Overview of Histopathology of Ulcerative Colitis and Crohn’s Disease

Normal Histology of the Small Intestine

The histology of the small bowel reflects its functional roles, which principally involve digestion and nutrient absorption. As with most portions of the GI tract, the small intestine comprised four major “layers” that are concentrically arranged from the lumen outward as follows: mucosa, submucosa, muscularis propria , and serosa ( Fig. 5.1A ). The mucosa is further subdivided into three compartments: epithelium, lamina propria, and muscularis mucosae .

The mucosa of the small bowel is unique in that the surface epithelium and lamina propria form prominent intraluminal projections called villi, a morphologic modification that maximizes surface area for nutrient absorption. When well oriented on histologic sections, the villi are regularly arranged and relatively evenly spaced, oriented roughly perpendicular to the luminal surface ( Fig. 5.1B and C ). Each villus contains an arteriole with capillary network, veins, and a central lymphatic channel with numerous nerve fibers. This morphology is especially characteristic of the duodenum, where the villi are somewhat shorter and broader than in the distal small bowel. As one progresses into the jejunum and ileum, the villi become longer and more complex with frequent branching. Directly subjacent to the villous epithelium is the crypt compartment; the ratio of the length of the villi to crypt length should be approximately 3:1 to 5:1. Expansion or hyperplasia of the crypt compartment, or blunting of the villi, can occur in the setting of chronic mucosal injury. Either change should reduce the villus-to-crypt ratio. The surface epithelium consists of absorptive cells and goblet cells. The absorptive cells have abundant cytoplasm and with well-formed microvilli. The crypt epithelium is specialized for regeneration, secretion, and immunity, as evidenced by the presence of stem cells, goblet cells, neuroendocrine cells, and Paneth cells. Paneth cells are usually located at the base of the crypt and secrete lysozyme, defensins, and immunoglobulins and are thought to play a role in immunity in association with gut flora. Goblet cells are columnar in shape and have supranuclear mucus droplets. Goblet cells decrease toward the villus tip and increase in frequency distally along the small bowel.

The lamina propria of the small bowel contains loose connective tissue with a robust population of inflammatory cells, including T and B lymphocytes, plasma cells, histiocytes, a few eosinophils, and mast cells. The predominant component consists of plasma cells within the lamina propria. As a matter of routine practice, the presence of plasma cells should be checked in every small intestinal biopsy. While their presence does not exclude an immune deficiency disorder such as common variable immunodeficiency (CVID), up to two-thirds of patients with CVID lack plasma cells in the small intestine and/or colon. Lymphoid aggregates are also a normal component of the small intestine. These become more prominent and frequent in distribution distally, eponymously dubbed “Peyer patches” in the ileum. Lymphocytes are also noted in the epithelium, with a ratio not greater than one lymphocyte per five enterocytes.

Gastric metaplasia and gastric heterotopia are commonly found in the small bowel. Gastric metaplasia is often a normal variant in the duodenal bulb. Away from the bulb, it is most commonly a result of peptic injury (peptic duodenitis), in which case it is typically associated with hyperplasia of intramucosal mucin-secreting Brunner glands and active inflammation. Gastric heterotopia, on the other hand, usually takes the form of a polyp or nodule, and is considered to be a mostly innocuous developmental anomaly. Most cases of gastric heterotopia are incidental findings on endoscopic or histologic examination. Pyloric gland metaplasia (a.k.a. pseudopyloric metaplasia), in which some crypts assume a morphology akin to the crypts in the gastric pylorus, is an indicator of chronic mucosal injury and is often seen in the ileum in IBD. Again, the presence or absence of pyloric gland metaplasia is routinely assessed in small bowel (jejunum and ileum) biopsies, taken from patients when there is a clinical suspicion for IBD, or in pouch biopsies.

The submucosa of the small bowel consists of delicate connective tissue without significant inflammation. Variably sized arteries, veins, capillaries, and lymphatics are present. Ganglion cells and nerve trunks (Meissner's plexus) are present but without evidence of inflammation or hypertrophy. In the duodenum, Brunner's glands are a normal finding in the submucosa. There should be no submucosal fibrosis in the normal small bowel.

The muscularis propria of the small bowel consists of two layers of smooth muscle fibers, the inner circular and outer longitudinal layers, with myenteric ganglion cells and interstitial cells of Cajal (Auerbach's plexus) situated between these two layers. The thickness of the muscularis propria is relatively uniform throughout the length of the normal small bowel. Inflammation, fibrosis, or degeneration should be absent in the muscularis propria of the normal small bowel.

The subserosa and serosa of the small bowel consists of a thin layer of delicate connective tissue covered by a layer of inconspicuous mesothelium. There should be no inflammation, fibrosis, or mesothelial hyperplasia in the subserosa and serosa of the normal small bowel. The mesentery of the small bowel has lobulated yellow fat and that fat should not go beyond the mesenteric attachment.

Normal Histology of the Large Intestine

Like the small bowel, the colon has four layers that are concentrically arranged from the lumen outward as follows: mucosa, submucosa, muscularis propria , and serosa. The mucosa is also further subdivided into three compartments: epithelium, lamina propria, and muscularis mucosae .

In contrast to the small intestine, the colon functions primarily in water absorption, propulsion of fecal matter, and antigen sampling. The mucosa of the colon has regularly arranged crypts that extend from the surface epithelium to the muscularis mucosae , where they “anchor” on the muscularis mucosae . The crypts are lined up in parallel to each other and perpendicular to the longitudinal axis of the colonic lumen, imparting the so-called “test tubes in a rack” appearance ( Fig. 5.2 ). Some mild crypt architectural distortion can occur adjacent to normal lymphoid follicles or aggregates. Crypts can also appear mildly distorted in the normal anatomic mucosal folds of the colon, known as innominate grooves. The crypts in the sigmoid colon and rectum often have a hyperplastic appearance, and crypts at these sites can be dilated or distorted by increased surrounding fibromuscular stroma, perhaps secondary to mucosal prolapse. On biopsy material where the mucosa was evulsed without the underlying muscularis mucosae to anchor it, crypts can also appear unusually oriented. The surface epithelium consists of low columnar to cuboidal absorptive cells and goblet cells, containing abundant cytoplasm and mucus droplets, respectively. The surface epithelium rests on a thin basement membrane. The crypts open into surface epithelium or innominate grooves. The crypts represent a proliferative compartment and usually contain stem cells, endocrine cells, and basally located Paneth cells (in the right colon).

The lamina propria of the colon usually contains loose connective tissue with uniform capillaries and lymphatics just above the muscularis mucosae . Mononuclear inflammatory cells are normally present in the lamina propria of the colon but with some variation in different areas of the colon. The cecum and ascending colon tend to have greater mononuclear cell infiltrates, eosinophils, lymphoid follicles, and lymphoplasmacytic aggregates, as this is an antigen-rich environment. The inflammatory cells are mostly confined to the lamina propria and should not obliterate or expand the lamina propria. The left colon, on the other hand, tends to have sparser lymphoplasmacytic infiltrates, increased muciphages in the lamina propria, and increased goblet cells within the epithelium. A few T lymphocytes (less than 20 per 100 surface epithelial cells) can be seen in the normal colon. Surface intraepithelial lymphocytes numbering greater than 20 per 100 surface epithelial cells, known as surface intraepithelial lymphocytosis, is abnormal. Some individuals, especially young patients, may have intramucosal lymphoid aggregates that disrupt the muscularis mucosae , causing slight crypt distortion. In addition, the epithelium overlying lymphoid aggregates often contains abundant intraepithelial lymphocytes; thus these areas should be not be used to evaluate surface intraepithelial lymphocytosis. Neutrophils should not involve normal epithelium, although significant bowel preparation can produce focal active inflammation.

In adults, Paneth cells are normally present in the small intestine, cecum, appendix, ascending colon, and transverse colon. Infants and children may have Paneth cells in the descending colon and rectum. The presence of Paneth cells in histologically normal rectums in children is strongly associated with idiopathic constipation but does not predict the development of IBD. However, the appearance of metaplastic Paneth cells in areas of the GI tract in which they should not normally exist, as in the descending colon or rectum in adults, is an important feature of chronic mucosal injury.

The submucosa of the colon consists of delicate connective tissue without significant inflammation. Ganglion cells and nerve trunk are presents, but without inflammation or hypertrophy. In addition, variably sized arteries, veins, capillaries, and lymphatics are present. There should be no submucosal fibrosis in the normal colon.

The muscularis propria of the colon consists of two layers of smooth muscle fibers, the inner circular and outer longitudinal layers, with myenteric ganglion cells and interstitial cells of Cajal (Auerbach's plexus) situated between these two layers. The thickness of the muscularis propria is relatively uniform throughout the colon. Inflammation, fibrosis, or degeneration should be absent in the muscularis propria of the colon.

The serosa of the colon consists of a thin layer of delicate connective tissue covered by an inconspicuous mesothelium. There should be no inflammation, fibrosis, or mesothelial hyperplasia in the serosa of the normal colon. The rectum is variably covered by serosa; the distal third of the rectum is not covered by serosa at all. The mesentery of the colon has lobulated yellow fat and that fat should not go beyond the mesenteric attachment.

Histopathology of Ulcerative Colitis

The histologic hallmark of UC is a diffuse superficial chronic active colitis. The mucosa is affected, while deeper layers of the bowel wall are spared ( Fig. 5.4 ). The degree and severity of active inflammation is dependent on disease activity and treatment and is histologically classified according to the extent of crypt involvement and the presence or absence of ulceration ( Table 5.3 ). The Montreal classification of UC is a clinical classification scheme that emphasizes the importance of disease extent and severity at diagnosis: E1 is inflammation limited to the rectum (proctitis), E2 is inflammation limited to the splenic flexure (left-sided colitis), and E3 is pancolitis.

UC tends to involve the colon in a diffuse and continuous, rather than segmental or patchy, distribution. Conventional wisdom asserts that the rectum is universally involved and that UC preferentially affects the left side of the colon, with proximal extension as the disease progresses. However, it has been established that UC can present with patchy disease and relative rectal sparing, especially in the following circumstances: on initial presentation in children, in the setting of fulminant colitis, and in response to therapy. Whether the patient was treated with topical or systemic therapy, posttreatment biopsies are notoriously unreliable for differentiating UC from CD. The initial presentation of IBD in children may manifest with only focal or patchy active inflammation. In left-sided UC, there may be focal involvement of the appendix or cecum with normal intervening colonic mucosa, referred to as an “appendiceal skip lesion” or “cecal patch.” Care should be taken not to interpret this as CD. Patchy right-sided colonic inflammation in the setting of left-sided UC does not portend significant differences in the natural history of disease when compared with only left-sided UC. Children also tend to present more often with pancolitis and a lesser degree of diffuse crypt architectural distortion, whereas adults are more likely to present with a classic left-sided colitis and significant chronic changes.

As its name implies, UC manifests as ulceration in severe disease. An ulcer is an area of markedly eroded mucosa with fibrin deposition, inflammatory cell infiltration, and granulation tissue formation. Ulceration exceeding 50% of the examined mucosa is referred to as fulminant colitis. Diffuse ulceration leaves polypoid portions of nonulcerated mucosa in its wake; these are inflammatory pseudopolyps, not true neoplasms, but rather islands of relatively intact mucosa surrounded by ulcer. Filiform pseudopolyps take on an exaggerated, prominent, vermiform appearance.