Key aspects defining UC as a distinct entity are observed macroscopically. Typically, the diffusely affected UC resection specimen lies flat when opened on the pathologist’s bench, in contrast to the rigid CD specimen (Fig. 22.4). Further inspection reveals a smooth external surface (serosa) and bowel wall of normal thickness, devoid of strictures and fistulas . These simple observations reflect two characteristic pathologic features of UC: diffuse superficial mucosal inflammation and absence of fibrosis. Inflamed mucosal surfaces appear red, granular and friable with areas of hemorrhage and ulceration in severe cases. The following histologic correlates provide explanation for these macroscopic features.

Depth of disease: In differentiating UC from CD, it is important to consider depth of disease. Active UC shows varying degrees of neutrophilic inflammation; usually limited to the mucosa and superficial submucosa, superimposed on chronic injury (Fig. 22.5). Significant mural fibrosis is not usually present. However, in severe cases with extensive ulceration (i.e., severely active disease), inflammation may extend to the muscularis propria or even the subserosal tissues.

Type of ulcer formation: UC ulcers are morphologically distinct from those observed in CD. Broad based superficial ulcers (Fig. 22.5), typical of UC, markedly contrast with the deep knife-like ulcerations associated with CD (below). These different types of ulcers reflect the superficial and transmural extent of active disease in UC and CD, respectively.

Inflammatory polyps: Also known as pseudopolyps , inflammatory polyps are believed to form during repeated cycles of ulceration and regeneration in both UC and CD. Pseudopolyps are not associated with an increased risk for neoplastic transformation; however, they may be extensive (Fig. 22.6) and are frequently biopsied to rule out polypoid dysplasia. Although not a premalignant lesion, the presence of pseudopolyps, in general, indicates long duration of severe disease, a factor which increases overall risk for dysplasia or frank malignancy anywhere in the affected colorectum [8].

Continuous distribution and superficial extent of disease are hallmarks of UC; however, overlapping features with CD may arise and are discussed in this section. Backwash ileitis [9, 10]: Activity and even low grade chronic injury may extend into the distal ileum, particularly in severe UC pan-colitis. In contrast to Crohn’s ileitis, which typically shows a patchy pattern throughout the ileum, involvement in UC is distal, diffuse, and predominately limited to the ileocecal valve. As ileal involvement by UC resolves following totally colectomy, the inflammation is believed to be caused by proximal extension of colonic disease through an incompetent ileocecal valve. Thus, the clever name “backwash ileitis” is a diagnosis which should be only made if cecal disease is severe. It can be a challenge to make a definitive diagnosis of backwash ileitis and completely rule out CD, therefore a detailed diagnostic comment should be added to the pathology report to facilitate clear communication amongst the clinical team.

Cecal red patch [11–13]: Disease localized to the appendix and periappendiceal cecal mucosa, or “cecal red patch,” and can be seen in up to one third of patients with UC. Histologically, these biopsies resemble mildly active ulcerative colitis (i.e., evidence of chronic injury and intraepithelial neutrophils) and should not be interpreted as patchy CD-like distribution.

True rectal sparing : Although rectal involvement is one of the key features of UC, pediatric patients may present with rectal sparing [14, 15]. This unconventional distribution of disease is considered a normal variant in the pediatric UC population.

Granuloma formation : Presence or absence of granulomas is a common histologic feature used to differentiate UC from CD. Well or poorly formed granulomas, characteristic of CD, appear as pale compact aggregates of histiocytes surrounded by lymphocytes, discussed in detail below. Diagnostic confusion may arise when similar features are seen in UC patients. Although well-formed granulomas are not associated with UC pathogenesis, loose aggregates of histiocytes, or macrophages, may be seen in UC patients. Histiocytes function to clear cellular debris and foreign material following injury. Therefore, during episodes of active inflammation, crypts may rupture, releasing mucin into the lamina propria. The extracellular mucin signals histiocytes to the affected area, and results in formation of the so-called “mucin granulomas.” Additionally, multinucleated histiocytes, known as “foreign body type giant cells” can cluster near areas of ulceration and mimic granuloma formation. Thus, it is essential to carefully inspect the quality of the histiocytic reaction in respect to the associated background features to determine the significance of granuloma formation in IBD patients.

Unique gross and microscopic features of CD and UC are shown in Table 22.1. CD occurs in a patchy or segmental distribution anywhere in the gastrointestinal tract in contrast to UC which is diffuse and limited to the colon and rectum. Segmental distribution is illustrated in Fig. 22.7. Here the involved external serosa reveals “creeping fat” or “fat wrapping” due to fibrous adhesions and increased fat deposition (Fig. 22.7 inset). The affected area in this resection specimen is characteristically narrowed from stricture formation and flanked by discrete regions of normal appearing intestine. Most notably, the opened specimen does not lay flat (compare Fig. 22.7 CD specimen to Fig. 22.4 UC specimen), a result of extensive fibrosis and transmural disease. On closer inspection, a markedly thickened bowel wall and strikingly narrowed luminal diameter can be appreciated in the strictured segment. The mucosa takes on a cobblestone appearance due to alternating areas of ulcerated and preserved mucosa. Deep, knife-like ulcerations, which give rise to fistula tracts, are common but not easily appreciated in this image. When examining a severely active CD specimen such as this, it is not difficult to understand how stricture and fistula formation carry a high risk of perforation and abscess formation, both indicators for segmental resection. Pseudopolyps (e.g., Fig. 22.6), created by cycles of regeneration and injury, are identical to those observed in UC (see above discussion).

As CD may involve any part of the gastrointestinal tract classic histologic features can be observed in the oral cavity (Fig. 22.8a), esophagus, stomach (Fig. 22.8b), and small (Fig. 22.8c) and large intestines (Fig. 22.8d). Along with distribution and depth of disease, several additional histologic features define CD: type of ulcer, fibrosis, granuloma formation and neuronal hyperplasia.

Patchy chronic injury: Analogous to the gross morphologic features described in the previous discussion, histologic discontinuous disease distribution is illustrated by distinct areas of normal and diseased mucosa within a single biopsy (Fig. 22.8d), as well as separate affected and non affected biopsies from sequential segments of small and large intestine. Please refer to the to the UC section on caveats to disease distribution.

Depth of disease: Similar to UC, active neutrophilic inflammation ranging from quiescent to severely active is superimposed on chronic injury (Fig. 22.4). However, in CD, inflammation may extend transmurally to form strictures and fistula tracts, features not present in UC. Limited superficial mucosal inflammation without full thickness involvement can occur and should not rule out a diagnosis of CD.

Type of ulcer: Small aphthous ulcers and deep , knifelike, fissuring ulcers are characteristic of CD. Aphthous ulcers seen endoscopically correlate with small collections of intraepithelial neutrophils overlying lymphoid aggregates histologically (Fig. 22.9). These are believed to coalesce, resulting in deep ulceration which eventually can extend into the muscularis propria. Fistula formation likely develops from these large deep fissuring, knife-like, ulcers extending through the serosa and into pericolonic fibroadipose tissue (Fig. 22.10).