Chapter 17 – Normal Lower Gastrointestinal Mucosa


The lower gastrointestinal tract consists of ileum, vermiform appendix, colon, and rectum. The main epithelial cell types are absorptive cells, goblet cells, Paneth cells and endocrine cells. Structurally the ileum resembles the duodenum, and includes villi and crypts. Gut-associated lymphoid tissue plays an important role in immune defence and has focal and diffuse elements in the small bowel. Lymphoid tissue is particularly prominent in the most distal part of the ileum. The mucosa of the large bowel is less complex than that of the small bowel, with parallel crypts and a smooth surface. In the normal colorectal mucosa, the density of plasma cells is highest in the upper one third and lowest in the lower one third. Eosinophilia in the ileum and large bowel is difficult to diagnose unless numbers are greatly increased. There may be a few neutrophils in the normal lamina propria but intraepithelial neutrophils are very infrequent. Apoptosis is a normal finding but the number of well-developed crypt epithelial cell apoptosis should be small. The intraepithelial lymphocyte count in the ileum is 0-9 per 100 surface epithelial cells and in the colon 0-5 per 100. Knowledge of the range of normality is important and helps pathologists to avoid overdiagnosis of inflammatory changes and of neoplasia.

Chapter 17 Normal Lower Gastrointestinal Mucosa

Roger M. Feakins


The term ‘lower GI tract’ is not precise. From an endoscopic point of view, it includes the terminal ileum, vermiform appendix, colon, rectum, and anus, while the upper gastrointestinal (GI) tract extends from the oesophagus to the duodenum. Allocation of the jejunum and more proximal ileum to upper or lower GI tract is variable, and sometimes these portions seem to belong in neither category.

The distal part of the ileum is the terminal ileum, which is the most proximal portion of the lower GI tract that is accessible to colonoscopy. Sometimes, an endoscopist takes a biopsy of the terminal ileum in order to confirm passage of the endoscope through the entire colon, although some guidelines actively discourage this practice. The terminal ileum is continuous with the caecum at the ileocaecal valve. Endoscopists can also identify and biopsy the appendix orifice while in the caecum. The large bowel from proximal to distal comprises caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, and rectum (Figure 17.1). The term rectosigmoid has various meanings and is ambiguous unless there is qualification, e.g. rectosigmoid junction.

Figure 17.1 Anatomy of ileum, colon, and rectum.

Knowledge of the range of normality and of the variation between histological appearances at different sites in large bowel is important and reduces the risk of overdiagnosis of inflammatory changes and of neoplasia.


Ileal Epithelium

The ileal mucosa is similar to the duodenal and jejunal mucosa (see Chapter 9) and consists of villi and crypts (Figure 17.2). The crypt/villus ratio is typically 4:1 or lower. Cell types include absorptive cells (Figure 17.3A), goblet cells, Paneth cells (Figures 9.23A and 17.3B), and endocrine cells (Figure 17.3C). Absorptive cells are tall and columnar and have eosinophilic cytoplasm and oval, basally located nuclei. Beneath the absorptive cells there is a thin basement membrane that assists with cell orientation and consists of collagen, proteoglycan, fibronectin, and laminin.1 The microvillus brush border on the luminal surface of the cell is identifiable microscopically as a thin line (Figure 17.3A). Prominent glycocalyx on the surface stains with periodic acid–Schiff (PAS) and Alcian blue.1 Goblet cells are easily identifiable and their density is higher in the distal ileum than the proximal ileum (Figure 17.3A).1 Paneth cells may be numerous in the ileum.

Figure 17.2 Low-power view of ileal mucosa. Villi and crypts are present, as in the duodenum. Compared to the duodenum, villi are shorter and more tortuous and often adopt a variety of angles in a microscopic section resulting in fewer full-length profiles. Goblet cells are more numerous and Brunner’s glands are never present.

(A) Goblet cells with a large mucin droplet and tall columnar absorptive cells with oval, basal nuclei are present in villi and crypts. As in the duodenum, there is a brush border at the surface consisting of microvilli and glycocalyx.

(B) Paneth cells have supranuclear brightly eosinophilic cytoplasm and may be numerous in the ileum.

(C) Endocrine cells. Compared to Paneth cells, endocrine cells (arrows) are typically smaller and have a suprabasal rather than basal nucleus, and their eosinophilic granules (if present) are less bright. Some endocrine cells have a transparent perinuclear halo or pale cytoplasm.

(D) Diagrammatic representation of small bowel villus and cell types.

Figure 17.3 Main ileal epithelial cell types.

Comparing the ileum to the duodenum, goblet cells are more numerous, Brunner’s glands are never seen, and lymphoid tissue is often more obvious and more prominent. Also, the villi are shorter and more tortuous resulting in a higher number of cross-cut villi and fewer full-length profiles in a biopsy (Figure 17.2).1 Brunner’s glands exclude ileal location, but the other features are not always very reliable as a means of discrimination between ileum and duodenum (Table 17.1).

Table 17.1 Differences between duodenal and ileal mucosa

Duodenum Ileum
Brunner’s glands

  • May be present in a biopsy

  • More likely proximally

  • Rare distal to D2

Never present
Goblet cells Less numerous than in ileum More numerous than in duodenum
Villous height Taller Shorter
Villus orientation Less tortuous More tortuous, resulting in more cross-cut profiles in a histological section
Crypt/villus ratio At least 3:1 At least 4:1
IEL number Range 2–25/100 epithelial cells Mean 3.8–13.9/100 epithelial cells
IEL composition Mostly CD8+ T cells Mostly T cells CD8+ CD4-
Lymphoid aggregates and lymphoid follicles May be present Not numerous Numerous and prominent, especially distally. May be confluent and may form Peyer’s patches, especially distally

IEL, intraepithelial lymphocyte.

Endocrine cells (Figures 9.23B and 17.3C) are similar to those in the duodenum and include S cells (producing secretin), K cells (GIP), I cells (CCK), L cells (PYY, GLP-1/GLP-2), and N cells (neurotensin) but no X/A like cells. Pan-GI tract endocrine cells are also present and include D cells (somatostatin) and EC cells (5-hydroxytryptamine [5-HT]). S, K, I, D, and EC cells are probably sparser in the ileum than in the duodenum. However, publications that document their presence and frequency at each location do not always give consistent information. In practice, histopathologists are rarely required to distinguish between these cell types.

Ileal Lamina Propria and Inflammatory Cells (Fact Sheet 17.1)

Lamina propria is located within villi and between crypts. It comprises a collagen and elastin meshwork and a mixture of glycosaminoglycans and noncollagenous proteins such as fibronectin, laminin, tenascin, and proteoglycans. There are a few vertical strands of smooth muscle in the lamina propria, both within the villi and around crypts. Other constituents of the lamina propria include fibroblasts, arterioles, venules, capillaries, lymphatics, and nerve fibres, together with a population of inflammatory cells comprising plasma cells, eosinophils and lymphocytes (Figures 17.3A and 17.4).1

Figure 17.4 The lamina propria includes various inflammatory cells and small blood vessels. Intraepithelial lymphocytes (IELs) (arrow) are sparse in the villi, especially superficially. IELs tend to be located in the basal part of the cell. Overall, IELs are less numerous in the ileum than in the duodenum.

The GI tract is ‘the largest lymphoid organ in the body’. The gut-associated lymphoid tissue (GALT) in the intestine helps to protect the body from microorganisms (see also Chapter 19).2 Lymphoid tissue is abundant in the small bowel and is both focal and diffuse. Focal forms include lymphoid aggregates, lymphoid follicles, and Peyer’s patches, while diffuse forms include T and B lymphocytes in the lamina propria and in the epithelium. According to some experts, mesenteric lymph nodes are also a component of the GALT. Gut-related mechanisms that enhance immunity include IgA production, lymphocyte responses to antigens, and enterocyte functions.

Ileal mucosal lymphoid aggregates and follicles have a wide range of sizes, are often confluent (forming Peyer’s patches), are more prominent in children than in adults, and may be continuous with submucosal lymphoid aggregates. They tend to be larger and more confluent in the distal than in the proximal ileum. The follicles are closely apposed to the overlying follicle-associated epithelium (FAE) (‘dome epithelium’) (Figure 17.5A and B). The germinal centres of follicles consist mainly of B lymphocytes and include a few tingible body macrophages. There is a parafollicular T-cell area with dendritic cells. There are macrophages in the superficial ‘dome’ area. The follicles have no capsule or afferent/efferent lymphatic vessels.2

(A) Lymphoid follicles are numerous in the ileum and may be large and confluent.

(B) The follicle-associated epithelium (FAE) overlying the follicle has fewer goblet cells and more intraepithelial lymphocytes than the epithelium in other areas.

(C) Large lymphoid aggregates and lymphoid follicles are acceptable and are not sufficient for a diagnosis of lymphoma.

(D) Intraepithelial lymphocytes (IELs) are more numerous in the crypts than in the villi.

Figure 17.5 Lymphoid tissue.

Lymphoid aggregates and follicles may be very dense, risking misinterpretation as chronic inflammation or lymphoma (Figure 17.5C). Dense or extensive lymphoid tissue, or even a focal collection of lymphocytes, may suggest lymphoma and should prompt a search for other evidence of neoplasia, e.g. lymphoid cell nuclear atypia, an excess of immature forms, and destructive lymphoepithelial lesions (a feature of marginal zone lymphoma) (see Chapter 19 for more detail). Immunohistochemistry is often helpful in making the distinction, e.g. kappa and lambda light chains and markers for specific types of lymphoma.

Intraepithelial lymphocytes (IELs) are more numerous in villous than crypt epithelium and their density is higher at the base of the villus than in the upper part of the villus (Figures 17.4 and 17.5D). They are typically less abundant in the ileum than in the duodenum and appear to diminish in number with age.3 Mean numbers in the ileum were 3.8 per 100 epithelial cells (range 0–9) in one report and 13.9 per 100 in another.3, 4 IELs are all, or nearly all, T lymphocytes. Most have a suppressor phenotype, i.e. CD8 positive and CD4 negative, although follicle-associated epithelium IELs are mainly CD4 positive (see later). IELs tend to occupy the basal or suprabasal part of the epithelial cell. They interact in several ways with the epithelium. Possible functions of IELs include modulation of epithelial cell proliferation; effects on immunoglobulin responses to antigens; cytokine release; reduction of epithelial barrier function, ion transport, and chloride secretion; and participation in cytolysis.1

IEL counts in the ileum are a less reliable marker for coeliac disease than IEL counts in the duodenum, but an increase may alert the pathologist and clinician to the possibility of the diagnosis. In one report, a threshold of 25 per 100 IELs in the terminal ileum yielded a sensitivity of 45% and a specificity of 97.8% for a diagnosis of coeliac disease.4

The lamina propria also contains more T lymphocytes than B lymphocytes. Unlike IELs, approximately two-thirds of the lamina propria T cells express CD4 (T helper phenotype) and one-third express CD8. Similarly, most CD4-positive lymphocytes are found in the lamina propria.3

Follicle-associated epithelium (FAE) covers lymphoid follicles or Peyer’s patches and has fewer goblet cells than the surrounding epithelium. FAE cells may contain clusters of lymphocytes1 although some of the lymphocytes may not actually lie within the epithelium but instead immediately adjacent to it, pushed towards it by the lymphoid follicle beneath (Figure 17.5AC). The marginal zone of the lymphoid follicle beneath the FAE includes CD4-positive T lymphocytes, plasma cells, and macrophages.1 Beneath the marginal zone is a thin mantle cell zone, overlying the follicle centre.1 FAE also contains scarce M cells that have no microvilli and differ from absorptive cells ultrastructurally but are not obviously different when examined by conventional microscopy.1 In inflamed mucosa, M cells increase in number and may comprise up to 24% of FAE cells. In chronic ileitis, they may undergo rupture and necrosis with breaks in the epithelium, allowing lymphocytes to reach the lumen and luminal contents to access lymphoid tissue. This process may form the basis for aphthoid ulcer formation.1

Innate lymphoid cells (ILCs) have a role within GALT. They reside at mucosal barriers where they respond to various microorganisms, influence other processes such as wound repair, and release cytokines in response to infection or cell damage. They lack the specific receptors of T and B lymphocytes, but their cytokine expression profiles are similar to those of T-helper cells.5, 6

Plasma cells are a constituent of normal small bowel mucosa. In contrast to the colonic mucosa, a plasma cell gradient is not a feature of ileal mucosa. Indeed, plasma cells are often present at the base of the normal small bowel lamina propria, particularly in the terminal ileum. Therefore, the concepts of loss of the plasma cell gradient and basal plasmacytosis are not valid in the ileum. In turn, statements about chronic inflammation at this site should be cautious, and may depend on a rather subjective assessment of chronic inflammatory cell density (see also Chapter 19). Plasma cells express mainly IgA.1

Mast cells are present in the lamina propria. They are usually pericryptal and less often intraepithelial, have IgE receptors, and express CD117 immunohistochemically. Documentation of their density in normal mucosa is not extensive. Clusters of mast cells are a clue to a mast cell disorder, but mast cell numbers and density are not reliable.7, 8

Macrophages are numerous but are difficult to see unless they contain pigment, mucin, or debris. Some reside immediately beneath the surface epithelium, where they may form aggregates and may contain nuclear debris and pigment.

There may be a few neutrophils in the lamina propria and very small numbers in the surface epithelium. Even if sparse, they should prompt a search for other evidence of inflammation.

Fact Sheet 17.1 Ileal Mucosal Inflammatory Cells

Gut-Associated Lymphoid Tissue

  • Extensive

  • Focal and diffuse forms of GALT occur

    • Focal: lymphoid aggregates and lymphoid follicles

    • Diffuse: IELs and lamina propria lymphocytes

Lymphoid Follicles

  • Components: outer marginal zone, adjacent mantle zone, follicle centre

  • Peyer’s patches comprise confluent lymphoid follicles

  • Avoid overdiagnosis of lymphoma

Intraepithelial Lymphocytes

  • Villi> crypts

  • Base of villi> upper parts of villi

  • Mostly T cells; mostly CD8+ CD4–

  • >25 per 100 villous epithelial cells may suggest coeliac disease, but duodenal biopsy more reliable than ileal

Lamina Propria Lymphocytes

  • T> B cells

  • T cells: 65% are CD4+ and 35% CD8+

Plasma Cells

  • Basal plasma cells are normal in the ileal mucosa

  • Basal plasmacytosis is not a reliable marker of chronic inflammation in the ileum

Follicle-Associated Epithelium

  • Covers lymphoid follicles

  • Has fewer goblet cells than other types of epithelium

  • Is unsuitable for assessment of IELs

Mast Cells

  • Normal number uncertain

  • Clusters may indicate a mast cell disorder


  • Lamina propria neutrophils

    • Usually absent

    • A few may be present, but should prompt a search for other evidence of inflammation

  • Intraepithelial neutrophils

    • Usually absent

    • May occur in small numbers, especially near lymphoid aggregates

Chronic ileal inflammatory conditions may show architectural changes including blunting, broadening and shortening of villi, branching and atrophy of crypts, and pyloric metaplasia (see Chapter 19).1 However, the small bowel mucosa does not show well-defined patterns of abnormal branching or crypt atrophy that are features of chronic idiopathic inflammatory bowel disease (IBD) or other chronic inflammatory states of the large bowel mucosa.

Ileal Submucosa

The muscularis mucosae is a longitudinal thin layer of smooth muscle cells that separates the mucosa from the submucosa. The ileal submucosa comprises loose connective tissue and may contain lymphoid aggregates/follicles and fat.1 A morphometric autopsy analysis of submucosal fat in the ileum and colon showed prominent deposition at the ileocaecal valve, variable amounts at other ileal and colonic locations, and no correlation between the types of fat deposition and body weight or BMI.9 Ganglion cells are present in the submucosa. They are also present, but are rare, in the mucosa (see Figure 23.5).

Colon and Rectum

Large Intestinal Mucosa: Epithelium

The large bowel mucosa is less complex than the gastric or small bowel mucosa. The main components are the surface epithelium, crypt epithelium, and lamina propria. Types of epithelium include columnar absorptive cells, goblet cells, Paneth cells, endocrine cells, and ‘tuft cells’. Their relative numbers vary according to the anatomical site.

Columnar absorptive cells are the main constituent of the surface epithelium. They are tall, with a nucleus at the base or close to the base of the cell, and they contain mucin that is not always readily apparent on examination of haematoxylin and eosin (H&E) slides (Figure 17.6A). Beneath the surface epithelium is a thin band of collagen, which ranges from 3 to 7 μm in thickness (Figure 17.6B). Sometimes the surface epithelial cell nuclei lie significantly above the base of the cell, resulting in a subnuclear ‘band’ of cytoplasm that could be mistaken for a thickened subepithelial collagen band (Figure 17.6C).

Sep 2, 2020 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 17 – Normal Lower Gastrointestinal Mucosa
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