Inflammatory Disorders of the Large Intestine

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Chapter 17

Inflammatory Disorders of the Large Intestine

Deepa T. Patil

Joel K. Greenson

Robert D. Odze

Approach to Evaluating Colitis

Pathologists are asked to evaluate colorectal biopsy specimens for a variety of reasons, but often only a pattern of injury can be identified, at best. This evaluation is performed with the hope that a specific diagnosis can be rendered once appropriate clinical, radiologic, and laboratory information is obtained. However, some forms of colitis, such as lymphocytic colitis, collagenous colitis, and ischemic colitis, do have specific histologic features, and a diagnosis can be rendered in the absence of clinical information. Many histologic features are characteristic of chronic inflammatory bowel disease (IBD). However, it is often difficult or impossible to distinguish ulcerative colitis (UC) from Crohn’s disease (CD) on the basis of colorectal biopsy specimens only, particularly after the patient has been treated medically, in which case the features of these two disorders overlap considerably.

Normal Versus Abnormal

Perhaps the most important aspect of evaluating colorectal biopsy specimens is to determine normal from abnormal, which can be difficult because of the presence of bowel preparation and biopsy procedure artifacts. These artifacts include surface epithelial degeneration, edema, hemorrhage and congestion (Figs. 17.1 and 17.2), aggregation of inflammatory cells, pseudolipomatosis (intramucosal air; Fig. 17.3), mucin depletion, and even neutrophilic cryptitis in extreme cases. Pathologists should not be afraid to render a diagnosis of “normal colon.” After all, that is the most common diagnosis in the general population. Terms such as “nonspecific (or increased) chronic inflammation,” “nonspecific colitis,” and “increased acute and chronic inflammation” are inappropriate pathologic diagnoses that often cause confusion for clinicians.

Pathologists should be aware of several important points when evaluating colorectal biopsy specimens, particularly with regard to histologic findings that are considered normal. For example, lymphocytes and plasma cells are always present in the lamina propria of colorectal mucosa, regardless of the anatomic location. However, the density of lamina propria inflammatory cells varies among the different anatomic locations. In general, the cecum and right colon are more cellular than other segments of the colon. A progressive decrease in the cellular constituents of the lamina propria is normal from the right to the left colon (Fig. 17.4). In addition, although the colonic crypts are arranged in a straight and tubular configuration, show an even distribution, and typically extend directly up to the muscularis mucosae, the distal rectum shows variation in crypt architecture under normal circumstances (Fig. 17.5). Lymphocytes are normally present in the surface epithelium of the colorectal epithelium and number approximately 5 per 100 epithelial cells.1 Surface intraepithelial lymphocytes are generally more prominent in the cecum and right colon than in the remainder of the distal colon. In addition, intraepithelial lymphocytes are more numerous in areas of mucosa overlying lymphoid follicles (Fig. 17.6).2,3 Eosinophil counts also vary substantially in different portions of the colon (more in the right colon than in the left), and “normal” numbers depend on other factors, such as the geographic location and the latitude of patient’s principal habitat.4,5 Individuals who live in the southern states of North America or closer to the equator have a higher number of lamina propria eosinophils compared with individuals who live in more northern states. Knowledge of the anatomic location of the colonic biopsy specimens is important but has become increasingly difficult because gastroenterologists have a tendency to place biopsy specimens from different sites into one specimen container.

Acute Versus Chronic Colitis

Evaluation of patterns of injury in colorectal biopsy specimens is often best performed at low magnification (see Chapter 13). For example, lamina propria cellularity and crypt architecture are easier to evaluate at low magnification than at high magnification. In addition, it is easier to compare histologic changes among different fragments of tissue within the same specimen block under low-power examination.

After a biopsy is determined to be “abnormal,” distinction of acute from chronic changes is important clinically. The most consistent and reliable markers of chronic injury (colitis) are crypt architectural distortion, basally located lymphoid aggregates, basal plasmacytosis, diffuse mixed inflammation, Paneth cell (or pyloric gland) metaplasia (or hyperplasia in biopsy specimens from the right colon), and lamina propria fibrosis (Table 17.1). Many types of colitides, including acute infectious colitis, may result in an expansion of the lamina propria by plasma cells; however, basal plasmacytosis, wherein plasma cells fill the space between the bases of the crypts and the muscularis mucosae, is an excellent histologic marker of chronic colitis.6 This feature is also helpful to differentiate acute infectious colitis from acute-onset IBD: In IBD, features of chronicity are almost always present in the cecum, right colon, and proximal portion of the transverse colon,7 even in these portions of the colon, an increase in the number and a change in the distribution of Paneth cells helps to indicate and confirm the presence of chronic injury.

Features of “active injury” in the colon include neutrophil- or eosinophil-mediated epithelial injury in the form of cryptitis, crypt abscesses, mucosal erosions and ulceration, and epithelial degenerative changes. These changes may be superimposed on a background of chronic colitis, in which case they are termed chronic active colitis.

Ulcerative Colitis

Epidemiology

UC is a chronic, episodic inflammatory disease of the colon. It has a propensity to develop in adolescents and young adults, although there is a second incidence peak among middle-aged men. The incidence and prevalence rates of UC are highest in North America, England, northern Europe, and Australia. Estimates of the annual incidence of UC in North America and Europe range from 1.5 to 20.3 cases per 100,000 individuals.8 The incidence of UC appears to have stabilized during the past 25 years and is no longer increasing, unlike that of CD, which seems to be increasing in incidence. It has been estimated that UC will develop in approximately 1% of the U.S. and European population during their lifetime. There is marked ethnic variation in the incidence of UC, with a high incidence in the Jewish population. In the United States, the annual incidence of UC among Jews is 13 per 100,000 person-years, compared with 3.8 per 100,000 among non-Jewish whites.9 UC is more common in industrialized countries compared with less-developed countries, and in urban compared with rural populations. The incidence rate of UC among immigrants who have moved to high-risk geographic regions is higher than that of the same ethnic groups in their native countries.

Clinical Features

The clinical symptoms of UC vary depending on the phase and extent of disease. They include urgency, passage of mucus, tenesmus and rectal bleeding in patients with proctitis, and diarrhea (mainly bloody), rectal bleeding, abdominal pain, fever, and weight loss in patients with extensive colitis. Among patients who are seen with fulminant colitis, the symptoms include fever, generalized abdominal pain, rectal bleeding, and abdominal distention. Patients may also complain of symptoms related to anemia and hypoalbuminemia, such as fatigue, dyspnea, and peripheral edema. In general, the clinical symptoms correlate with the severity of disease. However, on occasion, there may be evidence of histologically or endoscopically active disease in asymptomatic patients. The onset of symptoms is typically slow and insidious. In most cases, patients are symptomatic for weeks or months before seeking medical attention. Some patients with UC are seen more acutely and show symptoms that mimic acute infectious colitis. In some instances, infection such as with Salmonella or Clostridium difficile precedes an initial episode of UC (see Acute Self-Limited [Infectious] Colitis).

Extraintestinal manifestations of UC can affect any organ system but are most common in the skin, eyes, mouth, joints, and liver. Cutaneous hypersensitivity, photosensitivity, and urticarial rashes may occur in response to medical therapy (especially sulfasalazine) rather than the underlying disease itself. Erythema nodosum occurs in 2% to 4% of patients with UC. It manifests as single or multiple, tender, erythematous nodules on the extensor surfaces of extremities. Pyoderma gangrenosum is less common, occurring in 1% to 2% of patients with UC. The lesions may be single or multiple and may occur on the trunk, extremities, face, breast, and stoma sites. Less common skin manifestations include Sweet syndrome and oral aphthous ulcers.

The two most common ocular manifestations of UC are episcleritis and uveitis; these occur in 5% and 8% of patients, respectively. Seronegative arthropathy (type 1-pauciarticular or type 2- polyarticular) occurs in 5% to 20% of individuals with UC and is more common than axial arthropathy; the latter manifests as sacroiliitis and ankylosing spondylitis. In terms of liver involvement, most patients with UC have mild elevations of serum aminotransferase and alkaline phosphatase levels. The most important complication is primary sclerosing cholangitis (PSC), which occurs in almost 3% of patients with UC. Unlike all of the complications listed previously, which typically follow the colonic disease activity, PSC may follow an independent progressive course, even when UC has been stable or inactive for years.

Patients with mild or moderately severe disease usually exhibit minimal signs on physical examination. The affected portion of the colon may be tender on abdominal palpation, but abdominal rigidity or guarding is highly unusual. Severe (fulminant) colitis is usually associated with generalized abdominal tenderness, with either normal or hyperactive bowel sounds, which decrease with disease progression. Distention of the abdomen with absent bowel sounds is an ominous sign that suggests peritoneal irritation in cases of fulminant colitis. Other signs that may be associated with UC include aphthous ulceration of oral mucosa, clubbing of fingernails (typically in long-standing UC), peripheral edema, and mild perianal disease. Digital rectal examination is often normal but may occasionally reveal velvety and edematous mucosa. In addition to anemia that results from acute or chronic gastrointestinal (GI) blood loss, patients with UC are predisposed to hypercoagulability and its complications, such as deep vein thrombosis, pulmonary embolism, renal artery thrombosis, cerebrovascular accidents, mesenteric vein thrombosis (and consequent ischemic colitis), and coronary thrombosis.10

Laboratory findings in UC depend on disease activity. Anemia, leukocytosis, thrombocytosis, increased erythrocyte sedimentation rate (ESR), elevated C-reactive protein level, and hypoalbuminemia are typically associated with active disease. Stool cultures for organisms such as C. difficile, Campylobacter species, and Escherichia coli are usually performed to exclude an infectious cause or complication. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) are positive in 60% to 80% of patients with UC.11 Immunoglobulin A (IgA) anti–Saccharomyces cerevisiae antibody (ASCA) is found in fewer than 1% of patients with UC, whereas IgG ASCA may be seen in as many as 20% of patients (see Ancillary [Serologic] Diagnostic Tests for IBD).

Radiologic studies help to provide a general assessment of the extent of disease and complications associated with UC. Plain radiographs are indicated in cases of severe UC to assess for the presence of intraperitoneal air. The finding of marked colonic dilatation suggests fulminant colitis. Because the transverse colon is the least dependent part of the colon, a diameter larger than 5 cm is highly suggestive of toxic megacolon. In the earliest stage of UC, a double-contrast barium enema may show a fine granular appearance of the colon. With advanced disease, deep submucosal ulcers result in characteristic “collar-button” ulcers. Diffuse absence of mucosal haustrations, thumbprinting, and narrowing or shortening of the colon, are some of the features associated with pancolitis. Computed tomography (CT) is not very helpful in detecting mucosal changes in early disease. However, in advanced UC, the hallmark finding is the presence of mural thickening. In almost 70% of patients with UC, CT with contrast reveals the classic target or double halo sign caused by inhomogeneous enhancement of the thickened bowel wall. Rectal narrowing and widening of the presacral space are typical findings of long-standing UC.12

Assessment of disease activity and prognosis is based on clinical, endoscopic, or histologic findings or a combination of these indices. Although it is not standardized, a widely accepted clinical classification is that of Truelove and Witts.13 Frequency of bowel movements, rectal bleeding, fever, tachycardia, anemia, and elevated ESR are used to classify disease activity as mild, moderate, or severe. Because this classification does not correlate with disease status in patients with limited colitis, a numerical disease activity score, known as the Sutherland index or UC disease activity index, is now more commonly used, especially in clinical trials. It combines scores from four components (stool frequency, rectal bleeding, sigmoidoscopic findings, and physician’s global assessment).14

Risk Factors and Pathogenesis

The exact etiology of UC still remains unknown. However, its pathogenesis is related to a combination of three major elements: genetic susceptibility of the host, immunity, and environmental factors. Although specific agents may incite an inflammatory response in a susceptible host, such agents have not yet been identified. However, studies have shown that luminal microorganisms, their metabolic byproducts, and interactions with normal epithelial structures play key roles in stimulating a host immune response in UC.15

Genetic Factors

The observation that 10% to 20% of patients have at least one other affected family member lends support to the role of genetic factors in the development of UC.16 The strongest evidence of a genetic influence is derived from three European studies wherein 6% to 16% of monozygotic twin pairs had concordant UC, compared with 0% to 5% of dizygotic twin pairs.1719 The lifetime risk of developing disease is higher among first-degree relatives of a patient of Jewish descent and among relatives of patients with early-onset disease.20

A wide array of genes are responsible for conferring genetic susceptibility, disease specificity, and phenotype in patients with UC.21 Linkage analyses have demonstrated that chromosomes 1, 2, 3, 5, 6, 7, 10, 12, and 17 harbor susceptibility genes for UC.22 Specifically, the IBD2 locus on chromosome 12 has a strong association among families with UC.23 Additionally, the C3435T polymorphism of the human multidrug resistance 1 (MDR1) gene is also linked to susceptibility to UC.24

Besides susceptibility genes, human leukocyte antigen (HLA) alleles also influence disease behavior in UC. A significantly increased frequency of HLA-A11 and HLA-A7 has been observed to occur in patients with UC. Specifically, HLA-DR1 (DRB1*0103) has been associated with severe colitis.25 HLA-DR2 (DRB1*1502) has been associated with UC in Japanese and Jewish populations.26,27

Environmental Factors

It is now widely accepted that continuous antigenic stimulation by commensal bacteria, fungi, or viruses leads to chronic inflammation in individuals who have defects in immunoregulation, mucosal barrier function, and microbial killing. The distal terminal ileum and colon contain the highest concentrations of bacteria (almost 1012 organisms per gram of luminal content), and they are a source of constant antigenic stimulus to the host immune system. Animal studies have shown rapid development of colitis when germ-free HLA-B27 transgenic rats28 and interleukin 10 (IL10)-deficient mice29 are populated with normal specific pathogen-free bacteria. Administration of antibiotics effectively prevents and reduces the severity of colitis in these animal models.30 There are several postulated mechanisms by which gut flora may initiate, or contribute to, the development of colitis (see Immune Factors). By virtue of their ability to adhere to or invade the surface epithelium or to produce enterotoxins, microbial organisms stimulate production of inflammatory cytokines. Alteration of the balance between protective and harmful bacteria (e.g., Bacteroides species) reduces the concentration of short-chain fatty acids, which provide nourishment to colonocytes. An impaired mucosal barrier and inability to kill microbes because of impaired host defense mechanisms also contribute to hyperresponsiveness and production of high levels of inflammatory cytokines. Abnormal antigen processing, loss of tolerance, autoimmunity, and an abnormally excessive T-cell response are some other mechanisms that influence the severity of inflammation.

A T-cell α-chain receptor knockout mouse model of colitis has demonstrated lack of development of inflammation after appendectomy in animals at 3 to 5 weeks of age.31 Subsequent case-control studies on humans have also suggested that appendectomy may have a beneficial effect on the disease course.3234 However, there have been no prospective studies confirming a possible protective effect.

The best-characterized environmental factor associated with UC is cigarette smoking. UC is more common among nonsmokers than current smokers.35 In fact, the second incidence peak in middle-aged men may, in part, be linked to patients who have stopped smoking later in life. A recent prospective study of a cohort of 229,111 women who were followed over a period of 32 years (Nurses Health I and II cohort) showed that the risk of UC is highest during the first 2 to 5 years after cessation of smoking but remains elevated for more than 20 years.36 The postulated mechanisms for the protective effect of smoking include modulation of cellular and humoral immunity, increased generation of oxygen free radicals, and alteration of cytokine levels.

Immune Factors

Both humoral and cell-mediated immunologic mechanisms play major roles in the pathogenesis of UC. UC is associated with an increase in the synthesis of IgG, notably the IgG1 and IgG3 subclasses. Most patients have circulating antibodies to a variety of dietary, bacterial, and self-antigens that are of the IgG1 subclass, and these are polyclonal in nature. Because serum antibody titers usually do not correlate with disease activity or course, it has been postulated that cross-reactivity between antibodies to bacterial antigens and colonocyte epithelial epitopes may help trigger an immunologic response that leads to mucosal inflammation.37

UC is associated with several autoimmune diseases such as diabetes mellitus, pernicious anemia, and thyroid disease. The possibility that UC is an autoimmune disease is supported by the fact that patients with UC have serum antibodies directed against lymphocytes, ribonucleic acid, smooth muscle, gastric parietal cells, and thyroid tissue. Patients also have antibodies to epithelial cell–associated components, notably an autoantibody against a 40-kDa epithelial antigen found in normal colonic epithelium. This IgG autoantibody was eluted specifically from colonic mucosa of patients with UC and was not found in patients with CD or other colonic inflammatory conditions.38 This antigen also shares epitopes with antigens found in the bile ducts, skin, eyes, and joints, sites that are commonly associated with extraintestinal manifestations of UC. The other autoantibody associated with UC is pANCA. It is found in 60% to 80% of UC patients and belongs to the IgG3 subclass. The exact antigen to which pANCA is directed is unknown. There is some evidence that the antigen is a 50-kDa nuclear envelope protein that is specific to myeloid cells.39 The pathogenic relevance of pANCA is unclear. It appears to be associated with an aggressive disease course and development of pouchitis.40

Bacterial antigens also trigger innate immunity by activation of pattern-recognition receptors, which include Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Activation of TLRs and NLRs results in downstream activation of nuclear factor κB, which further stimulates production of various proinflammatory cytokines and chemokines. Defects in any of these pathways can result in abnormal bacterial processing and possibly IBD.41

Colonic epithelial cells express class II major histocompatibility complex (MHC) antigens and can initiate an inflammatory response by acting as antigen-presenting cells.42 Increased turnover of colonic epithelium, reduced metabolism of short-chain fatty acids, abnormal membrane permeability, and altered composition of mucus layers contribute to the pathogenesis of UC.43,44 Animal models of colitis produced by disruption of colonic epithelium further support the role of epithelial cells in the pathogenesis of IBD.45

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

Pathologic Features

Gross Features

In untreated cases, the extent of colonic involvement depends on the clinical severity of disease. UC classically involves the rectum with variable, but continuous, involvement of the colon more proximally (Fig. 17.7). According to the Montreal classification, the extent of UC is divided into ulcerative proctitis (involvement limited to the rectum), left-sided or distal UC (involvement limited to a portion of the colorectum distal to the splenic flexure), and extensive UC or pancolitis (involvement of the colon proximal to the splenic flexure).46 At the initial onset of disease, pancolitis occurs in approximately 20% of patients, left-sided colitis in 50% to 60%, and proctitis or rectosigmoiditis in approximately 45% of patients.47 Skip lesions, in the form of appendiceal, periappendiceal, or ascending colon/cecal involvement, have been observed in as many as 80% of patients with subtotal UC (see Unusual Morphologic Variants of Ulcerative Colitis).47 Based on a long-term follow-up study by Farmer and colleagues, pancolitis eventually develops in almost half (46%) of patients with proctitis or rectosigmoiditis and in more than 70% of those with left-sided colitis.48

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

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

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

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

Microscopic Findings

Depending on the phase of disease and the degree of inflammatory activity, UC-related colitis is categorized as chronic inactive, chronic active, or active (without features of chronicity) for the purpose of sign-out. Chronic colitis (regardless of “activity”) is defined by the presence of histologic features of chronicity (Box 17.1), such as crypt architectural distortion, crypt atrophy, diffuse mixed lamina propria inflammation, basal plasmacytosis, basally located lymphoid aggregates, and Paneth cell metaplasia (in the left colon). Other changes of chronicity include lamina propria fibrosis, pyloric gland metaplasia, and Paneth cell hyperplasia in the right colon. Common changes of “activity” include neutrophilic or eosinophilic cryptitis, crypt abscesses, regenerative or degenerative epithelial changes, hemorrhage, necrosis, erosions, and ulceration. The degree of activity is graded as mild if less than 50% of the mucosa shows evidence of activity, moderate if more than 50% shows these features, and severe if surface erosion or ulceration is present.

Chronic Active Colitis.

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

UC characteristically involves the mucosa and sometimes the superficial submucosa (Fig. 17.9). The histologic findings vary depending on the clinical phase of disease. Ultimately, in periods of clinical activity, UC is predominantly a lymphoplasmacytic inflammatory process with superimposed neutrophils, hemorrhage, and epithelial degeneration. A dense, homogeneous lymphoplasmacytic infiltrate typically expands the lamina propria (Fig. 17.10).4951 The density of plasma cells is usually greatest in the basal region of the lamina propria (termed “basal plasmacytosis”). Basally located lymphoid aggregates (situated between the bases of the crypts and the muscularis mucosae) are also common. They may show germinal centers. Expansion of the lamina propria and the presence of basal lymphoid aggregates contribute to irregular spacing of the crypts.

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

Depending on the severity of active disease, a neutrophilic inflammatory cell infiltrate (with or without eosinophils) may be seen within the lamina propria and surface and crypt epithelium (cryptitis); it may be minimal, focal and patchy, or diffuse and severe. Similarly, aggregates of neutrophils within the crypt lumina (crypt abscesses) may be focal or diffuse (Figs. 17.11 and 17.12). Rupture of crypts because of inflammation can lead to the development of aggregates of histiocytes, foreign body giant cells, and even well-developed granulomas, as a response to extravasated mucin (Fig. 17.13). So-called mucin granulomas (crypt rupture–associated granulomas) are usually present in the deeper portions of the mucosa, where crypts tend to rupture. Often, deeper cuts though tissue blocks are necessary to determine whether a mucosa-based granuloma is related to a ruptured crypt. Some patients show a marked foreign body giant cell response, or even a fully developed granulomatous response, which can be seen at the base of the mucosa. Distinguishing granulomas in UC from those in CD can be challenging, but the latter are more often randomly located in the mucosa and are more often superficial in location (see Crohn’s Colitis). When a mucosal granuloma is identified, serial sections should be evaluated to determine whether it is located immediately adjacent to a ruptured crypt. The presence of eosinophils within a granuloma is often a clue that one is dealing with a mucin granuloma.

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

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

Occasionally, the rectum appears grossly free of disease (absolute rectal sparing) or has less activity than the proximal colon (relative rectal sparing). This is usually a result of prior medical treatment, either orally, or more commonly, with steroid enemas.

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

Most patients with UC eventually enter a resolving, or healing, phase of disease, characterized by decreasing activity (and symptoms) after an active colitis episode. This phase of disease is characterized morphologically by less activity and less crypt injury, but higher levels of crypt regeneration and remodeling (Fig. 17.16). Injured crypts typically heal from the base of the mucosa progressively upward toward the luminal surface. Neutrophils and other active components of crypt injury decrease first, followed by a reduction in lamina propria lymphocytes and plasma cells. During this initial healing phase, there is often much variability in the type and degree of mucosal inflammatory changes within biopsy fragments from different regions of the colon and even within individual fragments of mucosa from a single site. Neuroendocrine cell hyperplasia occurs in some patients, whereas others develop prominent lymphoid follicles that are more common in the distal colon and rectum (follicular proctitis). Follicular proctitis appears to identify a subgroup of patients who have a less favorable response to medical therapy.52,53

Chronic Inactive (Quiescent) Colitis.

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

Effects of Prior Treatment on the Histology of Ulcerative Colitis.

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

Classic teaching emphasizes that UC is characterized morphologically by the presence of diffuse fixed archi­tectural or cellular mucosal changes (or both) that categorize the process as chronic. However, in 1993, Odze and colleagues prospectively evaluated 123 rectal mucosal biopsy specimens from 14 patients with pathologically confirmed UC treated with either 5-aminosalicylic acid (5-ASA) or placebo enemas.54 During the course of treatment, 29% of rectal biopsies from 64% of patients were histologically normal, showing no evidence of chronic or active disease. Patients treated with 5-ASA showed a significantly higher percentage of normal biopsy specimens (obtained from areas of mucosa previously shown to be involved with chronic active disease) than did the placebo group. This was the first report to demonstrate that “fixed” chronic features in UC may revert to normal in the natural course of the patient’s illness, and that this phenomenon may be enhanced by topical therapy. Subsequent studies by Kleer and Appelman,55 Bernstein and colleagues,56 and Kim and colleagues,57 all of whom evaluated patchiness of disease and patterns of involvement in UC colorectal biopsy specimens with time, confirmed and expanded the initial findings of Odze’s group.

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

Unusual Morphologic Variants of Ulcerative Colitis

A summary of the causes of unusual morphologic patterns of disease in UC is provided in Box 17.2. It is important that pathologists recognize these variants so they can avoid falling into diagnostic traps and misdiagnosing UC as CD. This section provides a summary of many of the causes of Crohn’s-like changes in UC, which include segmental or patchy involvement of the colon, rectal sparing, skip lesions, ileal or upper GI inflammation, aphthous ulceration, and granulomas.

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

Some patients with either subtotal or left-sided colitis show patchy, mild, chronic, or active inflammation in the cecum or ascending colon that may be falsely interpreted as CD because of the impression of segmental involvement.5860 As many as 65% of patients with UC have limited left-sided involvement initially, but eventual extension to more proximal portions of the colon occurs in 29% to 58% of such patients.58,61,62 In one study by D’Haens and colleagues of 20 patients with established left-sided UC, 6 showed a sharp demarcation between affected and unaffected portions of colon, whereas 14 showed a more gradual transition.58 The area of transition in such cases may appear somewhat patchy, giving a false impression of skip lesions. Seventy-five percent of this latter group of patients showed an area of inflammation in the cecum, primarily in the periappendiceal mucosa, that was separate from the distal inflamed segment. In a study by Mutinga and co-workers, 14 patients with both left-sided UC and pathologically confirmed patchy right-sided chronic inflammation were compared with 35 control patients who had limited left-sided UC only.47 The two groups had similar demographic features, extraintestinal manifestations, severity of disease, prevalence of extension to pancolitis, and natural history, which suggests that patchy right-sided inflammation in patients with left-sided colitis has little clinical significance. This fact should be recognized by pathologists so that a false diagnosis of CD can be prevented.

In a prospective study of 271 patients with UC, including 63 with inactive left-sided or subtotal colitis, skip areas of periappendiceal cecal mucosal involvement were identified in 32% of patients. Similarly, since the original description by Davison and Dixon in 1990 of “discontinuous involvement” wherein the appendix was found to be inflamed in 21% of 62 cases of distal UC,63 several other studies have shown that the appendix may be involved as a “skip lesion” in this disease,64,65 although at least one other study failed to confirm this finding.66 In another study by Groisman and colleagues, ulcerative appendicitis was present in 86% and 87% of patients with “nonuniversal” and “universal” UC, respectively.64 Their study included two cases with limited left-sided involvement combined with appendiceal involvement. Overall, the role of the appendix in UC is poorly understood. Patients with prior appendectomy have been shown to have a lower risk for UC.67,68 In one study, the severity of appendiceal inflammation (ulceration) in patients with UC was a strong predictor of the development of pouchitis after a total proctocolectomy and ileoanal pouch procedure.69 In summary, involvement of both the appendix and the cecal or ascending colon can occur in patients with subtotal colitis. This phenomenon should be recognized by pathologists as an acceptable potential skip lesion in UC.

Initial Presentation of Ulcerative Colitis in Pediatric Patients

Several recent studies have shown that pediatric patients with untreated UC at presentation may show evidence of relative, or even complete, rectal sparing or patchy colonic disease.7074 Markowitz and co-workers reported on 12 pediatric patients with untreated UC, 5 (42%) of whom showed patchy, mild active inflammation and mild crypt changes in rectal, compared with proximal, colonic biopsy specimens.70 One patient had a completely normal rectal biopsy specimen. A study by Glickman and associates compared the rectal mucosal biopsy appearance of 70 pediatric patients who had UC with that of 44 adult patients, all at initial presentation before treatment.71 Compared with adults, pediatric patients showed significantly fewer cases of chronic active disease and a greater number of patients with microscopic skip areas and relative rectal sparing. Two of the 70 pediatric patients had completely normal rectal biopsy specimens at initial presentation, in contrast to none of the adult patients. Therefore, an absence of features of chronicity or the presence of mild active disease and microscopic skip areas at initial presentation in pediatric patients does not exclude a diagnosis of UC. In adults, relative (but not absolute) rectal sparing (i.e., less severe inflammation in the rectum compared with the proximal colon) may be seen, rarely, at initial presentation before treatment.75,76 In one study, a 31% prevalence rate of relative rectal sparing was noted in a series of 46 adult patients with UC at initial presentation, but even in those cases, histologic features of chronicity were almost always present in rectal mucosa at the time of initial diagnosis.76

Ileitis in Ulcerative Colitis

Patients with severe pancolitis, including involvement of the cecum and ileocecal valve, may show a mild degree of active inflammation in the distal few centimeters of terminal ileum; this is presumably related to inflammation-induced incompetence of the ileocecal valve and subsequent reflux of colonic contents,77,78 termed backwash ileitis. Pathologic criteria for backwash ileitis were defined in 2005.79 Haskell and colleagues reviewed 200 UC resection specimens and found active ileitis in 17%, confined in most cases to the distal 1 cm of ileum.79 Ninety percent of the cases consisted of mild, patchy neutrophilic inflammation in the lamina propria, focal cryptitis or crypt abscesses, and patchy villous atrophy and regenerative changes (Fig. 17.18, A). In rare instances, surface ulceration or even pyloric (mucous gland) metaplasia was present (see Fig 17.18, B). In their study, a backwash mechanism for ileitis in UC was questioned in some cases that showed lack of cecal involvement (or only mild inflammation in the cecum) and patchy or discontinuous ileal involvement. These cases may have resulted from a drug effect or bowel preparation effect. Nevertheless, ileal findings such as crypt architectural distortion, fissuring ulceration, submucosal inflammation, granulomas, or greater lengths of ileal involvement (>5 cm) should raise a strong suspicion for CD, particularly if the patient does not have severe disease up to and involving the proximal cecum and ileocecal valve. More recently, in a large case-control study, Arrossi and associates evaluated pouch outcome in patients with UC and IBD of indeterminate type and reported that the presence of backwash ileitis was not a significant risk factor for the development of pouchitis.80

Rarely, premalignant dysplastic changes and even adenocarcinoma have been shown to develop in the setting of backwash ileitis.81 Heuschen and colleagues found a strong association between backwash ileitis and the development of colorectal cancer in patients with UC who had undergone proctocolectomy.82 However, discrete pathologic criteria for backwash ileitis were not defined, and it is likely that most of the patients in whom cancer developed had CD. Neither Haskell’s nor Arrossi’s group found an increased risk for dysplasia or cancer in patients who had UC with ileitis, compared with those without ileitis.79,80

Other factors may also lead to the development of active inflammation in the distal ileum (active ileitis) in UC, including infections, drugs (e.g., nonsteroidal antiinflammatory drugs [NSAIDs]), and, most commonly, the effects of certain bowel preparatory agents.83 It has been speculated that the ileum may be involved by UC in some cases, but this is controversial.8385 In a study consisting of 50 patients with active UC, 16% of patients had ileal inflammation but without involvement of the cecum, indicating that backwash was not the cause of the ileitis (“non-backwash ileitis”).86 These patients had higher levels of ileal inflammatory cytokines (IL6, IL8, and tumor necrosis factor-α [TNF-α]) and, more commonly, had extraintestinal manifestations of UC (e.g., arthritis, pyoderma gangrenosum) at presentation. This condition should not be confused with CD of the terminal ileum. In CD, the distal ileum typically shows longer lengths of involvement (often >5 cm) and is associated with histologic features of chronicity, such as pyloric gland metaplasia, ulceration, and established radiologic abnormalities.78

Upper GI Involvement in Ulcerative Colitis

Gastric or duodenal involvement, or both, has been rarely reported in association with clinically and pathologically confirmed UC.8792 A study by Valdez and co-workers described four patients with chronic active inflammation in the duodenum similar in appearance to the patients’ colonic disease.87 In another study, five patients had chronic active gastritis and four had chronic active duodenitis; in these cases, the upper GI findings resolved after colectomy.93 Several similar cases have been reported in the Japanese literature.94 In a recent study by Lin and colleagues, esophageal, gastric, and duodenal biopsies from 69 patients with proven UC were compared with those of 97 control subjects.95 The most common pattern of inflammation in the upper GI tract was “focal gastritis,” followed by mixed inflammation in the basal aspect of gastric mucosa and superficial plasmacytosis. Diffuse chronic duodenitis was observed in 10% of UC patients, even after colectomy. The authors did not find specific mucosal changes in esophageal biopsy specimens from patients with UC. Until such cases have been followed for longer periods, it is difficult to know whether upper GI involvement in UC represents a manifestation of the primary inflammatory disorder or simply an unidentified, but unrelated, inflammatory disorder. Precise characterization of these cases with long-term follow-up is needed to help establish specific criteria for upper GI involvement in patients with UC.

Crohn’s-Like Aphthous Ulcers in Ulcerative Colitis

Although aphthous ulcers are characteristic of CD, they may occur in other types of colitides and even in UC. They have been reported in infectious colitis, diverticular disease, and diversion colitis, among other conditions.83 In one study, aphthous-type ulcers were present in 17% of UC resection specimens.69 In that study, manifestations of CD did not develop in any of the patients, nor was the presence of aphthous ulcers associated with the subsequent development of pouchitis.

Granulomas in Ulcerative Colitis

Some cases of active UC may show granulomas in association with ruptured crypts (see Fig. 17.13). This finding may be prominent and may involve many crypts at the base of the mucosa. Granulomas may also develop in UC from unrelated causes, such as degenerated collagen, particulate matter, superimposed infections, or as a result of drug reaction.96100 In equivocal cases, mucin granulomas related to ruptured crypts may be distinguished from granulomas in CD by use of histochemical stains or evaluation of multiple deep tissue sections. In general, granulomas present in the superficial mucosa (and certainly in the submucosa) are more likely to be CD related than basal mucosal granulomas, which are often crypt related.

Natural History and Treatment

Current therapeutic strategies for UC are separated into those that treat active disease (induction therapy) and those that prevent recurrence of disease once remission has been achieved (maintenance therapy). Medical therapy focuses on agents that alter the host’s immune response in an effort to decrease mucosal inflammation. First-line therapy consists of oral 5-ASA preparations such as sulfasalazine, Pentasa, Asacol, and Balsalazide. Sulphasalazine induces remission in 39% to 62% of patients with mild to moderate UC.101 Topical 5-ASA enemas can be used to treat disease located as much as 20 cm from the anal verge. Moderate to severe flares of UC are treated with systemic glucocorticosteroids. Azathioprine and 6-mercaptopurine are two purine analogue immunomodulators that interfere with nucleic acid metabolism and exert a cytotoxic effect on lymphocytes. Cyclosporine A, another potent inhibitor of cell-mediated immunity, is primarily indicated in patients with severe steroid-refractory disease.

Surgical therapy is indicated in cases of medically refractory disease, recurrent systemic complications, unacceptable side effects of medical therapy, colonic perforation, colonic dysplasia, or carcinoma. Surgical choices include subtotal colectomy with ileostomy, colectomy with ileorectal anastomosis, and proctocolectomy with ileal pouch–anal anastomosis (IPAA).

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

Colonic strictures develop in almost 5% of UC patients. Their presence should always prompt a high index of suspicion for malignancy, especially if the stricture is located proximal to the splenic flexure. In a retrospective study comprising 1156 patients, 24% of strictures were found to be malignant.102 Most of the malignant strictures were located proximal to the splenic flexure, were clinically symptomatic, and developed late in the course of disease (after 20 years). Cancers associated with strictures tend to be more advanced than those not associated with a stricture.

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