Active colitis refers to the presence of neutrophils either in the lamina propria, in crypt epithelium (cryptitis) or within the lumen, forming small abscesses (crypt abscesses). Neutrophils confined to the lumen of mucosal vessels are not considered part of the process of active colitis. A predominantly neutrophilic infiltrate without significant architectural changes is generally a feature of diseases with a self-limiting course, such as infections and drug reactions. Neutrophils in these cases are frequently confined to the superficial portion of the mucosa, and may be associated with small erosions or ulcers (Fig. 22.3).

Focal active colitis (FAC) is observed in acute self-limited colitis and can be an early manifestation of idiopathic inflammatory bowel disease . In a recent report of 29 pediatric patients with FAC, 8 developed Crohn’s disease, whereas the other patients had either infectious colitis or remained idiopathic [10].

Eosinophilic colitis refers to a patchy or diffuse infiltrate dominated by eosinophils, usually with infiltration of the crypt or surface epithelium. Wide variations in the number of eosinophils in the normal colonic mucosa are due to differences in specimen site (greater numbers of eosinophils in the cecum as opposed to the rectum), age, and geography [11, 12]. In infants, the main consideration is milk allergy; parasitic infection and chronic inflammatory bowel disease (very early-onset IBD) are also possibilities.

The features of chronic colitis are based on the recognition of architectural changes in the mucosa, such as a “villiform” aspect of the surface epithelium, crypt destruction, and atrophy, and shortening of the crypts with irregular branching and loss of their regular outline. Shortening of the crypts is most often due to the presence of a basally situated chronic inflammatory infiltrate (basal plasmacytosis), which separates the base of the crypts from the muscularis mucosae (Fig. 22.4). Paneth cell metaplasia and pyloric metaplasia are other useful findings (Fig. 22.5). In the normal colon, Paneth cells usually extend into the right colon, but their presence in the left colon is a feature of chronic damage, especially in the older child. Pyloric metaplasia is the presence of mucous glands normally present in the gastric antrum and pylorus. It is more frequently noted in Crohn’s disease than ulcerative colitis (UC), but is also a useful feature of chronic damage. The presence of an increased mononuclear inflammatory cell infiltrate, usually an integral part of the process, is the least useful histologic parameter given the wide range in numbers of lymphocytes and plasma cells in normal specimens. Though considered a hallmark of chronic idiopathic inflammatory bowel disease, histologic features of chronicity may also be seen in other settings in pediatrics, such as immunodeficiency disorders, metabolic diseases such as glycogen storage disease type Ib, or result from mucosal injury due to ischemia or Hirschsprung’s disease. Chronic active colitis refers to the presence of a neutrophilic infiltrate superimposed on the above changes, and is usually seen during exacerbations of IBD.

Endoscopic features alone may not reliably distinguish acute self-limited colitis (ASLC) from IBD. Stool cultures and duration of diarrhea may help, as patients without an identifiable pathogen or in whom diarrhea lasts more than several weeks are more likely to have IBD. However, microbiologic investigations can reveal a colitis-causing pathogen such as Salmonella, Campylobacter, and Yersinia in up to 15% of patients with IBD [13]. ASLC is characterized by a predominantly neutrophilic infiltrate without significant crypt architectural changes. Neutrophils in these cases predominate in the superficial portion of the mucosa, and may be associated with small erosions or ulcers [14]. Neutrophils may also invade the crypt epithelium (cryptitis) or form small abscesses within the crypt lumen (crypt abscesses). Although numerous crypt abscesses suggest UC, they may be noted in CD as well as in infections and Clostridium difficile–related injury. The histologic diagnosis of IBD rests on the recognition of chronic mucosal damage, chronic colitis. Multiple biopsy studies of new-onset IBD in adults have shown that histologic features of chronic damage as noted above can reliably distinguish IBD from self-limited colitis [14–17].

Despite the importance of recognizing chronic mucosal changes in the biopsies of patients with IBD, it has been well documented that initial colonic or rectal biopsies from 10% to 34% of pediatric patients ultimately shown to have UC lacked architectural distortion or other histologic features of chronic colitis [18–23]. This is seen particularly in younger patients (<10 years) and may be due to shorter duration of symptoms or longer progression to chronicity in children [24] (Fig. 22.6a,b). Focal active colitis may be a feature of self-limited colitis but may also be an early manifestation of IBD [10]. Close follow-up and repeat biopsies may be necessary in these cases. Increased mucosal eosinophils may be seen in the earliest biopsies of children eventually proven to have IBD, prompting a diagnosis of food allergy. In a recent case series of IBD diagnosed in 16 children less than 2 years of age, six children had an initial diagnosis of allergy [25]. On the other hand, histologic features similar to IBD may be seen in patients with primary immunodeficiencies and autoimmune enteropathy [26]. These conditions should always merit consideration when clinical manifestations of IBD occur in younger children. Histologic features that may point to a correct diagnosis in these patients include lack or paucity of plasma cells in the inflammatory infiltrate (as in Common Variable Immunodeficiency or Severe Combined Immunodeficiency), extensive crypt apoptotic activity, or absence of goblet and Paneth cells (as in autoimmune enteropathy). [27] An increasing number of rare monogenic diseases have been observed in patients with very early-onset inflammatory bowel disease [28] (Fig. 22.7).

The macroscopic and microscopic features which distinguish UC and Crohn’s disease are, in most respects, similar in children and adults, and are outlined in Table 22.2. Biopsy features helpful in differentiating these two entities in mucosal biopsies are outlined in Table 22.3. It should be noted, however, that, especially in early stages of disease, biopsies, even in combination with clinical and radiologic features, may not allow distinction between these two entities. Absence of ileal involvement does not rule out CD, and appears to be more frequent in younger patient with CD than older children or adults [29]. Similarly, diffuse colitis may be a manifestation of both CD and UC in children.

UC is classically defined as diffuse chronic mucosal inflammation limited to the colon, which invariably affects the rectum, and extends proximally in a symmetric uninterrupted pattern to involve part or all of the large intestine. The mucosa characteristically exhibits a diffuse hemorrhagic appearance (Fig. 22.8).

Microscopically, ulcerative colitis is characterized by inflammation limited to the mucosa and superficial submucosa (Fig. 22.9); deeper layers of the bowel are only exceptionally involved, as in toxic megacolon. Infiltration of the mucosa by neutrophils, with cryptitis, epithelial degeneration, goblet cell depletion, and crypt abscesses are characteristic though relatively nonspecific microscopic features of active UC. Chronicity, as previously defined, is characterized by crypt architectural changes such as irregular branching and atrophy, usually accompanied by a mononuclear inflammatory infiltrate. Increased crypt epithelial turnover in UC results in goblet cell depletion and Paneth cell metaplasia [30], less frequently observed in CD. The latter must be interpreted with caution in pediatric cases, as Paneth cells can be present in the distal colon in normal young children. Crypt abscesses are not specific, but when diffuse are suggestive of UC, whereas they tend to be more isolated in Crohn’s disease [31]. Rupture of crypt abscesses into the lamina propria or erosions may result in collections of histiocytes which may simulate but should be distinguished from true granulomas (Fig. 22.10).

Pseudopolyps, more commonly found in UC than CD, are discrete areas resulting from surviving islands of mucosa or heaped-up granulation tissue. The latter are more accurately referred to as “inflammatory polyps”. Occasionally, regenerating mucosa within such an inflammatory polyp may form irregular, dilated glands, which bear a marked resemblance to retention or “juvenile” polyps [31]. In contrast to adenomas, pseudopolyps have a short stalk and are generally smooth surfaced (Fig. 22.11). Extensive arborization and fusion of the polyps may result in mucosal bridging.

In contrast to UC, CD features segmental intestinal involvement, with thickening of the bowel wall consequent to transmural inflammation and fibrosis, resulting in obstructive strictures, especially in the ileocecal area. The serosa is typically congested, with the presence of adhesions and fat wrapping, or “creeping fat”. Mucosal involvement can be patchy and discontinuous. Aphthous ulcers overlying lymphoid tissue are among the earliest lesions observed endoscopically, but are nonspecific and may be seen in other conditions. Uneven involvement of the mucosa results in a typical “cobblestone” appearance (Fig. 22.12). Transmural involvement in resected specimens and the presence of granulomas are the major histologic features which distinguish CD from UC and other colitides. Transmural disease in CD usually results from submucosal edema, fibrosis and inflammation, typically in the form of lymphoid aggregates, also involving the muscle layers and the serosa (Fig. 22.13). Intramural abscesses are also noted, with fistulae, perforations and adhesions, which can involve multiple loops of bowel and form a mass. The identification of pyloric metaplasia indicates chronic damage [32], and is seen more frequently with Crohn’s disease than with UC. Lymphangiectasia, neural hyperplasia and vascular changes are frequently observed in CD and are almost never seen in UC.

Granulomas are virtually diagnostic of CD when they are well-formed, nonnecrotic, basally situated, and remote from areas of active inflammation (Fig. 22.14). Their presence in biopsies may predate radiologic evidence of disease, and prolonged follow-up is necessary when they are observed in the absence of grossly evident disease [33]. The likelihood of finding granulomas is clearly a function of the diligence with which they are sought, increasing with the number of biopsies and sections examined [34]. Granulomas appear to be more frequently observed in the pediatric age group. One large study in Germany found them in 26% of biopsy specimens from 42% of patients, twice as commonly as in adults [35]. Comparison of initial biopsies of children with and without rectosigmoid granulomas showed similar age of onset of disease in the two groups, though those with granulomas tended to have more extensive disease and perianal complications [36]. Shepherd and colleagues observed granulomas more frequently in their younger patients and those with a shorter clinical course, with an increased prevalence in the more distal portion of the gastrointestinal tract [37]. In a recent study at The Children’s Hospital of Philadelphia, granulomas were identified in 61% of pediatric CD patients undergoing upper and lower endoscopy and were more frequent in untreated patients [38]. In nearly half of those patients, granulomas were present in the upper GI tract, in the terminal ileum, or both, but not in the colon.

Granulomas can also be seen, however, in a number of other conditions (Table 22.4). The granulomas seen in tuberculous infections of the gastrointestinal tract are typically multiple, large, and have caseous necrosis [39]. Those associated with yersiniosis are also necrotic and frequently present in mesenteric lymph nodes [40]. Chronic granulomatous disease (CGD) can present with a colitis similar to CD [41]. Numerous necrotizing granulomas may be observed; in noninflamed or quiescent cases, collections of pigmented macrophages may be noted in the mucosa (Fig. 22.15).

Colonic malignancy is a well-recognized long-term complication of UC. Recent evidence suggests that patients with Crohn’s colitis incur a similar risk of colorectal cancer [42]. Duration of disease and pancolitis are well recognized as risk factors for the development of malignancy, with the risk of cancer increasing over that of the general population by 1% each year after 10 years of disease [43, 44]. Unfortunately, there is a paucity of prospective data describing long-term inflammatory bowel disease with early-onset ulcerative colitis and ultimate cancer risk in pediatric patients. Other less well-characterized risk factors include concomitant sclerosing cholangitis, an excluded, defunctionalized or bypassed segment and depressed red blood cell folate levels [43]. Children who develop colitis before the age of 10 years should undergo colonoscopy screening during their adolescence, and dysplasia and adenocarcinoma have been documented in adolescents and young adults with long-standing colitis [45]. Dysplasia in colitics is generally plaque-like or nodular, frequently referred to as the DALM (dysplasia-associated lesion or mass) lesion [46] (Fig. 22.16a, b). Epithelial dysplasia generally precedes carcinoma; therefore yearly surveillance colonoscopy is recommended. Since reliability and patient compliance of serial colonoscopy to detect dysplasia are not perfect, prophylactic colectomy should be considered in any individual who developed ulcerative colitis during childhood.