrees of inflammation, sometimes covered by regenerating surface epithelium. Glands within the polyp show marked architectural distortion. Sometimes, endoscopically visible pseudopolyps are biopsied to exclude dysplasia. Other pseudopolyps contain mucosa, muscularis mucosae, edematous submucosa, submucosal fibrosis, and smooth muscle hyperplasia. These postinflammatory polyps may be small and flat or large and filiform (Fig. 11.52) and represent residual mucosal islands.

FIG. 11.45 Neural hyperplasia in Crohn disease. Submucosal nerves are prominent in this ulcerated area from a resection specimen.

FIG. 11.46 Submucosal inflammation in Crohn disease. The photograph is taken at the midportion of the submucosa and shows an intense mononuclear infiltrate and cross sections of numerous hyperplastic neural structures.

Misplaced Epithelium

It is not uncommon to encounter misplaced epithelium in resection specimens of CD patients. This entity is referred to as enteritis cystica profunda or colitis cystica profunda when it affects the small bowel or colon, respectively (Fig. 11.53). Enteritis cystica profunda occurs less commonly than its colonic counterpart, colitis cystica profunda. Misplaced epithelium results from epithelial implantation into the submucosa, muscularis propria, or serosa following mucosal ulceration or fissures. Mucosal repair following regeneration of an ulcer leaves the detached epithelium buried in the submucosa. It eventually becomes covered by an intact mucosa (Fig. 11.53). Misplaced epithelium also results from epithelialization of fissures or fistulous tracts. The misplaced epithelium often becomes cystically dilated, containing large mucin accumulations.

FIG. 11.47 Stricture in Crohn disease. A: There is prominent submucosal fibrosis present. In addition, there is marked neural hyperplasia in the submucosa. B: The fibrosis extends along the vascular structures into the muscularis propria of the colon. C: Serosal fibrosis is also present.

Grossly, the bowel wall appears thickened. The cut surface of the bowel discloses the presence of numerous cystic submucosal spaces. These are often quite prominent and glisten because of their mucinous content. The mucosa overlying such lesions usually demonstrates histologic evidence of active or healed CD. Histologically, one sees mucus-filled cysts in the submucosa, muscularis propria, and serosa. These are lined by cuboidal to columnar epithelium containing numerous goblet cells, enterocytes, and Paneth cells, all supported by a normal lamina propria. Sometimes, the cyst lining disappears due to pressure atrophy from large intracystic mucinous accumulations.

FIG. 11.48 Stricture in Crohn disease. The muscularis mucosae often becomes markedly thickened and obliterates the submucosa in areas of stricture. The muscularis propria is also thickened. In this photomicrograph, the myenteric plexus can be seen at the bottom left.

Sometimes, it is difficult to determine whether the misplaced epithelium represents an invasive mucinous carcinoma, especially when lamina propria does not surround the glands or when the benign epithelium produces excessive amounts of mucin, resulting in large mucinous cysts containing scant epithelial elements (Fig. 11.54). Features that help to rule out malignancy include the absence of desmoplasia, the presence of surrounding lamina propria, and an absence of cytologic atypia within the misplaced glands. Hemosiderin within the stroma also favors misplaced epithelium. Cytologic atypia and areas of desmoplasia around angular, irregularly shaped glands characterize invasive cancers, particularly of the nonmucinous type.

FIG. 11.49 Polypoid neural hyperplasia in Crohn disease (CD). A: Low magnification of a polypoid lesion in the colon of a patient with CD demonstrating the presence of a prominent proliferation consisting of nerve fibers and fibroblasts. These are arranged in prominent swirling bundles. B: Higher magnification showing the structure of these bundles. C: S100 stain indicating the presence of neural elements.

In some cases, it may be impossible to determine whether one is dealing with misplaced epithelium or an invasive cancer. Sometimes, careful sampling and examination of the surface epithelium helps resolve the diagnostic dilemma. If the surface epithelium appears dysplastic, the possibility of an invasive lesion increases.

Serosal and Mesenteric Changes

The subserosa becomes considerably thickened, often as the result of hyperplasia of the subserosal fatty tissues, edema, fibrosis, acute and chronic inflammation, and granuloma formation. Nodular lymphoid aggregates are very common and define transmural inflammation of CD. The serosa may also become covered with a fibropurulent exudate. The mesenteric changes closely parallel those seen in the serosa. The draining lymph nodes often become enlarged and may contain granulomas.

Histologic Features of Proximal Gastrointestinal Lesions

The proximal small bowel, namely, the duodenum and proximal jejunum, may be seen as biopsy specimens.

FIG. 11.50 Crohn disease. A: Multiple inflammatory pseudopolyps. The mucosa immediately adjacent is essentially normal. B: Filiform polyposis. The mucosa has multiple fingerlike extensions measuring several centimeters in length and extending from the surface. When these fuse, mucosal bridges are produced. C: Pseudopolyp composed essentially of residual, more or less normal colonic mucosa covering an area of ulceration.

FIG. 11.51 Inflammatory pseudopolyps. A: The inflammatory pseudopolyps present in this photograph differ from those shown in Figure 11.50, in that they represent residual islands of mucosa and submucosa. They contain a prominent submucosal core. The surrounding tissues are ulcerated down to the level of the muscularis propria. B: Higher magnification of the pedunculated lesion indicated by the arrow in (A). One can see the central fibrovascular submucosal core with a covering of granulation tissue and extravasated red cells. C: Higher magnification of the lesion.

FIG. 11.52 Filiform polyp in Crohn disease. This long filiform polyp was one of dozens present in the colon. They are characterized by long submucosal extensions covered by regenerative mucosa.

Similar chronic and active mucosal injury as described in the ileum can be seen in the duodenum and jejunum. The changes may be patchy and may consist of only active neutrophilic inflammation, only chronic mucosal injury, or both. Granulomas may also be present with or without active inflammation or chronic injury. In addition, increased intraepithelial lymphocytes, often without villous blunting as would be characteristic of celiac disease, can be seen in CD (101). There is often a prominent lymphoplasmacytic lamina propria infiltrate. Crypt branching is not a reliable feature of architectural distortion in the small bowel, due to the normal histologic background and tangential sectioning. Also, pyloric gland metaplasia is difficult to determine, as they morphologically resemble normal duodenal Brunner glands. Crypt hyperplasia is a reliable indicator of architectural distortion and chronic mucosal injury in the proximal small bowel. A normal biopsy does not exclude the possibility of involvement by CD, since the inflammation is usually patchy.

FIG. 11.53 Epithelial misplacement in Crohn disease. A: Whole mount section showing a large knifelike fissure, the mouth of which is indicated by the arrow. The thickened bowel wall contains submucosal islands of glands surrounded by lamina propria. B: Higher magnification of the misplaced epithelium. Many of the glands are surrounded by residual lamina propria.

Small bowel resections of the jejunum or ileum may be seen due to strictures and/or fistulas. In many cases, severe adhesions cause kinking of the bowel wall into an inflammatory mass, which may be difficult to orient grossly. Gross examination should focus on identification of proximal, distal, and vascular margins, as well as examination of mesenteric fat for abscess and fistula tracts. Serosal fat wrapping is often present. Presence of strictures, prior anastomotic sites, or prior stricturoplasty sites should be noted. The mucosa should be inspected for cobblestoning, ulcers, fistula tracts, and polyps or mass lesions. Areas of stricture should be thoroughly sectioned to exclude gross evidence of malignancy.

Gastric biopsies show some degree of abnormality in as many as 75% of patients with CD (102,103). The most commonly identified alteration is focal infiltration of the gastric pits and glands by inflammatory cells (Fig. 11.55). These infiltrates may include neutrophils, T lymphocytes,

and histiocytes in variable numbers. This focal inflammation affects both the neck region and deep aspects of the gastric glands and is more commonly seen in the antrum than in the body of the stomach. In addition, granulomas may be seen in 9% to 16% of patients (102,103) (Fig. 11.55).

FIG. 11.54 Epithelial misplacement in Crohn disease. A: The displaced glands in this photo are filled with large amounts of mucin, some of which have extravasated into the wall of the small intestine. B: Higher magnification demonstrating the residual epithelium lining the gland. There is no cytologic atypia present, a feature that distinguishes this lesion from invasive carcinoma.

FIG. 11.55 Gastric Crohn disease. A: Patchy nonspecific chronic inflammation is present in the gastric body of a child with known Crohn disease. B: A compact, sarcoidlike granuloma is present. C: Duodenal biopsy from the same patient showing patchy inflammation and granulomas.

The major differential diagnosis is with Helicobacter pylori gastritis. H. pylori gastritis may also demonstrate chronic active inflammation, but the infiltrates localize to the neck region of the glands. The presence of deep active inflammation should alert the pathologist to the possibility of CD. However, the possibility of H. pylori infection should be ruled out with the use of special stains in all patients demonstrating any form of chronic active gastritis. It is important to note that some patients with CD may have superimposed H. pylori infection. Studies have found an inverse correlation between H. pylori infection and IBD, in both children and adults, which may be due to an immunologically protective effect of having had the infection (104,105).

Focally enhanced gastritis is a localized finding, which has been associated with pediatric IBD, especially CD (106,107,108). Focally enhanced gastritis is defined as one or more foci of pit or glandular inflammation with lymphocytes, plasma cells, and histocytes, in a normal background gastric mucosa. Neutrophils, granulomas, and gland damage may also be present. The finding is considered nonspecific in adults.

FIG. 11.56 Esophageal Crohn disease. Figures (A) and (B) are from the esophagus of the child whose stomach is depicted in Figure 11.55. A: The esophageal squamous mucosa shows nonspecific inflammation and regenerative changes. B: Although no granulomas were present in this biopsy, a multinucleated giant cell is present in the submucosa. C: Increased intraepithelial lymphocytes, with or without a few eosinophils and neutrophils can be seen in esophageal biopsies, especially in children.

Crohn disease may affect the esophagus, and when it does, it may be difficult to separate the lesions from other forms of granulomatous esophagitis, especially if one is unaware that the patient has known Crohn disease (Fig. 11.56). Lymphocytic esophagitis, characterized by increased peripapillary lymphocytes with spongiosis, and no neutrophilic or eosinophilic inflammation, can also be seen in CD patients, especially children (109) (Fig. 11.56).

Crohn Disease of the Orogenital System

Oral vesicular lesions and aphthous ulcers affect 49% of patients with CD. Typical CD is usually present in the gut, but occasionally, CD first presents as oral lesions. Lesions of oral CD mimic a wide variety of other oral lesions, including orofacial granulomatosis, characterized by granulomas and ulcers without intestinal involvement (110). Lesions may develop in the teeth, gums, lips, tongue, buccal mucosa, and rarely the epiglottis. Biopsies showing granulomas are characteristic; however, there is a broad differential, including infections, which must be ruled out. Granulomas may be compact and well-formed or loose macrophage clusters. Lymphocytes and fibrosis are also often present (110). Oral
lesions remain in up to one third of patients and are associated with more severe CD phenotype in pediatric patients (110,111).

FIG. 11.57 Vulvar Crohn disease. A: Low magnification showing the presence of prominent acanthosis. The underlying submucosa contains numerous collections of lymphocytes and plasma cells. A small fissure containing large numbers of acute inflammatory cells passes through the lower portion of the photograph. B: Higher magnification of one of the areas of inflammation showing the presence of a giant cell.

Anal or perianal disease affects the majority of CD patients, especially those with colorectal involvement. Skin tags, fistulas with or without abscess, fissures, and hemorrhoids may be seen (75). Fistulas may involve the vagina as well. Occasionally, granulomas are present (Fig. 11.57).

Evaluation of Resection Margins in Crohn Disease

Frozen sections of resection margins are unnecessary and should be avoided. This is because the rate of recurrence in CD following surgical resection is not influenced by the status of the resection margins (112). Factors that do affect the risk of postoperative recurrence of CD include extent of disease at the time of surgery and the indication for surgery, with those who failed medical therapy or had perforating disease having a higher risk of recurrence (112,113). Smoking is also a factor affecting disease recurrence (114,115).

Complications

The complications of CD are listed in Table 11.9. The extraintestinal and neoplastic manifestations are discussed later in this chapter. Complications also result from therapy. These
include steroid-related osteonecrosis often affecting the hip or knee, as well as secondary viral or bacterial infections. An increased risk of melanoma has also been reported in IBD patients while taking immunomodulators (116).

TABLE 11.9 COMPLICATIONS OF CROHN DISEASE

Local intestinal
	Perforation
	Hemorrhage
	Fistulas to adjacent bowel
	Fistulas to urinary bladder (pneumaturia)
	Fistulas to vagina
	Intestinal obstruction
	Enterolith production
	Malabsorption
	Lactose deficiency
	Zinc deficiency
	Enteritis cystica profunda
	Toxic megacolon
	Psoas abscesses
Respiratory
	Bronchitis
	Emphysema
	Asthma
Amyloid
Tumors
	Small bowel carcinoma
	Large intestinal carcinoma
	Cholangiocarcinoma
	Renal oncocytoma
	Lymphoma, leukemia, and Hodgkin disease
	Carcinoid
	Squamous cell carcinoma, anus and vagina

▪ ULCERATIVE COLITIS

Incidence

In recent decades, the incidence of UC in the United States and in Europe has risen, whereas in other countries the incidence has plateaued (84). It is likely that two factors have contributed to this increase: (a) improved survival of incident cases and (b) diagnosis of milder cases due to increased use of sigmoidoscopy and fecal occult blood testing in the community. UC is increasingly being recognized as a disease that affects many ages and many ethnic groups (2,3,5). The incidence of UC inversely correlates with smoking and clinical relapses have been associated with smoking cessation (16).

Clinical Features

UC demonstrates a wide clinical spectrum affecting all age groups, with a predominance of the disease after the second decade (2). Men are more commonly affected than women (2). Mean age at diagnosis is 32 years (117). UC is less common in ethnic minorities than in non-Hispanic Whites in the United States (5). Clinical presentation includes diarrhea, hematochezia, tenesmus, and lower abdominal pain (118). In children, growth failure, characterized by decreased linear growth and delayed sexual maturation (119), and constipation (120) have also been reported.

Diarrhea, hematochezia, urgency of defecation, attacks of crampy abdominal pain, and perianal soreness are common in early stages of the disease. Abdominal pain is usually less severe than in CD. When UC remains limited to the left colon, constipation rather than diarrhea may result because colonic spasm results in stool retention in the right colon where the normal absorptive capacity is unimpaired.

Disease onset can be abrupt, with a sudden onset of acute diarrhea, frequent bloody stools, continuous abdominal pain, anorexia, rapid weight loss, chronic iron deficiency anemia, and a persistent fever. The bleeding originates from large denuded areas of the mucosa in the face of widespread telangiectatic lamina propria vessels. In contrast, the bleeding seen in CD usually originates from a localized source such as an eroded blood vessel in the submucosa or deeper layers.

Characteristically, UC is a chronic mucosal disease with relapses and spontaneous remissions. It usually starts in the rectum and then spreads more proximally. Most patients have distal disease at the time of first attack, but some have more extensive disease extending proximally, including total colonic involvement. Disease distribution can remain constant from the time of initial diagnosis, although between 16% and 60% of UC patients develop proximal extension of disease by 10 years after diagnosis (121). The distribution of disease varies geographically, with approximately 20% to 30% having pancolitis, 30% to 52% having left-sided colitis, and 21% to 37% having proctitis (121). About half of pediatric patients present with pancolitis (122).

There are several major clinical presentations: (a) acute fulminant colitis, in which the whole colon and rectum are affected with extensive and deep ulcerations; (b) continuous colitis, in which the symptoms persist from the onset and vary in severity (usually only affecting the left side of the colon); and (c) recurrent colitis, in which the attacks are limited and separated by varying periods of remission. About half of patients are in clinical remission at any one time. Relapses are unpredictable except that the disease activity in foregoing years indicates a 70% to 80% probability that the disease will continue the following year (123). The cumulative probability of having a relapsing course is 90% after 25 years of disease. Activity in the first 2 years of diagnosis significantly correlates with having an increased probability of 5 consecutive years of disease activity.

UC progresses to a more serious form in about half of patients. Factors associated with disease progression include toxic colitis, extent of disease at diagnosis, presence of joint symptoms, younger age at diagnosis, and severe bleeding (117). Various infections (CMV, Salmonella, and Clostridium difficile), medications, and intervening ischemic disease also exacerbate UC (Table 11.10).

Toxic Megacolon

Acute toxic megacolon is a potentially lethal complication that affects less than 5% of all UC patients and 17% of severe attacks of UC (124). Toxic megacolon usually affects patients with pancolitis and is characterized by total or segmental colonic dilation, loss of contractile ability, and rapid clinical deterioration associated with systemic toxicity. The colonic wall progressively thins and perforation may occur. Disturbed motility with loss of contractility results from extension of the inflammation into muscularis propria, serosa, and visceral peritoneum. The hypertrophic muscle loses its muscular tone with stretching and the pressure of the intraluminal contents. Damage to the myenteric plexus can also result in atony. Hypokalemia aggravates the already weakened
peristalsis and hypoproteinemia augments the bowel wall edema. The mortality associated with toxic megacolon has decreased, likely due to early recognition and optimized medical and surgical management. Other complications include massive hemorrhage and pulmonary embolism.

TABLE 11.10 FACTORS ASSOCIATED WITH RELAPSE OR EXACERBATION OF ULCERATIVE COLITIS SYMPTOMS

Infections		Medications
Viral			Antibiotics
	Cytomegalovirus		Sulfasalazine
	Upper respiratory viruses		5-Aminosalicylic acid
	Enteroviruses		Azodisalicylate
Bacterial		Ischemia
	Salmonella	Neoplasia
	Clostridium difficile
	Other enteric pathogens
	Mycoplasma pneumoniae
	Entamoeba histolytica

Toxic megacolon not only complicates UC, but can also develop in association with any inflammatory condition of the colon including CD, infectious colitis (C. difficile, Salmonella, Shigella, Campylobacter, and amoeba), and ischemic colitis.

Ileitis

Inflammation in the terminal ileum occurs in 5% to 17% of patients with ulcerative colitis (125,126). The ileal inflammation known as backwash ileitis, occurs in continuity with cecal inflammation, and is thought to result from incompetence of the ileocecal valve with resultant reflux of intestinal contents. The ileitis usually resolves following colectomy.

Inflammation occurring in the setting of colectomy followed by ileostomy is usually not due to the UC per se but is secondary to the ileostomy. It is called prestomal ileitis. In this disorder, one sees ulcers scattered throughout the ileum and jejunum with the intervening mucosa appearing normal or edematous. Because these ulcers have a tendency to perforate, peritonitis and fistulae develop, and the lesions may prove fatal.

Perianal Disease

Some patients first seek medical advice because of the presence of extraintestinal manifestations, such as arthritis or perianal disease. Perianal disease is usually limited to hemorrhoids, anal excoriations, and fissures. The complications of UC in the anus are acute and superficial, contrasting with the abscess and fistulas seen in CD.

Role of Surgery

Surgical therapy for ulcerative colitis may be for either emergencies or elective treatment. Indications for urgent surgery include failed medical treatment in patients with acute severe colitis, toxic megacolon, perforation, or severe bleeding. There are essentially three indications for elective colectomy for UC: failed medical treatment, growth retardation in a child with UC, and the development, or concern for, neoplastic transformation in a patient with long-standing disease. Failed medical treatment includes chronic disease, recurrent acute exacerbations, severe symptoms in an otherwise systemically well patient, suboptimal quality of life, steroid dependence, or extraintestinal manifestations of the disease.

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