Nondisease-related alterations in the colonic mucosa may be induced by certain enemas used in bowel preparation or by the procedure itself. For example, soap suds enemas may result in hyperemia and edema of the bowel, especially noted on endoscopy [1]. Oral sodium phosphate solutions (oral fleet) may cause aphthoid-like erosions endoscopically similar to Crohn’s disease [2]. These correspond histologically to large lymphoid aggregates, although edema, hemorrhages or mild acute inflammation have also been described (Fig. 21.1) [3]. Mucin depletion and increased cell proliferation can be noted in the crypts [4, 5]. Hypertonic saline and bisacodyl enemas can cause mucin depletion, focal disruption of surface epithelium, mild acute inflammation and edema, which usually resolve within 1 week [6]. Minor trauma to the mucosa may allow penetration of gas insufflated into the bowel during endoscopy, resulting in “pseudolipomatosis,” characterized by the formation of numerous clear spaces in the mucosa (Fig. 21.2) [7]. Cleansing solutions used to disinfect endoscopes, such as hydrogen peroxide, may produce adherent mucosal plaques, mucosal vacuolar changes, congestion, hemorrhage, and even pseudolipomatosis [8, 9].

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. 21.3).

Focal active colitis (FAC) is observed in acute self-limited colitis and can be an early manifestation of idiopathic IBD. 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 IBD are also possible.

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. 21.3). 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 IBD, 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 (Fig. 21.3) [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 can reliably distinguish IBD from self-limited colitis [14–17]. These include irregular branching of the crypts with loss of their regular outline, shortening of the crypts, and areas of crypt loss. Shortening of the crypts most often results from the presence of a basal chronic inflammatory infiltrate (basal plasmacytosis) between the base of the crypts and the muscularis mucosae (Fig. 21.4). The presence of an increased mononuclear inflammatory cell infiltrate alone is the least useful histologic marker given the variable numbers of lymphocytes and plasma cells in normal specimens.

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 (Fig. 21.5a,b) [24]. FAC 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, 6 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 which 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). Mutations in genes coding for cytokines, such as interleukin-10, have been demonstrated in patients with the onset of IBD in infancy [27].

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 21.2. Biopsy features helpful in differentiating these two entities in mucosal biopsies are outlined in Table 21.3. 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 patients with CD than older children or adults [28]. 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. 21.6).

Microscopically, ulcerative colitis is characterized by inflammation limited to the mucosa and superficial submucosa (Fig. 21.7); 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 [29], 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 [30]. 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. 21.8).

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 [30]. In contrast to adenomas, pseudopolyps have a short stalk and are generally smooth-surfaced (Fig. 21.9). 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. 21.10). 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. 21.11). 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 [31], 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, non-necrotic, basally situated, and remote from areas of active inflammation (Fig. 21.12). 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 [32]. 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 [33]. 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 [34]. 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 [35]. 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 [36]. 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 [37]. 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 21.4). The granulomas seen in tuberculous infections of the gastrointestinal tract are typically multiple, large and have caseous necrosis [38]. Those associated with yersiniosis are also necrotic, and frequently present in mesenteric lymph nodes [39]. Chronic granulomatous disease can present with a colitis similar to CD [40]. Numerous necrotizing granulomas may be observed; in noninflamed or quiescent cases, collections of pigmented macrophages may be noted in the mucosa (Fig. 21.13).

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 [41]. 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 [42, 43]. Unfortunately, there is a paucity of prospective data describing long-term IBD 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 [42]. 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 [44]. Dysplasia in colitics is generally plaque-like or nodular, frequently referred to as the DALM (dysplasia-associated lesion or mass) lesion (Fig. 21.14a, b) [45]. Epithelial dysplasia generally precedes carcinoma; therefore, yearly surveillance colonoscopy is recommended. Since reliability and patient compliance of serial colonoscopy to detect dysplasia is not perfect, prophylactic colectomy should be considered in any individual who developed ulcerative colitis during childhood.

Although ulcerative colitis is traditionally considered to be a diffuse process that begins in the rectum and extends proximally in a continuous fashion, a number of studies suggest that initial rectal biopsies in children with UC may not demonstrate mucosal architectural changes as consistently as in adults or may even be “normal” (rectal sparing) (Fig. 21.15). An unequivocal diagnosis of IBD may be more difficult in these cases, as may be distinction between UC and CD.

Five of 12 children with untreated UC in one study were found to have mild patchy inflammation or normal histology in the rectum [21], whereas relative rectal sparing compared to adults was found in one study of 53 children [23]. In one study, “absolute” rectal sparing, in which evidence of both inflammation and chronicity is absent, is nonetheless infrequent in children with UC (4% of 73 pediatric cases), though “relative” rectal sparing, defined as the presence of inflammation without changes of chronicity, is more frequent, noted in 26% of cases [19]. Faubion et al. identified a 27% prevalence of rectal sparing in children with IBD and sclerosing cholangitis, suggesting the possibility that rectal sparing may be more common in this subset of patients [46]. Moreover, discontinuous involvement and rectal healing have been reported during the course of long-standing disease in adults, which likely results from treatment effect or natural variation in the course of disease and also reflects the current clinical practice of sampling multiple mucosal biopsies over time [47, 48]. Medical therapy can have a profound but variable effect on mucosal histology, ranging from decreased intensity of the inflammatory infiltrate to complete normalization of the mucosa, including discontinuity of mucosal disease in UC [49]. Quiescent colitis is characterized by mucosal atrophy and crypt architectural changes in the absence of the acute inflammation, ulceration, and mucus depletion seen in the active phase (Fig. 21.16).