The Nonneoplastic Small Intestine

The Nonneoplastic Small Intestine

Jonathan N. Glickman


There are two major steps in gastrointestinal (GI) development: the formation of the gut tube and the formation of individual organs each with its own specialized cell types (1). The endoderm is the precursor to the gastrointestinal epithelial lining, and endodermal development requires multiple factors such as GATA transcription factors and WNT signaling (2,3). Multiple interactions occur between the endoderm, mesoderm, and ectoderm during development, involving a variety of signaling cascades including the Hedgehog, Hh, Bmp, FGF, and Wnt pathways (4,5,6,7). The endoderm induces the mesoderm, conferring on it a dorsal -ventral pattern. Endoderm and ectoderm contact one another in the 2- to 4-week embryo, with the endoderm forming the yolk sac roof. A primitive gut forms in the 3rd to 8th weeks secondary to cephalocaudal and lateral foldings that incorporate the dorsal endodermally lined yolk sac cavity. The amnion and yolk sac communicate through the neuroenteric canal (Fig. 6.1). The neuroenteric canal closes and the notochord grows forward, becoming intercalated within the endoderm. The neural tube then separates from the ectoderm. Mesoderm surrounds the notochord, separating the ectoderm and endoderm (8). Splanchnic mesoderm surrounding the primitive gut forms the muscular and connective tissue layers. The former yolk sac elongates under the developing nervous system to form the primitive foregut anteriorly and the primitive hindgut posteriorly. The central portion develops into the midgut, which has a free communication with the yolk sac (the vitellointestinal duct). The anterior abdominal wall develops by simultaneous cranial, caudal, and lateral infoldings, which attenuate the yolk sac, causing it to become intracoelomic in location (Fig. 6.1). The foregut is short at first, lying closely apposed to the developing vertebrae, and it becomes suspended by a short mesentery. The foregut gives rise to the esophagus, stomach, duodenum as far as the ampulla of Vater, liver, pancreas, and respiratory system, and it has its own arterial blood supply deriving from the celiac axis (9).

The duodenum distal to the bile duct, and the jejunum, ileum, cecum, ascending colon, and proximal one half to two thirds of the transverse colon derive from the midgut and are supplied by the superior mesenteric artery. At about the 5- to 12-mm stage, the midgut lengthens, becoming tubular and growing away from the vertebral axis. It then coils, inducing dorsal mesenteric development. During the 5th fetal week, the midgut is “U” shaped and suspended by a dorsal mesentery distributed around the superior mesenteric artery. The apex of the intestinal loop communicates with the vitelline duct, which rapidly decreases in size. During the 5th to 6th fetal weeks, increases in intestinal length, along with the disproportionate amount of abdominal space occupied by the fetal liver, cause the intestines to herniate into a mesotheliallined sac within the umbilical cord (9). The cecum develops on the caudal limb and the vitellointestinal duct lies at the apex. A small portion of the caudal limb, between the attachment of the vitellointestinal duct and cecum, forms the terminal ileum. The midgut starts sliding back into the abdomen between the 10th and 12th fetal weeks, a process accomplished in three phases (Fig. 6.2). The first is a 90-degree counterclockwise rotation around the superior mesenteric artery. The second occurs at about the 10th week, when there is enough room for the bowel to return to the abdominal cavity. The cranial loop of the small bowel reenters the abdomen, first passing to the right of the superior mesenteric artery and rotating a further 180 degrees, thereby making the total rotation 270 degrees. Small intestinal loops fill the central abdomen.

Although an anatomically distinguishable intestinal tract develops early in embryonic life, functional absorptive cells do not appear until later in gestation. Intestinal differentiation occurs along a proximal-to-distal gradient.
The epithelium develops from simple endodermal tubules early in embryogenesis (1) appearing as a multilayered sheet of undifferentiated endodermal cells with short microvilli. Deeper cells do not demonstrate any polarity; mitoses occur throughout the epithelium. Villous formation with mesenchymal infiltration into the villous core begins at the ninth gestational week. Between 9 and 10 weeks, the stratified epithelium converts to a simple columnar epithelium (1). The progenitor cell region, which gives rise to the crypts, localizes to the intervillous
area (10). Villi are long and tapering by 20 weeks, and the muscle coats are obvious at this time. Enterocyte proliferation occurs along the entire villous length until several days before birth.

FIG. 6.1 Diagram of early embryogenesis. A-E show the progressive formation of the gut.

FIG. 6.2 A: Intestinal rotations. Schematic drawing of the primitive intestinal loop after a 180-degree counterclockwise rotation. The transverse colon passes in front of the duodenum. B: Intestinal loop after a 270-degree counterclockwise rotation. Note the coiling of the intestinal loops. C: Intestinal loops in final position and their associated mesenteries.

FIG. 6.3 Lamina propria of a newborn. The hypocellular lamina propria contains few lymphocytes and plasma cells.

Enterocyte differentiation depends on the cell position along both the vertical (crypt-villus) axis as well as the location along the horizontal (proximal to distal) axis of the GI tract. Functional differences along both the vertical and the horizontal axes (11) reflect both different patterns of gene expression and the presence of multiple epithelial cell types. The basis for regional differences in gene expression results from differences in the transcription factors that interact with the promoter and enhancer region of these genes. Homeobox genes participate in establishing differentiation gradients during development and then maintaining these patterns in adult tissues. The epithelium finishes its morphologic differentiation into enterocytes, goblet cells, endocrine cells, and Paneth cells in the 4 to 5 days prior to birth. Expression of genes characteristic of terminally differentiated cell processes relies on transcription factors such as Math1 and Cdx2 (12,13,14).

Primordial intestinal lymphoid structures appear approximately halfway through gestation. At the time of birth, Peyer patches have the greatest density of any proliferating lymphoid tissue in the body although the lamina propria contains relatively few lymphocytes and plasma cells at this stage (Fig 6.3). T- and B-cell aggregates form early Peyer patches by 16 weeks’ gestation, and by 19 weeks, organized Peyer patches are present. T cells populate the lamina propria and epithelium from 11 weeks’ gestation and increase in number thereafter. Following birth, there is a marked increase in the number of Peyer patches, reflecting the initial response of the host immune system to environmental antigens passing through the intestinal tract.


The intestinal mucosa is in continuous contact with food antigens, the enteric commensal bacteria that constitute the normal gut flora, and potential pathogens that enter the host through the intestine. The upper intestinal bacterial count is normally low, and it increases as one progresses distally. Bacterial numbers are kept low by intestinal motility, mucus, and the antibacterial effects of pancreatic and biliary juice and gastric acid (Fig. 6.4). This resident microflora maintains a stable environment and eliminates pathogenic organisms by producing antimicrobial substances and short-chain fatty acids and other metabolites. It also stimulates mucosal epithelial growth by providing absorbable nutrients (15,16).

The small intestinal mucosa forms a barrier to the unimpeded movement of antigens, microorganisms, and potentially injurious substances from the lumen to the internal environment. A single layer of columnar epithelium, held together by tight junctions, lies on an intact basement membrane. Intercellular tight junctions, which are impermeable to large molecules and bacteria, help maintain epithelial integrity and prevent the entry of foreign material. The tight junctions are specialized membrane domains at the apical pole of the cells that not only create a primary barrier to prevent paracellular transport of solutes (barrier function) but also restrict the lateral diffusion of membrane lipids and proteins to maintain cellular polarity (gate function) (17). The tight junction complexes form a complete ring around
the apical pole of the cells. Tight junction permeability is plastic and can be altered by extracellular stimuli such as inflammatory mediators, drugs, and microorganisms (18). In addition, an unstirred water layer, varying from 25 to 170 &mgr;m in thickness, covers the epithelium and may regulate diffusion of other molecules (19).

FIG. 6.4 Mucosal barrier. The mucosal barrier consists of several nonspecific defenses, including the epithelium, which forms an intact single cell layer. It lies above an intact basement membrane (arrow) and tight junctions seal the upper intercellular spaces. The microvilli are covered by a glycocalyx. Overlying this is a mucous layer followed by the unstirred water layer. The epithelium pumps bicarbonate, water, hydrogen ions, and mucus, as well as secretory immunoglobulin into the unstirred layer above it. These substances interact with bacteria, toxins, or antigens in the lumen. Underlying the epithelium is the lamina propria, which contains abundant immune cells.

The proximal duodenal mucosa transports bicarbonate into an adherent mucus layer in a manner similar to that seen in the stomach, providing a protective barrier from damage caused by pepsin and acid (20). The alkaline pH environment beneath the mucin layer acts as a buffer and a lubricant. The mucus protects against microbial adherence to the epithelium and resists digestion by intraluminal enzymes. Mucus secretion is stimulated by immune complexes, chemical agents, soluble mediators, histamine, lymphokines, and neurotransmitters (21). Nitric oxide plays an important role in modulating duodenal fluid and bicarbonate secretion (22). The secreted mucus contains albumin; immunoglobulin, particularly secretory IgA; &agr;1-antitrypsin; lysozyme; lactoferrin; and EGF. Secretory IgA in the intestinal lumen acts in concert with nonspecific host defenses, including mucin, bacteriocidins, defensins, and lytic cells (23), to protect the host by neutralizing or excluding antigens, toxins, and organisms and regulating commensal bacteria (24). Granulocytes, macrophages, and Paneth cells act as intramucosal phagocytes.


The human small intestine, which extends from the gastric pylorus to the ileocecal valve, measures about 7 m in length. The C-shaped duodenum encloses the head of the pancreas in its concavity. It measures approximately 20 to 25 cm in length and, except for its first part, lies in the retroperitoneum. The first part of the duodenum measures approximately 5 cm in length, and it ascends posteriorly from the pylorus to the right. It lies above and anterior to the head of the pancreas, below the gallbladder, and anterior to the common bile duct, gastroduodenal artery, and portal vein. The second portion measures approximately 7 cm in length and is covered by the peritoneum of the infracolic compartment of the peritoneal cavity, which separates it from coils of the small bowel. The transverse colon and its mesentery cross it. The hilum of the right kidney and right renal vessels lie behind it, and the bodies of the lumbar vertebrae and inferior vena cava lie medially.

The common bile duct and pancreatic duct enter the second part of the duodenum posteromedially at the ampulla of Vater approximately 9 to 10 cm from the pyloric ring (Fig. 6.5). In most patients, the common bile duct and pancreatic duct join before draining into the ampulla (Fig. 6.6), but in about 10% of cases, the bile duct and pancreatic duct open separately into the intestinal lumen. In about 30% of patients, an accessory, more proximal pancreatic duct drains into the duodenal lumen. Both the bile duct and the pancreatic duct have their own muscular coats. A cross section through this area of the duodenum contains numerous ramifying ducts in all layers of the duodenal wall (Fig. 6.7). The sphincter of Oddi at the ampulla of Vater measures approximately 9.5 mm in length (25).

FIG. 6.5 Normal ampulla of Vater. Opened duodenum with gallbladder posteriorly. The common bile duct is shown by adjacent green and blue probes at ampulla of Vater. The solitary blue probe is an accessory duct of Wirsung.

The third part of the duodenum arches transversely across the vena cava and aorta at the level of the body of the third lumbar vertebra. It is 7 to 9 cm in length. The root of the mesentery obliquely crosses its terminal portion. It is also crossed by the superior mesenteric artery and vein. Superiorly, it relates to the pancreatic uncinate process. The fourth part of the duodenum varies in length and is difficult to distinguish from the third part. It curves up to the left to the duodenojejunal flexure, where it is attached by a suspensory duodenal ligament, the ligament of Treitz.

Although the duodenum has a fairly constant length, the length of the rest of the small intestine is not as clearly established. Measurements taken at autopsy suggest adult lengths between 300 and 900 cm with a mean of approximately 600 cm. Other measurements taken during life give
a much shorter length of 280 cm. The mesentery supporting the small intestine fans out from an origin only 15 to 20 cm long. The mesentery runs along an oblique line crossing the posterior abdominal wall from the left to right, from the duodenojejunal flexure to the right iliac fossa.

FIG. 6.6 Ampulla of Vater. The pancreatic and bile ducts enter separately and have been opened, showing their entrance into the duodenum.

FIG. 6.7 Ramifying ducts in the submucosa are surrounded by a muscular coat. The architecture in this area can normally be very complex.

There is no recognizable line of division between the three parts of the small intestine: duodenum, jejunum, and ileum. Traditionally, the jejunum represents the proximal 40 cm after the ligament of Treitz and the ileum the distal 60 cm of the small intestine. The lumen of the jejunum is wider than that of the ileum, and its wall is thicker due to prominent circular mucosal folds, known as folds of Kerckring (Fig. 6.8). These folds run parallel to the longitudinal axis of the bowel, are most prominent between the mid duodenum and jejunum, and are absent in the distal ileum. They contain both the mucosa and the underlying submucosa.

FIG. 6.8 Normal small intestine. A: The surface of the small intestine is covered by numerous regular folds (plicae circulares) with a submucosal core. B: Convolutions of mucosa and submucosa are the histologic equivalent of the folds of Kerckring.


The duodenum is supplied by the celiac and superior mesenteric arteries (Fig. 6.9). The celiac trunk branches into the gastroduodenal artery. The superior mesenteric artery supplies the jejunum, cecum, and appendix, traveling through the mesentery in several major branches (Fig. 6.10). Ten to fifteen jejunoileal arteries arise from the left side of the superior mesenteric artery, which originates 1 to 2 cm below the celiac artery. Each divides into two branches, which join adjacent branches to form a series of arcades. These in turn branch and form a second series of arcades before the vasa recta penetrate the intestinal wall (26). The ileocolic artery, which arises from the lower superior mesenteric artery, supplies the terminal ileum, cecum, appendix, and proximal ascending colon. It anastomoses with the right colic artery. This and subsequent branches form complex arcades.

Intramural arteries enter the intestinal serosa and pierce the muscularis propria to form an extensive submucosal vascular plexus (Fig. 6.11). The submucosal arterial plexus gives rise to arterioles, which supply the mucosa, submucosa, and muscular layers. However, the mucosal capillary bed is isolated from that of the muscularis propria. The capillary bed in the muscularis mucosae has two layers (27). These two groups of arteries make their way into the mucosa. Some ramify on the luminal side of the muscularis mucosae and give rise to a capillary network that surrounds the crypts. Others continue into the villus, entering it at its base before arborizing into a dense capillary network. A rich network of blood capillaries ramifies through the lamina propria and is closely apposed to the epithelial basement membranes (Figs. 6.12 and 6.13). Villi are more highly vascularized than are the crypts (28). The mucosa receives approximately 75% of the intestinal blood flow. The bowel can autoregulate its blood flow, which means that it maintains a constant blood flow in the face of fluctuating arterial pressures. Following

eating, small intestinal blood flow increases by over 100%, with the majority of the blood flow being diverted to the mucosa.

FIG. 6.9 Diagram of duodenal arterial supply.

FIG. 6.10 Distribution of superior mesenteric artery.

FIG. 6.11 Diagram of the submucosal vascular plexus.

FIG. 6.12 Diagram of distribution of arteries (red), veins (blue), lymphatics (yellow), and nerves (green) in the small intestine.

FIG. 6.13 Dilated capillaries in a small intestinal villus showing the prominent capillary structure.

Villous capillaries drain into a single venule that starts high in the villus. One or two veins form in each villus. These course downward, eventually joining veins at the crypt bases and merging with veins draining into the submucosal plexus. These vessels continue on through the muscularis propria and serosa, merging with other veins draining into the portal vein via the superior mesenteric vein. The superior mesenteric vein receives its drainage from the distal duodenum, jejunum, ileum, appendix, and cecum, as well as the ascending and transverse colon. Venous drainage of the duodenum parallels its arterial supply. Inferior pancreaticoduodenal veins drain to the right gastroepiploic vein. The major veins draining the GI tract form the portal system (Fig. 6.14). The portal vein forms by the junction of the splenic vein and the superior mesenteric vein. The portal vein receives direct input from the right and left gastric veins, superior pancreaticoduodenal vein, accessory pancreatic vein, and pyloric vein. Blood in the portal vein is carried to the liver, where nutrients are absorbed and processed.

FIG. 6.14 Diagram of the portal system.


Lymphatic drainage starts with the central lacteal, which drains into the submucosal lymphatic plexus (Figs. 6.12 and 6.15). The broad proximal villi contain two to five lacteals, whereas more distal thin villi contain only one. Lacteals measure 5 to 15 &mgr;m in diameter and run parallel to one another in the longitudinal direction of the villus. The endothelial lining contains gaps and has overlapping areas with adjacent endothelial cells through which chylomicron particles containing newly absorbed lipids can pass (29). The wall of the lacteal consists of endothelium and a reticulin fiber sheath to which smooth muscle fibers attach (Fig. 6.15) (30). Villi intermittently contract and shorten due to the activity of the smooth muscle cells. These contractions force lymph from the central lacteal into the basal lymphatics. The central lacteal is also completely surrounded by the subepithelial blood capillary network (Fig. 6.15). Lacteals anastomose with each other, which forms an expanded sinus. In the fasted state, lacteals are difficult to see.

FIG. 6.15 Dilated empty vascular space represents the central lacteal of this villus.

There are many blind-ending lymphatics in the upper part of the interfollicular area. These gradually fuse and form perifollicular lymphatic sinuses surrounding the lateral surfaces and bottoms of Peyer patch follicles. Between the perifollicular lymphatic networks and the interfollicular area are many high endothelial venules (HEVs) that connect to capillaries in the dome and follicle. The close association of HEVs with perifollicular lymphatics facilitates prompt drainage of fluid and keeps macromolecules from leaking out of HEVs during lymphocyte migration into the lymphatics. At the villous base, lymphatics empty into thicker lymphatics that then connect to form a flat, wide sinus (the intravillous lymphatic sinus). From the base of each sinus, several lymphatics descend perpendicularly to drain into submucosal lymphatics that run transversely beneath the muscularis mucosae to form a two-layer meshwork. The submucosal lymphatic plexus drains into large subserosal lymphatics (31) that drain into large conducting mesenteric lymphatics eventually flowing into the cisterna chyli.

Draining lymph nodes consist of the pancreaticolienal group lying along the splenic artery, the pyloric group lying along the gastroduodenal artery, and the superior mesenteric nodes. Small pancreaticoduodenal nodes lie scattered along the artery of the same name. The lymphatics also drain into the small pyloric nodes superiorly and preaortic lumbar nodes inferiorly. Pyloric nodes drain to the hepatic nodes along the common hepatic artery. Others drain to the root of the superior mesenteric lymph nodes, following the distribution of the superior mesenteric artery and draining the areas supplied by it. Small mesenteric lymph nodes lie along the vasa recta of the mesentery, adjacent to the bowel wall, and larger ones lie along the primary arcades and the intestinal arteries. There are about 200 mesenteric lymph nodes. Two major groups of ileocolic lymph nodes drain the terminal ileum and cecum: one near the bowel wall and another at the origin of the ileocolic artery.


The innervation of the small bowel resembles that of the large intestine described in Chapter 13. The intrinsic innervation is discussed in Chapter 10.


General Structure

Small intestinal epithelium is organized into two morphologic and functionally distinct compartments: The crypts of Lieberkühn and the villi. Villi that are unique to the adult small intestine are fingerlike or leaflike mucosal evaginations lined by epithelium overlying a connective tissue core that contains a highly cellular lamina propria, a capillary network, lacteals, and nerves. Simple tubular invaginations (crypts of Lieberkühn) at the base of the villi extend down toward the muscularis mucosae but do not penetrate it (Figs. 6.16 and 6.17). Several crypts open into the intervillous basin.

Villi vary in height and form in different regions of the small bowel. The duodenum has the greatest villous variability. Villi in the proximal duodenum are shorter and broader than elsewhere, not infrequently showing increased numbers of stunted and leaf-shaped or branched forms when compared to the jejunum. Jejunal villi vary little in their width from their base to their apex. In the ileum, the villi become broader and shorter than in the jejunum (Fig. 6.17).

The ratio of villous height to crypt length, a feature best appreciated in well-oriented sections, allows one to assess small intestinal absorptive function. In adults, villous height is approximately three or more times the length of the crypts, whereas in children, this ratio is lower, more typically being 2:1. The duodenal crypt-villus ratio is 3:1 to 7:1, whereas the ileal crypt-villus ratio is 4:1. Villi overlying lymphoid areas are often stubby or absent. Tangentially sectioned villi are a common source of misinterpretation of this ratio since they appear broadened and shortened. Each villus contains an arteriole with capillary network veins and a central lymphatic as well as numerous nerve fibers (Fig. 6.18).

FIG. 6.16 Ileal mucosa. A: Crypts and villi. The crypts contain numerous goblet cells, allowing one to identify this area as ileal. B: Higher magnification of the crypts shows prominent Paneth cell differentiation.

Each crypt consists of a single clone of cells; several crypts contribute cells to each villus. The epithelial lining harbors a heterogeneous cell population, including Paneth cells, crypt stem cells, endocrine cells, cup cells, tuft cells, goblet cells, absorptive cells (enterocytes), and M cells. Each cell type possesses distinctive structural features and functions (see below). The epithelium maintains a close association with the underlying stroma.

Cell Proliferation and Differentiation

Maintaining the integrity of the gut epithelium as well as ensuring its continuous turnover is essential for mucosal defense. As a result, the gut has one of the most rapid proliferative rates in the body. When the mucosa is damaged, replacement of the injured cells guarantees mucosal integrity. New epithelial cells arise from a fixed proliferating stem cell population located in the lower part of the crypt (Fig. 6.19) (32). These pluripotential stem cells give rise to descendants that undergo three or four divisions while migrating up the villus or to the top of the lymphoid dome.

FIG. 6.17 A comparison of proximal ileal (A) versus jejunal (B) villi. The more distal villi are more irregular in shape than those of the proximal region.

FIG. 6.18 Diagrammatic summary of the structures found in the villus.

FIG. 6.19 Mucosal renewal. The mucosa continuously generates new epithelial cells from a population of anchored stem cells. These give rise to all of the epithelial cell types lining the crypts and villi. Most of the cells migrate upward, undergoing progressive differentiation into enterocytes, goblet cells, and endocrine cells, as well as a minor population of other cells. At the surface, the mature and effete cells either undergo extrusion into the lumen via shedding from the basement membrane or undergo apoptosis and apoptotic bodies are passed into the underlying lamina propria, where macrophages ingest them. In contrast to the upward migration, some cells migrate downward, differentiating into Paneth cells and endocrine cells.

The duration of cellular proliferation and migration is approximately 5 to 6 days in most of the human small intestine and 3 days in the ileum. Cells at the villous tip undergo Fas-mediated apoptosis (33) and slough off and are extruded into the lumen; sloughing cells can also be seen on the edges of the villi (34). Apoptotic cell death occurs without any apparent disruption of the mucosal barrier integrity (35).

Stem cells give rise to four major epithelial cell types: absorptive cells (enterocytes), goblet cells, endocrine cells, and Paneth cells (1). The production and maturation of these cells is under the control of homeobox genes including Cdx1 and Cdx2 (12,13) and the Wnt signaling pathway (4). The Notch signaling pathway, through factors such as Hes 1 and Math1, is another key regulator of intestinal cell maturation (36).

Cell migration occurs in a linear fashion, with cells moving directly vertically upward or downward from their site of genesis in the crypt bases and acquiring expression of markers of terminal differentiation. Genes that are up-regulated in the crypt and down-regulated at the villous tip include those related to the cell cycle, RNA processing, and protein translation. In contrast, genes related to cytoskeletal assembly, lipid uptake, and enzyme biosynthesis show the opposite pattern (37).

Enterocytes (Absorptive Cells)

Enterocytes are highly polarized cells with two structurally and functionally distinct plasma membrane domains: The apical microvillous membrane and the basolateral membrane (38). The apical domain includes the brush border and extends to the tight junction that forms a band around the membrane, creating a relatively impermeable joint between adjacent epithelial cells. The remainder of the cell membrane constitutes the basolateral domain. The basolateral membranes contain abundant Na+, K+-ATPase, and adenylate cyclase and are the site of the receptor for dimeric IgA attachment before its transport to the apical membrane. It is also the transfer site for chylomicrons and other foodstuffs from the enterocyte into the intercellular space and the lamina propria (Fig. 6.20). This activity is restricted from the apical surface by tight junctions that maintain these differences and prevent lateral movement of membrane components.

Enterocytes continuously synthesize new components of the cell membrane and surface coat and transport them to the microvillous surface. Microvilli exhibit bidirectional cell trafficking with various metabolites being absorbed and transported inward while the hydrolytic enzymes are synthesized in the endoplasmic reticulum, glycosylated in the Golgi, and transported to the brush border for insertion into the brush border membranes (Fig. 6.20). Some intestinal diseases result from impaired membrane protein trafficking including microvillous inclusion disease (MID), congenital sucrase-isomaltase deficiency, and adult lactase deficiency disease.

FIG. 6.20 Enterocytes are highly polarized cells with distinct apical, lateral, basolateral, and basal portions, each of which serves special roles.

The mature brush border, which covers the cell apex, consists of closely packed microvilli and the terminal web (Fig. 6.21). Microvilli vary in length, increasing in height as the cells migrate up the crypt-villus axis. Mature microvilli measure approximately 1.5 to 2 &mgr;m in length and 100 nm in diameter. These structures are periodic acid-Schiff (PAS) positive (Fig. 6.22). Each microvillus contains a core bundle of approximately 20 vertically oriented, polarized actin filaments extending from the tip of the microvillus to the base
of the terminal web (Fig. 6.23). These are cross-linked by the actin-bundling proteins fimbrin and villin. The other major actin-binding protein of the microvillous core is myosin 1 (39). Myosin 1, coupled with ezrin and other proteins, forms a double spiral of bridges cross-linking the actin bundles to the plasma membrane (40). The microvilli house a wide array of brush border enzymes that play critical roles in the digestion and absorption of proteins, fats, and carbohydrates. A complex anastomosing meshwork of filaments called the terminal web surrounds the microvillous rootlets. It consists of a network of actin filaments cross-linked with myosin 2, nonerythroid spectrins, &agr;-actinin, and tropomyosin (39). The filamentous network links with the junctional complex at the edge of the cell.

FIG. 6.21 Enterocytes. This photograph is from a thick section showing mature enterocytes and goblet cells at the free surface. The enterocytes are covered by a prominent purple fringe, which corresponds to the brush border.

FIG. 6.22 Normal jejunum. The brush border is highlighted by a periodic acid-Schiff stain.

FIG. 6.23 Normal small intestine. Striated border of absorptive cells is made of large numbers of closely packed parallel microvilli.

The intercellular space is a dynamic area, and the permeability of the intercellular junctional space to water and solutes is regulated (40). The junctional complex, a series of intercellular junctions, is present at the apical end of the intercellular space. The most basal member of this complex is usually the desmosome, a macular structure resembling a spot weld or adhesion point between adjacent epithelial cells (41). The zonula adherens (ZA), or intermediate junction, is a more apically located circumferential adhesive structure. Filaments from the ZA extend into the terminal web to form part of the cytoskeleton. The tight junction or zonula occludens lies at the most apical aspect of the lateral cell surface, and it surrounds each epithelial cell, forming a gasketlike seal that restricts the movement of substances through the paracellular pathway by forming semipermeable barriers (41). Signaling via interactions of the cytoskeleton with the tight junctions may regulate paracellular permeability of solutes and water (40). Diverse microfilament-associated proteins contribute to the cellular morphology, motility, and other cellular specialized functions.

Goblet Cells

Goblet cells play an important role in mucosal protection. They secrete mucus, ions, and water into the overlying mucous gel that protects epithelial cell surfaces and regulates access to antigens and organisms to the mucosal immune system (21). Goblet cells also produce trefoil peptides, which are important in preventing intestinal injury and promoting wound healing (42). Goblet cells are found in the crypts (Fig. 6.24) and among the surface absorptive cells, but they progressively decrease in number as one progresses toward the villous tip (Fig. 6.25). At the tip of the villus, the ratio of enterocytes to goblet cells is about 8:1. Goblet cells increase in frequency along the length of the small intestine, being most numerous in the lower ileum. Goblet cells are primarily columnar in shape and mucus droplets accumulate in the supranuclear cytoplasm, distending the cell and displacing the nucleus to a basal position. This area also contains the Golgi apparatus at its center and rough endoplasmic reticulum at its periphery. When the vacuole opens into the intestinal lumen, mucus pours out (Fig. 6.26). The microvilli resemble those on enterocytes, although they are fewer in number. The terminal web of goblet cells is poorly developed, facilitating mucus release from the apical cytoplasm.

Follicle-Associated Epithelium

Follicle-associated epithelium (FAE), a one-cell-thick layer, forms the interface between intestinal lymphoid aggregates and the intestinal luminal environment (Figs. 6.27 and 6.28). This area has fewer goblet cells, no endocrine cells, and abundant intraepithelial lymphocytes (IELs) when compared with the epithelium of the crypts and the villi (43).
FAE has a different differentiation program than cells along the crypt-villus axis. The epithelium of the FAE originates from crypts and differentiates into FAE enterocytes and M cells as they move toward the apex of the dome of the lymphoid follicle (44).

FIG. 6.24 Pericryptal fibroblasts are flattened fusiform cells closely apposed to the crypt basement membrane (arrowheads). Notice the Paneth cells in the crypt base identified by their eosinophilic apical granules.

FIG. 6.25 Decreased numbers of goblet cells are present at the luminal surface.

FIG. 6.26 Thick section of the superficial mucosa with several prominent goblet cells, two of which are extruding mucus into the overlying lumen.

M (microfold) cells are a unique epithelial subtype that only exists in the FAE, where they are seen at the periphery of the dome at sites where the epithelial cells exit the crypts (44). Intestinal M cells derive their name from the luminal microfolds or membranous projections formed by lymphocytes invaginating their basolateral surfaces (Fig. 6.27). Other key structural features include a lack of
microvilli; invaginations of the basolateral membrane; a thin apical cytoplasmic rim, which is the only epithelial barrier between the intestinal lumen and the immunocompetent cells; and numerous endocytic vesicles that are especially abundant in the apical cytoplasmic rim. These features allow the approach of microorganisms and other intestinal luminal particles that are normally kept at bay by the closely packed microvilli and thick glycocalyx of enterocytes. Additionally, M-cell apical membranes contain abundant glycoconjugates that serve as binding sites for cationic molecules and possibly for lectinlike microbial surface interactions.

FIG. 6.27 Electron micrograph of an M cell (MC) flanked on the left by an absorptive cell (AC). M cells characteristically have microvilli that are shorter and wider (arrowhead) than those of neighboring absorptive cells. Lymphoid cells (L) are often found within the central hollow of M cells. (Courtesy of Dr. James L. Madara, University of Chicago, Chicago, IL. Reprinted with permission from the author.)

FIG. 6.28 Paneth cells. Cross sections of several crypts demonstrating the presence of Paneth cells with their prominent supranuclear granules.

M cells facilitate uptake and transport a wide variety of macromolecules and microorganisms (45). The endocytosed material is delivered into apical endosomal tubules and vesicles (46), which then deliver the particles to lymphoid cells nestled in invaginations in their basolateral membranes (47). Antigens transported by the M cells first interact with antigen-presenting cells and lymphocytes in the intraepithelial pocket (48). This transepithelial transport delivers immunogens directly to organized mucosal lymphoid tissues, the inductive sites for mucosal immune responses. Thus, M cells form a crucial component of the afferent limb of the intestinal immune system, but they also provide a site through which potential pathogens and other noxious substances can breach the epithelial barrier (49). M cells may also rupture, releasing lymphocytes into the GI lumen. The bursting of the M cells or detachment of enterocytes at the top of the lymphoid follicles may contribute to the formation of aphthous ulcers (50).

Paneth Cells

Paneth cells populate the crypt bases, and their number differs along a cranial-caudal gradient, with a greater number of Paneth cells seen caudally. Paneth cells constitute approximately 1% of small intestinal cells, and they arise from a common stem cell in the crypt base (51). These strongly eosinophilic, pyramidal cells have the cytologic characteristics of zymogenic or secretory cells (Fig. 6.28). Irregular microvilli cover their apical ends. The supranuclear Golgi complex contains large, apical, membrane-bound, eosinophilic, refractile granules. The red staining quality of Paneth cells depends on the fixative used. If an acidic fixative such as Bouin’s is used, the cells may appear less eosinophilic. Paneth cells release granules into the crypt lumen where they participate in mucosal immunity. The granules contain various proteins involved in host defenses including lysozyme, secretory phospholipase A2, and &agr;-defensins, also known as cryptidins (52).

Endocrine Cells

At least 16 different subpopulations of endocrine cells are present in the small intestines. This cell population is discussed in Chapter 17, along with the proliferative lesions that arise from them.

Intestinal Crypt and Stem Cells

The crypt contains a population of rapidly dividing progenitor cells, which will migrate into the villi and terminally differentiate into the various cell types. They have basally located nuclei and short microvilli that are less numerous than are those seen on absorptive cells. The terminal web and glycocalyx are not well developed. Secretory granules may be present in the apical cytoplasm. The intestinal stem cells, which by definition are multipotent and self-renewing, are compact columnar cells that give rise to rapidly dividing progenitor cells. They express unique markers such as Lgr5 and comprise two populations: (a) at the crypt bases between the Paneth cells (crypt base cells), which are thought to supply epithelial progenitors during normal homeostasis, and (b) slowly dividing cells at the fourth cellular position above the crypt base (so-called +4 reserve cells), which replenish the crypt base stem cells during conditions of epithelial injury (32).

Pericryptal Myofibroblasts

Intestinal subepithelial myofibroblasts are present immediately subjacent to the basement membrane and close to the basal surface of the epithelium in the intestinal crypts and villi (53) (Fig. 6.24). These cells express smooth muscle actin and appear to be related to perivascular cells. Their origin is somewhat controversial, with various studies providing evidence for differentiation from fibroblasts, from neural crest cells, from serosal mesothelium, and from bone
marrow precursors in the adult (54). Myofibroblasts play a crucial role in the differentiation of crypt and villous epithelium by elaborating the basal lamina and secreting Wnt, hedgehog, and bone morphogenetic protein (Bmp) family members, which act on the epithelium (54). They also play a key role in both initiating and suppressing mucosal inflammation via the secretion of proinflammatory cytokines, chemokines, and growth factors and arachidonic acid metabolites (55,56).

Lymphoid Tissues

The intestines have evolved protective mechanisms in which the lamina propria reacts to microbes and other foreign material by mounting an immunologic barrier. This immunologic barrier includes the gut-associated lymphoid tissues and the systemic immune system. In fact, the intestinal mucosa contains more lymphoid cells and produces more antibodies than does any other site in the body.

Immunologic responses specific to the intestine include IgA production and lymphocyte sensitization in Peyer patches or in the epithelium (57). Enterocytes can present antigen, express secretory component, and transport immunoglobulin into the intestinal lumen. Enterocytes also can produce and secrete interleukinlike substances that activate T cells in response to luminal antigens (58). Secretory IgA binds to toxins and modulates the intestinal microbiota by coating bacteria and inhibiting mucosal attachment interaction. IgA also mediates antibody-dependent, cell-mediated cytotoxicity resulting in pathogen killing and also activates complement, mainly via the alternate pathway (59).

The gut-associated lymphoid tissues are thought to function as secondary lymphoid organs (60), although recent evidence suggests that the small intestinal epithelium is a site of primary extrathymic T-cell differentiation (61). The organized gut-associated lymphoid tissue in the small intestines primarily consists of Peyer patches (PPs) and the mesenteric lymph nodes (60). Other forms of lymphoid aggregations include isolated lymphoid follicles (ILFs), which lie within the mucosa, and submucosal lymphoid aggregations (SLAs), which lie within the muscularis mucosae and represent submucosal extensions from an overlying ILF. Both ILFs and SLAs represent normal components of the small intestinal mucosa and have been shown to participate in intestinal IgA production. The numbers of all of these lymphoid structures increases in the distal small intestine (61). The typical ILF resembles the follicular units that comprise PPs. These lymphoid aggregates and Peyer patches differ from lymph nodes because they lack a capsule, do not have a medulla, and do not have afferent lymphatics or a capsule. The most recently described lymphoid structures are the lymphocyte-filled villi (LFV) described below.

FIG. 6.29 Normal ileum A: The ileum contains aggregated lymphoid nodules of Peyer patches. B: Higher power illustrates a germinal center with a prominent cuff of small lymphocytes.

Peyer Patches and Lymphoid Aggregates

PPs are lymphoid aggregates that are randomly distributed around the circumference of the small intestinal wall (62). They split the muscularis mucosae, being partially mucosal and partially submucosal, often with a central germinal center and surrounding mantle of B cells (Figs. 6.29 and 6.30). The number and size of PPs increases for the first 10 years of life and reaches a maximum at puberty, usually with prominent germinal centers. Recent evidence indicates that the commensal microbiota plays an essential role in the proper development and modulation of these lymphoid structures (63). They increase in number as one proceeds distally in the
small intestine, becoming confluent in the ileum. The duodenum may also contain well-formed lymphoid nodules that extend from the surface to the base of the mucosa.

FIG. 6.30 Lymphoid follicles. A: Slightly tangentially cut mucosa with several lymphoid follicles. B: The prominent germinal centers containing tingible body macrophages and a prominent lymphocytic rim.

Peyer patches contain three major domains: the follicular B-cell area, the parafollicular T-cell area, and the FAE described above (Fig. 6.31). Lymphocytes and other mononuclear cells are constantly migrating into and out of the spaces in the dome epithelium, often via transit through postcapillary HEVs (64). The subepithelial tissue immediately beneath the FAE contains IgM+ B cells, CD4+ T cells, dendritic cells, and macrophages, allowing for efficient antigen processing and antibody production, as Peyer patch-derived lymphocytes give rise to lamina propria plasma cells (65).

PPs contain at least three different populations of nonlymphoid cells: scavenger macrophages in the dome areas, dendritic cells just beneath the epithelium in the dome in the T-cell area, and tingible body macrophages in the germinal centers of the B-cell follicles. Macrophages, particularly those near the dome of the lymphoid tissue, may contain bacteria.

CD4+ and CD8+ cells are both present in the dome of Peyer patches, the site where B cells are preferentially found. The B cells may cluster in aggregates. B cells migrate more rapidly to the center of the Peyer patch follicles than do T cells. In contrast, CD4+ T cells accumulate in the interfollicular zones. The distribution of cells in the dome epithelium differs from non-Peyer patch areas of the mucosa where T cytotoxic/suppressor cells predominate and B cells are few.

If migrating lymphocytes do not engage in an immune response, they continue their migration through the PPs and exit via the efferent lymphatics. The lymphocytes then move toward the submucosal lymphatics under the Peyer patches. Lymphocytes from PPs follow a migratory pattern from mesenteric lymphatics to the mesenteric lymph nodes, the superior mesenteric duct, and the thoracic duct before draining into the peripheral circulation. This dynamic lymphocyte recirculation facilitates effective surveillance for foreign invaders and alterations within the body’s own immune system (66).

Lymphocyte-Filled Villi

LFV are recently described structures that resemble Peyer patches, which appear to be confined to the jejunum (67). Morphologic features that distinguish LFV from classical villi are the presence of tightly packed lymphocytes that fill most of the lamina propria and a high concentration of IELs in the overlying epithelium. These IELs are enriched for CD4+ T cells that are often found in clusters, but the majority of the cells do not express surface immunoglobulin, CD3, or the T-cell receptor (TCR). They also contain major histocompatibility complex (MHC) class II-positive dendritic cells and a variable B-cell component. The epithelium overlying these structures resembles that of the FAE and includes the presence of M cells. These features suggest that the epithelium
of LFV resembles the FAE, although HEVs and obvious lymphoid follicles are not present.

FIG. 6.31 Morphology of Peyer patches. A: CD20 immunostain shows B cells located primarily in germinal centers. B: T cells localize to the parafollicular region (UCHL-1 immunostain). C: Tingible body macrophages are present in the germinal centers, and scavenger macrophages are visible in the dome area overlying the follicle. The macrophages are highlighted with a HAM56 immunostain. D: Factor VIII immunostain highlights the capillaries and small vessels surrounding the follicle. E: Small nerve twigs populate the lamina propria surrounding the lymphoid follicles (synaptophysin immunostain).

Intraepithelial Lymphocytes

IELs constitute a distinct and heterogeneous lymphocyte population nestled among the epithelial cells (68). They are predominantly CD8-positive T cells that express the T-TCR &agr;&bgr; or &ggr;&dgr; and differ from peripheral lymphoid tissues in expressing natural killer cell antigens. There is also an intraepithelial population of functional killer lymphocytes (69). Cellular and molecular cross-talk between epithelial cells and IELs appears to play a key role in the reciprocal growth and activation of these cells and in the maintenance of intestinal homeostasis. IELs contribute to cytokine secretion, expression of MHC and adhesion molecules, and the integrity of mucosal defenses (70). They also possess cytotoxic activity, which is important in protecting against the invasion of luminal pathogens and the destruction of transformed epithelium.

IELs typically lie in the basal portion of the epithelium. They range from 3 to 11 &mgr;m in diameter and possess small dense nuclei, contrasting with the paler, more vesicular enterocyte nuclei, and scant cytoplasm (Fig. 6.32). The proximal small intestine contains the highest density of IELs in the GI tract, estimated to be approximately one IEL per five
to ten epithelial cells, or 10 to 20 lymphocytes per 100 epithelial cells (71). IEL density is usually highest at the bases of the villi, with progressively fewer IELs as one approaches the villous tip (72). Fewer numbers are present in the ileum. In contrast to the IELs in the villi, IELs overlying lymphoid follicles are predominantly of B-cell derivation.

FIG. 6.32 Lamina propria inflammatory infiltrate. A: The lamina propria contains a large number of lymphocytes and plasma cells, as well as eosinophils and mast cells. Additionally, intraepithelial lymphocytes are present. B: Higher magnification of the area of the lamina propria showing plasma cells and lymphocytes.

Lamina Propria

The lamina propria provides the scaffolding on which the intestinal epithelium rests. It contains the blood vessels that nourish the epithelium and supplies a support structure for the immune cells. The majority of the cells are in the crypt region rather than in the villous region and consist of primarily of plasma cells and lymphocytes (Fig. 6.32). The great majority are IgA-containing plasma cells, although IgM-, IgD-, IgG-, and IgE-containing cells are also present (73).

The majority of the lamina propria T lymphocytes exhibit a CD4+ helper phenotype, including an important population of regulatory T cells, which are important for maintaining antigenic tolerance (61).

Numerous macrophages aggregate in the lamina propria at the tips of the villi. They extend pseudopods into the epithelial lining, which sample antigens from the lumen and internalize components of apoptotic aging enterocytes. The basal lamina propria, especially in the small bowel, contains large numbers of dendritic cells. These present antigens to mucosal CD4+ T cells. Polymorphonuclear leukocytes (PMNs) are uncommon.

It is estimated that there are between 40 and 100 eosinophils per mm2 of lamina propria in the small intestine (74). However, this figure varies significantly depending on ethnicity and geographic location and among individuals depending on antigenic exposure. Basophils are not very prominent.

In the normal adult jejunum, there are up to 300 mast cells/mm2 of mucosa, or approximately 20 per high magnification field, although tissue fixation and the detection method may influence the apparent density in tissue sections (75,76). Mast cells may be highlighted by c-kit/CD117 or tryptase immunostains. The cells are evenly distributed throughout the bowel wall, and some maintain a relationship with neural structures.

Brunner Glands

Brunner glands form a continuous series of branched or coiled tubular glands in the submucosa and basal mucosa of the first part of the duodenum. In the first part of the duodenum, where Brunner glands are relatively large, bands of smooth muscle from the muscularis mucosae occasionally lie between the acinar lobules. Ducts of individual glands open either directly into the duodenal lumen or into the crypts of Lieberkühn. Occasionally, small groups of glands extend into the superficial portion of the mucosa, particularly in
patients with peptic duodenitis. Their size and number gradually decrease from the proximal to the distal duodenum (Fig. 6.33). In the second portion, at the level of the ampulla of Vater, they are scattered. In the third portion, only a few small glands are present.

FIG. 6.33 Brunner glands. A: The submucosa of the duodenum is almost completely filled with highly branched tubular duodenal glands (Brunner glands). The muscularis mucosae may be disrupted as these glands penetrate into the deep lamina propria of the mucosa. B: Higher magnification showing the clear cytoplasm of the Brunner glands.

Three morphologically distinctive epithelial cell types are present in Brunner glands: Cells with a central nucleus and uniform glassy eosinophilic basal cytoplasm, similar cells with a clear basal cytoplasm, and cells with basal nuclei and small clear perinuclear vacuoles. The glands produce neutral glycoproteins that do not stain with mucicarmine but are PAS positive. Brunner glands produce MUC6, bicarbonate, epidermal growth factor, trefoil peptides, bactericidal factors, proteinase inhibitors, and surface active lipids (77). Brunner glands also contain endocrine cells storing somatostatin, gastrin, cholecystokinin (CCK), and peptide YY.

Ampulla of Vater

The ampulla of Vater lies in the second part of the duodenum. The common bile duct and major pancreatic duct pass through this structure. A complex collection of glands lies in the submucosa and passes through the muscularis mucosae into the overlying mucosa. They are surrounded by smooth muscle cells and a loose stroma (Fig. 6.34). This area is the weakest part of the duodenal wall and hence the most common site for diverticula to develop.


Intestinal Malpositions

Intestinal malpositions include disorders of malrotation, malfixation, and situs inversus (78). Intestinal malrotations (Fig. 6.35) result from disordered or interrupted embryonic intestinal counterclockwise rotations around the superior mesenteric artery. Considered anatomically, “typical” malrotations result from an interruption early in the rotation, so that the duodenal-jejunal loop remains on the right side of the abdomen. Consequently, malrotations exhibit obvious intestinal misplacement within the abdominal cavity. The intestines often lie to one side, appearing as a large mass of nonrotated bowel. The cecal position varies, but it usually lies in the upper left quadrant of the abdomen (Fig. 6.35). Atypical forms of malrotation include reversed duodenal and colonic rotation, in which the dorsal and ventral loops rotate to the left rather than to the right (79). The cecum lies in the right iliac fossa, but the small bowel lies superficial to the transverse colon (Fig. 6.35), often herniating into the right colonic mesentery. The small bowel may also fail to rotate fully. A short small intestinal and mesenteric segment may become fixed to the retroperitoneum along a line generally confined to the right upper quadrant. Fibrous bands or adhesions often form between the bowel and other abdominal structures in an attempt to secure the mobile bowel (Fig. 6.36). These commonly cross and compress the duodenum, obstructing it.

Intestinal malrotations affect approximately 1 in 500 live births (79). Malrotations represent a mixture of isolated (nonsyndromic) instances, for which no genetic basis is known, and syndromic examples with identifiable gene defects or chromosomal abnormalities. In the latter instance, a variety of associated abnormalities are seen depending on the specific syndrome (80) (Table 6.1). It has been proposed that the etiologic basis can be classified into one of four groups: abnormalities of left-right patterning, of the dorsal mesentery, of the intestine itself, and of other abdominal contents (80). In many cases, patients present with signs and symptoms of duodenal obstruction, intermittent volvulus, left-sided appendicitis, or acute life-threatening midgut volvulus that requires immediate surgical correction. Infants may also develop malabsorption with steatorrhea and protein-losing enteropathy resulting from mesenteric lymphatic
obstruction. However, a significant proportion of patients may be minimally symptomatic or asymptomatic. Adults with malrotations often have a lifetime history of nonspecific abdominal complaints, including acute symptoms when they were children (81).

FIG. 6.34 Ampulla of Vater. A: Low magnification demonstrating the presence of numerous branching glands that enter at the area of the ampulla. A cross section of a larger duct is indicated by the star. B: Derives from the area to the right of the star in (A). C: Higher magnification from the area to the left of the star.

Situs Inversus

In situs inversus, the organs lie in mirror image locations of their normal positions. When complete, it affects both thoracic and abdominal organs. When incomplete, it affects only the abdominal organs. Limited situs inversus affects only the stomach and duodenum. Situs inversus affects approximately 1 in 10,000 live births, and a subset has Kartagener syndrome or primary ciliary dyskinesia (82). These patients have abnormal cilia, and as a result, they produce thick, tenacious bronchial and sinus secretions that lead to chronic sinusitis and bronchiectasis.

Many children with situs inversus and a neural tube defect have mothers with insulin-dependent diabetes mellitus. Partial situs inversus usually associates with other malformations, including asplenia, duodenal stenosis, and
cardiac defects. Major associated gastrointestinal anomalies include annular pancreas, midgut volvulus, duodenal atresia, and mucosal duodenal diaphragms. The occurrence of situs inversus does not result in altered organ function or histology.

FIG. 6.35 Malrotation. A: The small intestines lie matted together in the lower abdomen, pushing the colon to the right side. B: A mass of unrotated small intestine lies on the right side of the abdominal cavity. The cecum lies on the left side.

FIG. 6.36 Intestinal bands. Several views of the same intestinal band and its consequences. A: The mesenteries have herniated through a mesenteric defect underlying the band (probe). The surrounding bowel loops appear ischemic and erythematous secondary to a volvulus that occurred around the band. B: Further dissection shows the band elevated by the probe. A loop of dusky bowel is twisted around it (arrows).


Omphaloceles consist of an external mass of abdominal contents covered by a variably translucent peritoneal and/or amniotic membrane. They result from the failure of the anterior abdominal wall to form completely during fetal
development combined with the failure of the abdominal viscera to return to the abdomen at the end of the 10th fetal week. Omphaloceles affect approximately 2 to 4 per 10,000 live births (83). Significant heterogeneity exists in the prevalence rates among different geographic regions, with especially high prevalence rates occurring throughout the British Isles. The male-to-female incidence is 3:1; although the exact etiology of omphalocele is unknown, up to 54% of infants with omphaloceles have associated anomalies (Table 6.2) compared with only 5% of those with gastroschisis (78,83). Many fetuses with an omphalocele have an abnormal karyotype. Therefore, it is plausible that the occurrence of omphalocele may result from any of a number of developmental abnormalities rather than a single causative gene or pathway.


Biliary atresia or stenosis

Duodenal atresia or stenosis

Prune belly syndrome

Diaphragmatic hernia

Annular pancreas

Internal hernias

Paraduodenal hernia

Midgut volvulus and facial anomalies

Omphalocele and gastroschisis

Chronic idiopathic pseudoobstruction

Cardiovascular abnormalities.

Situs inversus


Heart anomalies

Intestinal atresia

Chromosomal defects

Genitourinary anomalies (cloacal or bladder exstrophy)

Craniofacial defects

Diaphragmatic abnormalities

Liver and bile duct abnormalities

Beckwith-Wiedemann syndrome




Umbilical abnormalities

Cantrell pentalogy

Ectopia cordis

Sternal cleft

Diaphragmatic defect

Cardiac disease


OEIS complex


Cloacal exstrophy

Imperforate anus

Spinal defects

The rare OEIS (omphalocele, cloacal exstrophy, imperforate anus, spinal defects) complex affects 1 per 200,000 to 400,000 pregnancies. OEIS occurs sporadically or it affects twins or siblings from separate pregnancies, suggesting that some cases have a genetic basis (84).

There is some evidence that the OEIS complex arises from a single localized mesodermal defect early in development that contributes to infraumbilical mesenchymal, cloacal septum, and caudal vertebral abnormalities. Four somatic folds (a cephalic fold, two lateral folds, and a caudal fold) define the anterior thoracic and abdominal walls during the 3rd fetal week. These folds migrate centrally to fuse at the umbilical ring, usually by the 18th gestational week. Arrested fold migration or development results in anterior wall defects and a widening of the umbilical ring.

Omphaloceles range in size from only a few centimeters to lesions involving almost the entire anterior abdominal wall (Fig. 6.37). Abdominal viscera are present within a sac that initially is moist and transparent but with time becomes dry, fibrotic, opaque, friable, and prone to rupture leading to secondary evisceration. Abdominal skin may cover the sac base, and the umbilical cord is usually attached to its apex or slightly to the side. Depending on their size, omphaloceles may contain only intestinal loops or also include the stomach, liver, spleen, and pancreas. The lining of the sac that covers the eviscerated organs consists of peritoneum internally and amnion externally.

The function and histology of the displaced organs tends to be normal unless there is a coexisting congenital abnormality.


Gastroschisis is the persistent herniation of abdominal viscera through an abdominal wall defect at the base of the umbilicus. The abdominal organs remain outside the abdominal cavity. No peritoneal sac or amniotic remnant covers the eviscerated abdominal contents. The incidence of gastroschisis is approximately 3 per 10,000 live births (78). Gastroschisis predominates among male infants. While it is often an isolated lesion, up to 20% of infants have associated congenital malformations, including total intestinal atresia (85,86). Omphalocele and gastroschisis are both associated with increased maternal serum and amniotic fluid &agr;-fetoprotein (AFP) levels (87). Antenatal ultrasound often allows an accurate diagnosis of gastroschisis.

The etiology of gastroschisis is uncertain but appears to result from improper body fold closure during the 5th to 10th weeks of gestation. Ischemic and teratogenic mechanisms have been proposed. Accordingly, risk factors for gastroschisis include intrauterine exposure to teratogenic agents such as recreational drugs, smoking, salicylates, or others.

Gastroschisis may involve only the intestines or it may affect many other organs. Parts of the stomach, small intestine, and colon herniate through an abdominal wall defect, usually to the right of the umbilical cord (Fig. 6.38). All infants with gastroschisis have coexisting malrotation and abnormal intestinal fixation.

The histology of the various organs may be normal (rarely) or changes may be present reflecting the presence
of associated congenital abnormalities, heterotopias, atresia, meconium peritonitis, or perivisceritis. The last two entities result from exposure of the bowel to inflamed amniotic fluid (88) and lead to gastrointestinal wall thickening, mural inflammation, serosal edema, and fibrinous exudates and fibrosis. The damaged bowel frequently develops secondary motility problems and malabsorption, which may develop even following surgical repair.

FIG. 6.37 Omphalocele. A: A large abdominal defect is covered by a thick white membrane extending into the base of the umbilical cord (dark red structure with clamp across it). The organs inside the omphalocele cannot be seen. B: The abdominal wall defect is smaller than that seen in (A), and a clear sac covers the herniated intestines. A whitish membrane is forming near the abdominal wall attachment. At the periphery of this whitish lesion and within the clear membranous sac is an erythematous zone. The lesion continues into the umbilical cord, which has an umbilical clamp on it.

Long-term outcome in the absence of major chromosomal and structural abnormalities is excellent. Patient prognosis depends in part on whether the gastroschisis is an isolated lesion or whether there are associated abnormalities such as bowel dysfunction. The goal of the surgeon in both gastroschisis and omphalocele is to accomplish abdominal wall closure in a single stage (89). An alternate approach is to perform a staged closure using prosthetic materials while maintaining adequate nutritional support.


Peritoneal bands, known as Ladd bands, represent incomplete absorption of the cecal and ascending colonic mesentery. They may extend from the cecum, ascending colon, or posterior wall transduodenally to the subhepatic region, compressing the duodenum and causing partial obstruction, vascular compression, and intestinal ischemia.

FIG. 6.38 Gastroschisis. This infant shows external herniation of most of the abdominal contents, including the liver, spleen, and intestinal tract.


Malrotation of the gut

Meckel diverticulum


Esophageal atresia

VACTERL associations

Imperforate anus

Biliary atresia

Annular pancreas

Pancreatic lipomatosis

Ocular abnormalities


Spina bifida

Gastrourinary abnormalities

Immunodeficiency states

Hirschsprung disease

Congenital heart disease

Cytogenetic changes

Internal deletion on chromosome 13

Ring chromosome 4

Trisomy 21 (Down syndrome)

Maternal lesions


Intrapartum hemorrhag

FIG. 6.39 Intestinal atresia. A: Blind-ending atresia is shown on the right. B: Fibrosis in atretic wall. C: Blind area of atresia on the right with stenotic area on the left. The atretic area is filled with meconium. D: Granulomatous reaction surrounding stenotic area.

Atresia and Stenosis

Intestinal atresia and stenosis is one of the most common causes of congenital intestinal obstruction, affecting 1 per 1,500 to 12,000 live births (90). Atresia is the more common condition and corresponds to complete occlusion of the lumen, whereas stenosis represents either a narrowed intestinal segment or a luminal diaphragm with a small central opening.

Intestinal atresia may occur sporadically or in a familial context (90). Associated congenital abnormalities affect fewer than 10% of patients with jejunoileal atresia, contrasting with a 35% incidence of associated congenital anomalies in patients with duodenal atresia (Table 6.3). In particular, approximately 30% of infants with duodenal atresia have a chromosomal anomaly, particularly trisomy 21 (Down syndrome) (91). Theorized mechanisms of their formation include (a) incomplete recanalization of the bowel lumen and (b) ischemic vascular injury resulting in necrosis with subsequent fibrosis of the affected bowel segment, with recent data favoring the latter mechanism (78). “Apple-peel” atresia, in which the duodenum ends in a blind pouch and the distal small intestine wraps around the mesenteric vessels in a spiral configuration, probably results from a narrow mesenteric attachment, volvulus, and occlusion of the superior mesenteric artery distal to its proximal branches (92). The presence of meconium, bile, squamous epithelial cells, and lanugo hair in the atretic areas (Fig. 6.39) supports an
intrauterine injury. Small intestinal atresia may also complicate midtrimester amniocentesis (93), intrauterine intussusception due to Meckel diverticulum, maternal cocaine use, or fetal infections (varicella and syphilis) (94). There is an increased frequency of cystic fibrosis among infants with small intestinal atresia (95). Ileal atresia may coexist with colonic aganglionosis (96).

FIG. 6.40 Intestinal atresia. A: The small intestinal lumen has been replaced by fibrous tissue. B: Another example showing complete occlusion of the lumen by fibrous tissue. In the center, fragments of calcified meconium can be seen suggesting that the bowel was at one time patent.

Most duodenal atresias lie in a postampullary location or at the ampulla of Vater. Duodenal atresia can be diagnosed ultrasonographically at 15 weeks’ gestation by finding polyhydramnios, a lack of amniotic fluid, intestinal dilation proximal to the atretic intestine, meconium peritonitis, and ascites.

Small intestinal atresias present in the neonatal period. Bilious vomiting (unless a coexisting esophageal atresia is also present) usually occurs during the first few hours after birth. Partial obstruction causes intermittent symptoms. The vomitus lacks bile staining when the obstruction lies proximal to the ampulla of Vater.

In contrast, because stenoses allow passage of some enteric contents, they present later in life. Some patients with duodenal stenosis remain asymptomatic, whereas others present with an intermittent or delayed history of duodenal ulcer, symptoms of duodenogastric reflux, a motility disturbance, duodenal diverticula, and bezoars (97).

In atresia, a bowel segment is entirely missing, leaving a proximal segment with a blind end separated some distance from the distal segment. Alternately, the proximal and distal segments are united by a solid fibrous cord, or there is an occluding mucosal diaphragm (Fig. 6.40). Intestinal atresia falls into four major types (Figs. 6.41 and 6.42). Two main types of stenosis exist. In type 1, a septum identical to that seen in type 1 atresia is present, but instead of being complete, it has a central hole within it. In type 2 lesions, the GI lumen appears uniformly narrowed over a variable length of intestine (Fig. 6.43).

Normal small intestinal mucosa is present away from the atretic or stenotic intestinal segment. The height of the circular folds declines due to stromal edema and the muscularis mucosa thickens as one approaches the blind segment.
In complex atresia, the proximal bowel appears dilated and gangrenous. The mucosa shows villous shortening or ulceration with granulation tissue and only a few residual crypts. Dystrophic calcification and inflammation at or near the atretic site suggest previous injury. The blind segment may contain dense fibrosis, meconium, keratinizing squamous cells, lanugo hair, bile pigment, and mucin. The muscularis propria eventually becomes markedly hypertrophic, and the myenteric plexus may show inflammatory or degenerative changes.

FIG. 6.41 Different types of atresia. A: In type 1, an imperforate septum, covered on each side by mucosa, stretches across an otherwise continuous bowel. B: In type 2, a thin fibromuscular cord with or without an associated mesenteric defect replaces the bowel. C: In type 3, a complete gap and a corresponding mesenteric defect separate the two blind intestinal ends. D: Type 4 atresia is characterized by the presence of atretic areas. The different forms of atresia may coexist and may be single or multiple.

FIG. 6.42 Intestinal atresia. A: Resected portion of small intestine showing intestinal dilation proximal to the atretic area. B: Close-up of atretic portion of small bowel showing a marked narrowing of a segment partially encircled by a fibrous band. C: Type 2 atresia with thin fibromuscular core. D: Type 2 atresia in situ. No mesenteric defect is present.

FIG. 6.43 Type 2 intestinal atresia that has been opened.

Annular Pancreas

Annular pancreas consists of a ring of pancreatic tissue surrounding the second part of the duodenum (Fig. 6.44). It occurs due to aberrant migration of the pancreatic precursors during fetal development (98). The incidence of annular pancreas is 1 in 20,000 persons. The disorder may present clinically in the neonatal period or in adulthood or be completely asymptomatic. Eighty percent of infants with annular pancreas have associated anomalies such as trisomy 21, tracheoesophageal fistulae, or cardiorenal abnormalities. The most common clinical presentation in neonates is duodenal obstruction. By contrast, in adults, the annular pancreas is
most commonly an isolated finding and when symptomatic is associated with duodenal stenosis, duodenitis peptic ulcers, upper abdominal pain, and chronic pancreatitis. Although the pancreatic location is abnormal, the pancreatic histology is completely normal.

FIG. 6.44 Annular pancreas. The annular pancreas wraps around the first portion of the duodenum. Note the lobulated appearance of the pancreatic tissue.

FIG. 6.45 Comparison of duplications, enterogenous cysts, and congenital diverticula. Panels (A) through (D) represent true duplications in which a significant portion of the intestinal length is duplicated. The arrows indicate the flow of intestinal contents. A: Both the proximal and distal ends of the duplicated segment communicate with the native intestinal lumen. This results in a free flow of intestinal contents through both lumens. B: The proximal portion of the duplication communicates with the native intestine. The distal portion of the duplication ends blindly. As a result, the intestinal contents pass into the duplication but then accumulate, causing dilation and inflammation. C: The duplicated segment fails to communicate with the native intestine, and as a result no intestinal contents flow into the duplicated lumen. If the lining of the duplicated segment produces significant secretions, these may accumulate and form a cystic dilation. D: Intestinal duplication in which the proximal end fails to communicate with the native intestinal lumen but the distal portion of the duplication does communicate with it. Intestinal contents do not enter the duplication and secretions produced by the duplicated segment are free to exit the duplicated segment and enter the main lumen. E: Enterogenous cyst. In this setting, the duplicated bowel represents a localized segment of duplicated bowel embedded within the intestinal wall. It fails to communicate with the native intestine. The enterogenous cyst may enlarge as the result of accumulated secretions. F: Congenital diverticulum. The duplication in this situation is relatively localized but it communicates freely with the intestinal lumen. The wall of the diverticulum contains all of the usual layers of the intestinal wall, distinguishing it from an acquired diverticulum.

Enterogenous Cysts, Congenital Diverticula, and Duplications

Congenital diverticula, duplications, and enterogenous cysts are related lesions that contain all three bowel layers (Fig. 6.45). A duplication is a complete or partial doubling of a variable length of bowel. Duplication cysts are localized duplications that become incorporated into the bowel wall or embedded within its serosa. The major distinction that separates this group of lesions is their gross appearance (Figs. 6.45 and 6.46). Duplications tend to be longer in their axial length than cysts or diverticula, and they appear as tubular intestinal reduplications that may or may not communicate with the native intestinal lumen. They have thick walls and are filled with mucus. Initial manifestations include obstruction, intussusception, and volvulus. Duplication cysts may be single or multiple and vary widely in size. Spherical duplications do not communicate with the intestine and are usually filled with clear secretions. Fistulae may result from the inflammation and necrosis.

FIG. 6.46 Enterogenous cyst. A: A large, cystically dilated mass extends from the mesenteric portion of the bowel. It fails to communicate with the intestinal lumen. It was filled with mucinous secretions. B: Same specimen opened to show its internal structure.


Thirty-nine percent of duplications involve the foregut; 61% originate in the midgut or hindgut. Approximately 50% of cases affect the ileocecal valve. Most patients are boys. The clinical manifestations depend on the form the duplication takes. Patients present with an abdominal mass, bouts of abdominal pain, vomiting, distention, chronic rectal bleeding, intussusception, perforation, and obstruction. Bleeding is especially likely if the anomaly contains ectopic gastric mucosa, which produces acid. Ileocecal duplications act as lead points for chronic or recurrent intussusception.

Hypotheses to explain duplications include persistence of embryonic diverticula, fusion of embryologic longitudinal folds (the most popular theory) (99), abortive twinning (100), intrauterine intestinal ischemia (101), and sequestration of embryonic tissues during embryonic movements. Small diverticula and epithelial islands in the mesentery of the developing small intestine may explain the presence of isolated intestinal duplications. Extensive intestinal duplications associated with multiple anomalies including the urinary bladder presumably result from teratogenic insults affecting several developing organs.

FIG. 6.47 Intestinal duplication. A: Unopened specimen. The native intestinal lumen that communicates with the rest of the gastrointestinal (GI) tract lies to the left of the smaller lumen. B: Both structures are opened, showing the wide dilated native GI lumen and a smaller lumen at the periphery and edge of the C-shaped structure. Several atretic areas are present in the duplicated bowel (arrows).

Grossly, duplications appear as hollow, cylindrical, oval, or spherical cystic masses ranging in size from a few millimeters to up to 15 cm (102). Duplications may communicate with the intestinal lumen by opening proximally, distally, or both (Figs. 6.45 and 6.47). In other cases, the duplicated segment fails to communicate with the intestinal lumen (Fig. 6.47). The three histologic criteria for the diagnosis of a duplication
are the presence of an intimate attachment to the GI tract, a smooth muscle coat, and an alimentary mucosal lining. Of these criteria, only the presence of a smooth muscle coat is absolutely necessary to define the lesion. Pressure within a cyst may lead to atrophy of the muscle component, causing it to appear incomplete. Generally, intestinal epithelium lines a duplicated segment (Fig. 6.48), but it may also contain heterotopic tissues, including thyroid stroma, pancreas, gastric mucosa (Fig. 6.49), lymphoid aggregates resembling Peyer patches, ciliated bronchial epithelium, lung tissue, and cartilage. A normal submucosa and inner circular muscle layer and myenteric plexus are present.

FIG. 6.48 Intestinal duplication. A: Cross section through duplicated segments shows two complete intestinal walls lying side by side. They share a common muscularis propria. B: Higher magnification showing strands of muscularis propria extending into the septum between the duplicated segments. The lumen of each segment is illustrated by the star, and the attenuated muscularis propria (MP) separates the two submucosae (SM).

FIG. 6.49 Small intestinal duplication. Aberrantly formed crypts are present. The glands superficially resemble those seen in the gastric foveolae. Histochemical stains showed that the mucin was small intestinal mucin. Gastric glands are present.

Congenital Diverticula

Duplication cysts that widely communicate with the lumen are termed congenital diverticula and affect 1% to 2% of all individuals. Patients with congenital diverticula may be asymptomatic or present with abdominal pain, distension, or fever due to superimposed diverticulitis; GI bleeding secondary to the presence of acid-secreting heterotopic gastric mucosa; or intussusception leading to sudden pain and bleeding. Duodenal diverticula may become large, causing obstructive jaundice, pancreatitis, duodenal obstruction, fistulas, hemorrhage, and perforation (103).

Congenital diverticula present as localized outpouchings (Fig. 6.50), sometimes being multiple. Some congenital duodenal diverticula pass upward behind the stomach
through a separate opening in the diaphragm to enter the right thoracic cavity, where they attach to defective thoracic vertebrae. Congenital diverticula consist of all three bowel layers (Fig. 6.51). The lining epithelium is usually that of the site of origin. Some diverticula contain heterotopic tissues, similar to those found in duplications and enterogenous cysts. Diverticula containing oxyntic mucosa may develop peptic ulcers within them. If the diverticular orifice becomes blocked, diverticulitis develops.

FIG. 6.50 Congenital duodenal diverticulum proximal to an intestinal band (arrow).

FIG. 6.51 Comparison of an acquired diverticulum versus a congenital diverticulum. A: An acquired diverticulum in which the mucosa and submucosa, and variable amounts of the muscularis propria and serosa (not shown), herniate through the bowel wall at areas of weakness. B: Congenital diverticulum. It is lined by all three layers of the bowel wall.

Meckel Diverticulum

Meckel diverticulum, which represents a persistent omphalomesenteric or vitellointestinal duct, affects 1% to 4% of the population. Meckel diverticulum always lies on the antimesenteric ileal border (Fig. 6.52). In the infant, it usually lies about 30 cm proximal to the ileocecal valve; in the adult, it usually lies within 100 cm of the ileocecal valve. An apical fibrous band may connect the diverticulum to the umbilicus or to other abdominal structures. Meckel diverticulum may also be connected to other intestinal loops or mesenteries by a congenital band or by adhesions resulting from previous episodes of diverticulitis.

FIG. 6.52 Meckel diverticulum. A: Typical Meckel diverticulum arising from antimesenteric border of distal ileum. B: Cross section through an opened Meckel diverticulum. The diverticulum lies in a plane perpendicular to the long axis of the intestine. The mouth of the diverticulum is illustrated by the arrow. The lining of the diverticulum resembles that of the native intestine.

Meckel diverticulum has no clinical consequences unless complications develop, which occurs in about 5% of individuals (Figs. 6.53 and 6.54). Hemorrhage occurs if the diverticulum contains acid-secreting epithelium causing peptic ulceration. Diverticulitis develops secondary to peptic ulceration or obstruction of the diverticular orifice. Intestinal obstruction affects 25% of symptomatic patients and may be secondary intussusception, volvulus, adhesions, or the presence of a tumor, heterotopic tissue, enteroliths, or bezoars.

FIG. 6.53 Complications of Meckel diverticulum. A: Inverted Meckel diverticulum causing intussusception. B: External appearance of an intussusception in which a Meckel diverticulum acted as the lead point.

Meckel diverticulum varies in length from 2 to 15 cm (Fig. 6.52), but it usually measures less than 2 cm in width and has a narrow lumen. Variations in size, location, and shape are common. Meckel diverticulum may coexist with a duplication. Sometimes, a giant Meckel diverticulum develops. These appear as rounded, fusiform dilations resembling duplications rather than as saclike diverticula. They are sometimes referred to as omphalomesenteric cysts.

Normal small intestinal epithelium lines the diverticulum, and heterotopic pancreatic tissue is common (Fig. 6.55). The latter usually appears as a nodular mass close to the diverticular tip. The presence of heterotopic gastric mucosa (Fig. 6.56) predisposes to peptic ulceration, bleeding, or perforation, especially if oxyntic mucosa is present. Other heterotopic tissues include duodenal, jejunal, colonic, or biliary epithelium. Tumors may also form in the diverticulum.

FIG. 6.54 Complications of Meckel diverticulum. A: Complications that lead to obstructions and diverticulitis and/or bleeding. B: Some of the tumors that may develop in the diverticula.

Umbilical Fistula

An umbilical fistula communicates from the umbilicus to the small bowel and is a consequence of a persistent vitelline duct, a yolk sac remnant in the umbilical cord that normally
obliterates between the 5th and 9th weeks of fetal life. It represents 2% of vitelline duct anomalies and presents with persistent umbilical drainage. The diagnosis is confirmed when the dye introduced into the umbilical side of the fistula is visualized in the lumen of the small bowel.

FIG. 6.55 Ectopic pancreas in Meckel diverticulum. A: Ectopic pancreatic tissue subjacent to mucosal lining. B: Pancreatic acini and ducts in ectopic pancreatic tissue. C: Junction between pancreatic parenchyma (left) and gastric-type mucosa (right) within a Meckel diverticulum.

FIG. 6.56 Ectopic gastric mucosa within a Meckel diverticulum. A: Low magnification showing the lining of the Meckel diverticulum. The majority consists of small intestinal epithelium. The arrow indicates the junction of the intestinal epithelium with gastric epithelium. B: Higher magnification of the gastric epithelium showing the foveolar epithelium lining the surface (star), a well-developed mucous neck region (double star), and well-formed glands containing parietal cells and chief cells. C: Portion of another Meckel diverticulum with a peptic ulcer in the mucosa adjacent to an area with oxyntic gastric epithelium.

Congenital Heterotopic Gastric Mucosa

Gastric-type epithelium occurs in the small intestine as the result of a congenital abnormality or as an acquired metaplasia. Acquired gastric mucosa (foveolar or pyloric metaplasia)
usually associates with peptic duodenitis or chronic inflammatory disorders. Congenital heterotopic gastric mucosa arises in isolation (Fig. 6.57), or it complicates other congenital anomalies such as Meckel diverticulum (Fig. 6.56), duplications, and heterotopic pancreas. Congenital heterotopic gastric epithelium often remains asymptomatic only to be discovered incidentally. Symptomatic lesions present with intestinal obstruction, peptic ulceration, or intussusception.

FIG. 6.57 Congenital heterotopic gastric epithelium. A: Biopsy of a duodenal “polyp.” The tissue consists of typical oxyntic mucosa. B: Higher magnification showing the surface lined by foveolar epithelium and the presence of oxyntic glands with parietal cells and chief cells.

Most cases of heterotopic gastric mucosa present as duodenal polyps at the time of upper endoscopy. Typically, the duodenal bulb appears nodular, often with small sessile polyps measuring less than 1.5 cm in maximum diameter. The ectopic tissue may appear solid or cystic. An exceptional example of extensive gastric heterotopia that presented as multiple, carpetlike nonpolypoid lesions that involved a large part of the small intestine in a child was recently reported (104). Larger lesions with central depressions may mimic a superficial ulcerating duodenal cancer (105).

Duodenal biopsies typically demonstrate intact duodenal villi and Brunner glands interrupted by discrete masses of gastric glands covered by foveolar epithelium. Congenital gastric mucosa usually consists of oxyntic mucosa with chief and parietal cells. Antral glands may also be present (Fig. 6.57). Rarely, the ectopic tissue develops hyperplastic polyps similar to their native gastric counterparts (Fig. 6.58). Figure 6.59 compares the appearance of heterotopic gastric mucosa and gastric metaplasia.

Heterotopic Pancreas

Heterotopic pancreatic tissue affects 0.55% to 13.7% of duodenal or jejunal strictures, duplications, and Meckel diverticula. It is particularly common in individuals with trisomies 13 and 18. While most cases remain asymptomatic, rarely inflammation or malignancy can arise, leading to variably sized and shaped duodenal wall cysts or duodenal stenosis (106).

Grossly and endoscopically, the lesion usually appears well demarcated. Heterotopic pancreas presents as a mass lesion that, on cut surface, has a solid, tan or cystic, lobular appearance, depending on whether or not the pancreatic ducts are dilated. The presence of a central mucosal dimple usually corresponds to the entrance of pancreatic ducts into the intestinal lumen. The lesion lies in the mucosa, in the submucosa, transmurally, or on the serosa (Figs. 6.60 and 6.61) and may coexist with heterotopic Brunner glands and/or gastric tissue (107).

Pancreatic acini, ducts, or islets occur alone or in combination with one another. When the lesion contains only ducts surrounded by the circular and longitudinal muscle of pancreatic ducts (Fig. 6.61), it is sometimes erroneously referred to as an adenomyoma. The orderly arrangement of the two muscle layers around the ducts distinguishes the two lesions.

Brunner Gland Hamartomas

Brunner gland hamartomas are very unusual polypoid or nodular lesions that occur in the fourth to sixth decades of life. It is difficult to ascertain their true incidence because the lesions are frequently confused with Brunner gland hyperplasia. They are usually incidental findings but may cause upper GI bleeding (108). These lesions usually lie in the submucosa and contain an admixture of muscular, glandular, and fatty elements, sometimes with heterotopic pancreatic acini and ducts. Dilation of the glandular acini or ducts may give them a cystic appearance.

Peritoneal Encapsulation

Peritoneal encapsulation is intestinal encasement by a peritoneal membrane. It probably results from the formation of an
accessory peritoneal membrane from the mesocolon during the return of the intestinal loop to the abdomen in the 10th fetal week. The dorsal mesentery covers most of the small intestine. It eventrates and moves counterclockwise, fusing with the posterior abdominal wall. Alternatively, the accessory membrane forms from part of the yolk sac peritoneum as it is drawn back into the abdominal cavity with the intestine (109).

FIG. 6.58 Hyperplastic polyp arising in ectopic gastric mucosa. A: Low-power picture of the polypectomy specimen. B: Higher magnification showing irregular gastric glands.

FIG. 6.59 Comparison of congenital gastric heterotopia versus gastric metaplasia. Congenital gastric epithelium usually shows an orderly arrangement of the foveolar epithelium usually covering oxyntic glands. In contrast, gastric metaplasia lacks the three components of surface epithelium, gastric pits, and glands. It comes in two forms: The foveolar metaplasia commonly associated with peptic duodenitis and pyloric metaplasia commonly complicating chronic inflammatory diseases such as Crohn disease. In foveolar metaplasia, a mucous neck region and glands are completely absent. In pyloric metaplasia, foveolar cells and the mucous neck region are absent.

The lesion usually remains asymptomatic and is detected incidentally. However, patients may present with cramps, obstruction, abdominal pain, vomiting, or altered bowel habits, mimicking a left mesocolic hernia. Peritoneal encapsulations can measure up to 20 cm. A thin membranous sac, histologically composed of fibrous tissue, encases the entire small bowel. The sac lies freely and does not adhere to the mesentery, the parietal peritoneum, or other abdominal organs. The encased intestinal loops often have their own mesenteries. The histology of the encapsulated organs is normal.


Duodenal Diverticula

Duodenal diverticula are found in 1% to 6% of radiologic examinations and in approximately 9% of autopsies (110). Most duodenal diverticula develop as a result of chronic
peptic ulcer disease, but may also complicate choledocholithiasis (111), duodenal obstruction, and genetic or systemic disorders such as Marfan syndrome (112). Their frequency increases with age; they rarely develop before age 40. The diverticula usually involve the second portion of the duodenum in a juxtapapillary location and are usually solitary and medial in location. Diverticula arise in weakened areas of the bowel wall that gradually balloon out, causing the diverticula to enlarge over time. The associated peptic injury results in fibrosis of the muscularis propria and abnormal contractility. The diverticular wall consists of variably inflamed mucosa and submucosa with only scattered muscle cells.

FIG. 6.60 Heterotopic pancreas. A: Cross section of a duodenal “polyp” produced by heterotopic pancreatic tissue in the submucosa. Prominent pancreatic ducts can be seen within the lesion. B: Histologic features. BG indicates surrounding Brunner glands.

Jejunal and Ileal Diverticulosis

Jejunal diverticulosis is a heterogeneous disorder affecting 1.3% to 4.6% of the population, usually adults over age 40 (113). It consists of single or multiple diverticula predominantly involving the jejunum either in isolation or along with other small intestinal segments (Fig. 6.62). Jejunal diverticula develop seven times more commonly than do ileal diverticula (114); men are affected twice as frequently as women. Neuromuscular disorders typically coexist with jejunal diverticulosis, including Fabry disease, visceral myopathies or neuropathies, scleroderma, and neuronal inclusion disease (113). As a result, patients often suffer from pseudo-obstruction or malabsorption secondary to bacterial overgrowth. Diverticular resection cures the malabsorption. Small intestinal diverticula perforate, bleed, become inflamed, and undergo other complications. These complications lead to morbidity and mortality rates as high as 40%.

FIG. 6.61 Heterotopic pancreas. This lesion, originally diagnosed as an adenomyoma, represents heterotopic pancreas. It consists of pancreatic ducts surrounded by smaller ductules and a prominent proliferation of muscle fibers. No acini or islets are present.

Small intestinal diverticula begin as a pair of small outpouchings along the mesenteric border. The mucosa herniates through the muscle layer along the path of the penetrating vessels. Alternatively, localized areas of muscular fibrosis and atrophy may weaken the bowel wall, creating localized mural sacculations. Uncoordinated muscular contractions from an underlying motility disorder lead to focal areas of increased intraluminal pressure and mucosal herniation through the weakened areas. The diverticula usually measure less than 1 cm in size, although they may be larger. Jejunal diverticula tend to be larger in the proximal jejunum and become smaller and fewer as one progresses distally in the GI tract.

Histologically, diverticula are lined by mucosa, muscularis mucosae, and submucosa, but they usually lack a muscularis propria. The mucosa usually shows some degree of crypt hyperplasia, villous atrophy, and chronic inflammation, probably resulting from intestinal stasis and bacterial overgrowth. The histology of the bowel wall sometimes shows an underlying myopathy or neuropathy (see Chapter 10) or only fibrosis of the muscularis propria.

FIG. 6.62 Jejunal diverticulosis. A: Multiple outpouchings along mesenteric border of jejunum characteristic of jejunal diverticulosis. B: Cut section demonstrating thin-walled diverticular outpouchings.


An intussusception results from invagination of an intestinal segment (the intussusceptum) into the next part of the intestine that forms a sheath around it (the intussuscipiens) (Figs. 6.63, 6.64, 6.65 and 6.66). Intussusceptions are classified as primary (without an identifiable cause) or secondary (due to a preexisting lesion). Intussusception is the most common cause of intestinal obstruction in children. The peak incidence occurs between 3 and 5 months of age (115) and affects 1.5 to 3.8 cases per 1,000 live births a year. The incidence varies considerably in different parts of the world (116).

Lead points are common in children 6 years of age or older. Predisposing factors include masses, bezoars, Meckel diverticula, motility disorders, inflammatory fibroid polyps, or localized lymphoid hyperplasia secondary to adenovirus or other infections or even vaccination (Figs. 6.66 and 6.67) (117,118).

FIG. 6.63 Diagram of an intussusception showing the relationship of the intussusceptum with the intussuscipiens and the overall intussusception.

The intussusception constricts the mesentery between the inner intussusceptum and the ensheathing intussuscipiens blocking both venous outflow and the arterial supply, leading to secondary ischemia. As a result, the intussusception continues to swell, causing bowel obstruction and possibly gangrene and perforation. Some intussusceptions reduce spontaneously.

The histologic findings vary depending on whether the intussusception is acute, chronic, or acute superimposed on chronic intussusception. In patients with chronic or recurrent intussusceptions, the muscularis mucosa sometimes buckles upward, indicating the lead point of the intussusception, and the subserosal or even intramural vessels may show evidence of a “pulling artifact” with tethering in the same direction as the muscularis mucosae. Recurrent intussusceptions can produce florid submucosal vascular proliferations that may be so pronounced as to raise the possibility of a primary vascular neoplasm (119). Characteristically, there is also prominent muscular hypertrophy and neural hyperplasia. Most intussusceptions show variable degrees of mucosal ischemia, depending on the duration and severity of the injury. In children with adenovirus infections, the lymphoid tissue appears markedly hyperplastic, and the epithelium overlying the lymphoid hyperplasia at the lead point appears damaged or even necrotic. Intranuclear viral inclusions appear as reddish globules surrounded by halos or as poorly demarcated purple nuclear smudges.


Volvulus accounts for 5% to 10% of all cases of intestinal obstruction. It develops when any portion of the intestine loops around itself (Fig. 6.68). Intestinal volvulus is divided into primary and secondary forms (120). Primary volvulus develops in patients lacking a predisposing cause. Secondary volvulus affects patients with an acquired or
congenital structural abnormality that predisposes the bowel to rotate on itself (Fig. 6.69). Examples of underlying abnormalities include a congenitally long mesentery with a narrow base, congenital bands, an elongated small intestine, Meckel diverticulum, or inflammatory diseases.

FIG. 6.64 Intussusception. A: External appearance of small bowel intussusception with secondary gangrenous necrosis. B: Opened specimen.

Small bowel volvulus is a rare but life-threatening surgical emergency. Volvulus occurs acutely, causing complete obstruction, or intermittently, producing partial or complete obstruction with compromise of the blood supply and ischemia, giving rise to symptoms of severe abdominal pain, bilious vomiting, abdominal distension, and rectal bleeding. As much as 50% of the blood volume may accumulate within the volvulus due to obstruction of venous outflow. A prodrome of recurrent minor attacks of similar problems is present in approximately 50% of patients. Histologically, the tissues manifest variable degrees of ischemia, with congestion and hemorrhage due to venous out-flow obstruction.

FIG. 6.65 Intussusception. The intussuscipiens exhibits early ischemic changes as demonstrated by the presence of the mottled speckling on the serosal surface and the dusky color in comparison to the paler intussusceptum.


Fistulae develop between the small intestine and adjacent organs or skin as a result of underlying bowel disorders (e.g., Crohn disease, radiation, or malignancy) or as complications of prior surgery. Enteroenteric fistulae represent communications between two portions of the GI tract. Bouveret syndrome consists of a cholecystoduodenal or choledochoduodenal fistula due to the passage of a gallstone into the duodenal bulb and subsequent gastric outlet obstruction.

FIG. 6.66 Adenovirus-induced intussusception in an 8-year-old child. The lead point of the intussusception (arrows) is an area of lymphoid hyperplasia secondary to an infection. One loop of bowel completely telescopes into another.

FIG. 6.67 Histologic features of the lesion shown in Figure 6.66. A: Low magnification showing marked lymphoid hyperplasia. B: Ischemic necrosis of the epithelium. C: The presence of bacterial overgrowth. D: The in situ hybridization (red) for adenovirus.

Primary fistulae between the abdominal aorta and the gut are rare and fatal. Aortoenteric fistulae usually result from disorders involving either the aorta (usually atherosclerosis or following the insertion of an aortic bypass graft) or the GI tract (cancer, peptic disease, infections, or trauma).


Intestinal perforations occur spontaneously or following trauma. The basis of the perforations differs from country to country. In countries with poor hygiene, underlying infectious diseases, including typhoid ulcers, intestinal tuberculosis, and parasitic diseases, result in perforation. In Western countries, foreign bodies, ischemia, Crohn disease, tumors, diverticula, trauma, and radiation therapy represent the most common causes of perforation.


Any time the peritoneal or serosal surfaces of the bowel become inflamed, fibrous or fibrinous bands can form causing loops of bowel to become adherent to one another (Fig. 6.70) or to become adherent to any peritoneal surface. Adhesions commonly complicate previous transmural small intestinal inflammation as seen in ischemia, perforation, Crohn disease, previous surgery, or radiation therapy. Adhesions in turn predispose to bowel obstruction, volvulus, and ischemia by
mechanical means. The adhesions appear as strands of variably fibrotic or inflamed tissue on the serosal aspect of the bowel wall, with variable degrees of mesothelial hyperplasia.

FIG. 6.68 Volvulus. A: The intestines rotated around an intestinal band, causing infarction of both the large and small intestine. B: Acute coagulative necrosis. The tissues lack an inflammatory response.

Stenosis of the Ampulla of Vater (Papillary Stenosis)

Papillary stenosis complicates impacted gallstones, biliary tract infections, previous endoscopic retrograde cholangiopancreatography, endoscopic sphincterotomy, and mass lesions such as heterotopic pancreas.

FIG. 6.69 Volvulus around intestinal band. A: This adult died from gangrenous necrosis of the small bowel. The cause of the necrosis was a torsion and volvulus around a congenital band demonstrated by the linear structure lying next to the thumb (arrow). B: The tissues are spread apart to show the bands and adhesions between various intra-abdominal structures.

The histologic features of papillary stenosis include edema with acute and/or chronic inflammation, glandular hyperplasia, granulation tissue, granulomatous inflammation, and submucosal fibrosis (Fig. 6.71). One often sees a hyperplastic, regenerative mucosa with marked epithelial atypia. Although these changes may raise the possibility of a neoplastic process, the presence of marked acute and
chronic inflammation and edema, together with the presence of clinical risk factors above, should indicate that the process is reactive in nature (Fig. 6.71).

FIG. 6.70 Adhesions. A: Opened abdomen in a child with necrotizing enterocolitis. The bowel is dusky and appears hemorrhagic and infarcted. Additionally, fibrinous adhesions attach the bowel loops to one another. The bubbly areas are patches of pneumatosis intestinalis. B: Well-formed fibrous adhesions in a patient with previous surgeries.

Other Stenoses

Small intestinal stenosis complicates a wide variety of conditions, including heterotopic pancreas; ischemia; peptic injury; radiation; drug injury, especially nonsteroidal antiinflammatory drugs (NSAIDs); Crohn disease; infections; and trauma.


Erosive duodenitis may develop in patients subjected to severe stress or in those consuming large quantities of alcohol. Acute erosive duodenitis and duodenal ulcers may also develop within a matter of hours in severely burned patients (Fig. 6.72). In these situations, the mucosal barrier breaks down, mediated in part by transient intestinal hypoperfusion and increased intestinal permeability. The duodenum appears diffusely hemorrhagic and reddened, usually in conjunction with similar changes in the stomach (Fig. 6.73). Erosive duodenitis begins as areas of localized interstitial edema (Fig. 6.74). Early enterocyte damage consists of cytoplasmic vacuolization with eventual epithelial loss. Enterocytes contain enlarged, hyperchromatic nuclei with prominent nucleoli, syncytial changes, and cytoplasmic tufting. The villi degenerate, the crypts become hyperplastic, and the epithelial cells become mucin depleted and cuboidal in shape. Neutrophils, lymphocytes, plasma cells, and sometimes eosinophils infiltrate the mucosa and the lamina propria (Fig. 6.75). The stroma may exhibit prominent telangiectasia. These evolve with red cell extravasation and the development of erosions and full-blown ulcers. Often, it is very difficult to distinguish the nonspecific effects of stress duodenitis from those of peptic duodenitis.


Peptic Duodenitis

Peptic duodenitis and peptic duodenal ulcers represent different phases in the response to increased acid secretion often as the result of antral predominant Helicobacter pylori gastritis (121). The incidence of duodenal ulcers also increases in cigarette smokers, patients with chronic renal disease, and alcoholics. Disturbed motility also predisposes to active duodenal ulceration due to prolonged mucosal contact with the acid. Factors associated with refractory ulcers are listed in Table 6.4.

FIG. 6.71 Papillary stenosis and papillitis. A: Low magnification of tissue removed endoscopically as a polyp. It came from the area around the ampulla of Vater. In the upper portion of the photograph, one sees more or less normal duodenal mucosa. The three lower fragments are abnormal. The largest piece (arrow) consists of edematous tissue covered by small intestinal epithelium. In some places, glandular crowding is evident. B: Higher magnification of the edematous, inflamed tissue. C, D: Higher magnifications of the epithelium from these tissue pieces that, if examined in isolation, might be interpreted as representing an area of dysplasia. One might be worried about high grade dysplasia in C due to the tangential cutting of the specimen. Features that suggest dysplasia are the glandular crowding, the nuclear palisading, and the high nuclear:cytoplasmic ratio. The intensity of the associated inflammatory changes and the gradual transition to more mature epithelium indicate that this is a reactive process, not a neoplastic one. D: Glands superficially resembling adenomatous epithelium lining the upper portion of the gland gradually merge with more normal-appearing epithelium.

FIG. 6.72 Curling ulcers in a patient who was caught in a house fire. The arrows mark the gastroduodenal junction. Several large geographic ulcers are present within the duodenum, as evidenced by the dark, irregular, geographic areas. Additionally, smaller punctate ulcers (double arrows) are present. The duodenal mucosa also demonstrates marked hyperemia.

Peptic duodenitis is typically confined to the duodenal bulb. Endoscopic appearances vary from simple erythema to mucosal friability and nodularity. Severe cases exhibit erosions and ulcers.

The principal histologic findings of peptic duodenitis include any or all of the following: (a) inflammatory cells (neutrophils, lymphocytes, plasma cells, and eosinophils) in the epithelium or lamina propria; (b) altered enterocyte morphology due to degeneration, regeneration, or the presence of foveolar metaplasia; (c) mucosal hemorrhage and edema; and (d) Brunner gland hyperplasia (Fig. 6.76). Patients may also develop lymphoid hyperplasia (Fig. 6.77). In the most severe form of duodenitis, the villi appear flat (Fig. 6.77).
The superficial epithelium and the brush border become progressively less distinct, with nuclear pseudostratification, mucosal erosions, and foveolar metaplasia. Neutrophils extend into the crypts and Brunner gland ducts.

FIG. 6.73 Erosive duodenitis. The stomach (S) lies in the upper lefthand portion of the photograph; the arrow indicates the gastroduodenal junction. The first portion of the duodenum appears markedly erythematous, and there are several punctate erosions.

FIG. 6.74 Erosive duodenitis. A: A congested duodenal mucosa shows artifactual denudation of the superficial epithelium. Red cells have extravasated into the lamina propria. There is also focal glandular dropout. B: Higher-power view demonstrating loss of the surface epithelium and neutrophilic infiltration of the lamina propria. The remaining crypts appear regenerative.

FIG. 6.75 Duodenitis. The epithelium appears very reactive and inflamed. There is syncytial formation.

FIG. 6.76 Peptic duodenitis. A: Low magnification showing Brunner gland hyperplasia, erosion and distortion of the overlying epithelium, and a lymphoid aggregate (arrows). B: Higher magnification of the lining epithelium demonstrates eroded foveolar metaplasia. No goblet cells or enterocytes are identified. C: Almost complete replacement of the duodenal villi by gastric surface (foveolar) epithelium. D: Higher magnification of the foveolar epithelium showing various degrees of metaplastic change. Helicobacter pylori is present in the overlying exudate (arrows).


Zollinger-Ellison syndrome

Intestinal wall penetration by the ulcer


Use of nonsteroidal anti-inflammatory drugs

Gastric outlet obstruction or duodenal stenosis

Postsurgical bypassed antrum without vagotomy

The presence of foveolar cell metaplasia (gastric surface epithelial metaplasia) may be focal or extensive (Fig. 6.77). This change probably represents an adaptive response to either duodenal hyperacidity or H. pylori infection (122) and may protect against ulceration because this epithelium has the ability to transport hydrogen ions out of the mucosa back into the GI lumen (see Chapter 4). Helicobacter pylori attached to the foveolar cells then contribute to an acute or chronic active duodenitis and the
development of duodenal peptic ulcer disease (123). The most persuasive argument supporting the dominant role of H. pylori in duodenal ulcer disease is the dramatic healing of the mucosa after successful cure of the infection (124). In patients with H. pylori gastritis, the duodenal IELs may be increased as well, which may prompt consideration of celiac sprue. The IEL density ranges from 3 to 42 per 100 enterocytes with a mean of 18.5. This contrasts with a mean of 6.6 in a control population (125). The increased duodenal IELs occur even when the H. pylori is restricted to the stomach. Treatment of the gastric infection leads to a decrease in IELs (126).

FIG. 6.77 Peptic duodenitis. A: Fully developed metaplastic epithelium above the arrows merges with well-developed small intestinal lining cells containing enterocytes and goblet cells. B: Prominent lymphoid follicle presenting as a polyp.

Brunner gland hyperplasia is common in patients with H. pylori infections and peptic duodenitis. It is characterized by a nodular proliferation of normal-sized or expanded lobules of Brunner glands that extend into the mucosa, accompanied by ducts and fibromuscular stroma. Larger polypoid lesions may become superficially eroded or they may bleed or cause obstruction, requiring endoscopic or surgical removal (127). Exceptionally, areas of dysplasia may develop in the hyperplastic Brunner glands (128).

It should be noted that many of the histologic features of peptic duodenitis are etiologically nonspecific and may also occur in patients with Crohn disease, stress-induced duodenitis, NSAID-induced injury, and certain infections.

Peptic Ulcer Disease

Helicobacter pylori plays a vital role in peptic ulcer development in both the stomach and duodenum. Indeed, H. pylori is found significantly more often in patients with peptic ulcer disease and duodenitis than in patients with normal endoscopic findings. However, while gastric peptic ulcers primarily result from altered mucosal defenses, duodenal ulcers (DUs) result from hyperchlorhydria. A complicated relationship exists between host defense mechanisms and the presence of elevated acid, pepsin levels, and H. pylori (Fig. 6.78). The decline in duodenal ulcer disease in recent decades is likely the result of two factors, the decline in the incidence of H. pylori infections as discussed in Chapter 4 and the widespread use of acid-suppressive therapies.

Peptic duodenitis progresses from erosive peptic duodenitis with superficial mucosal loss to frank peptic DUs. Most duodenal ulcers develop in the first part of the duodenum, usually immediately distal to the pylorus. Peptic ulcers in the second and third portions of the duodenum or jejunum, repeated penetrating or perforating ulcers in the third portion of the duodenum or first portion of the jejunum, or the presence of multiple ulcers (Fig. 6.79) should arouse suspicion of an acid hypersecretory state such as Zollinger-Ellison syndrome. Children with cystic fibrosis are particularly
prone to develop DUs due to decreased duodenal bicarbonate secretion.

FIG. 6.78 The pathogenesis of duodenal ulcer disease is multifactorial and involves host factors as well as environmental factors. Most patients exhibit increased acid secretion, increased parietal cell mass, and increased pepsinogen production. Environmental agents such as steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, or Helicobacter pylori further contribute to the injury by breaking down mucosal defenses.

Patients with DUs experience dyspepsia and intermittent abdominal pain. DUs are more prone to perforate (Fig. 6.79), bleed, or cause obstruction than are gastric ulcers. Bleeding causes massive upper GI hemorrhage in a significant number of cases. Rebleeding, sometimes massive, tends to affect older patients (especially those on NSAIDs) and occurs more commonly in patients with a visible vessel (Fig. 6.79) (129). DUs in children may present in atypical ways. Only about 50% of children experience dyspepsia, approximately 61% have nocturnal pain, abdominal pain occurs in 70%, and bleeding affects about 33% of patients.

Refractory ulcers heal slowly, recur rapidly after initial healing, or follow a prolonged course of exacerbation and short or absent remissions. Scarring leads to deformation of the duodenal bulb and stricture formation. Larger ulcers take longer to heal and recur more often once they have healed.

Grossly, DUs appear circular or oval, usually measuring less than 3.0 cm in maximum diameter (Fig. 6.80). Ulcers located posteriorly in the bulb are more likely to bleed than are those situated elsewhere (130) because two sizable arteries (i.e., the pancreaticoduodenal and the gastroduodenal) lie in the vicinity. Ulcer scarring may lead to the formation of a prestenotic diverticulum. Histologically, DUs exhibit a mixture of active inflammation, granulation tissue, and fibrinous exudate. The surrounding mucosa usually shows evidence of peptic duodenitis, which may be colonized by H. pylori in metaplastic areas.


Ischemic injury to the small bowel forms a continuum of changes secondary to tissue anoxia that range from epithelial cellular dysfunction to frank necrosis (Fig. 6.81). The clinical severity of ischemic enteritis varies widely from silent transient episodes to massive and sometimes fatal hemorrhagic infarctions. Vascular occlusion and periods of hypotension or vasoconstriction account for most cases of intestinal ischemia. The most common clinical scenario is an elderly individual with underlying cardiovascular disease. However, intestinal ischemia may also affect individuals of any age, including infants, in the setting of various vasculopathies, some infections, intussusception and torsion, and certain drug therapies (Table 6.5).

All forms of ischemic damage share the underlying feature that the blood supply fails to meet the local tissue demands required to fulfill normal functions and/or maintain normal structure. Prolonged cessation of blood flow inevitably results in cell death because of the diminished delivery of oxygen and metabolic substrates and the accumulation of potentially cytotoxic end products of anaerobic metabolism. Small intestinal blood supply has to be reduced by greater than 50% to induce detectable tissue injury (131). The extent and duration of the ischemia depends on several factors, including the nature of the intestinal vasculature, luminal bacterial virulence, and the duration of the ischemic episode. The first detectable sign of ischemic injury is increased capillary permeability. With continuing ischemia, detectable epithelial cell injury occurs. Mucosal cells are shed at an increased rate, and damage to the plasma membrane of unshed cells results in leakage of cytoplasmic digestive enzymes and tryptic digestion of the mucosa. Necrosis and subsequent bacterial invasion develop when the mucosal barrier becomes defective. The basic pathologic response to ischemia is mucosal coagulative necrosis. If reflow is reestablished, acute inflammation develops.

FIG. 6.79 Gross appearance of peptic duodenal ulcers. A and B derive from the same specimen dissected at the time of autopsy. The patient had numerous ulcerations involving the stomach, esophagus, and duodenum. The plastic arrow is inserted through a perforating duodenal ulcer. B: Higher magnification of a different ulcer showing the presence of a granular base. The specimen illustrated in (A) and (B) is from a patient with Zollinger-Ellison syndrome. C: Image from a different patient showing the presence of a large visible vessel containing a probe.

FIG. 6.80 Duodenal ulcer. A: An ulcer with typical overhanging margins is seen. It has the same zones as gastric peptic ulcers (see Chapter 4). B: Ulceration extends deep into the duodenal wall. Brunner gland hyperplasia is seen.

No single process represents the critical event in ischemic injury. Depletion of cellular energy stores and accumulation of toxic metabolites both contribute to cell death. Reestablishing the blood flow (reperfusion) is required to reverse the injury because it allows cellular regeneration and washout of toxic metabolites. However, reperfusion of ischemic tissues also paradoxically injures the tissues (Fig. 6.82) (183). In fact, most of the injury that occurs in intestinal ischemia occurs during the reperfusion period due to the production of reactive oxygen metabolites, including O2, H2O2, OH, HOCl, and certain n-chloramines, by activated neutrophils and other inflammatory cells, as a result of the reintroduction of oxygen (132). Superoxide and hydrogen peroxide increase mucosal and vascular permeability, recruit
and activate neutrophils, and act as the precursors of more damaging hydroxyl radicals via the Fenton and myeloperoxidase reactions (Fig. 6.82) (133).

FIG. 6.81 Intestinal ischemia. Intestinal ischemia develops when insufficient arterial blood reaches the intestinal mucosa through the presence of a thrombus, an embolus, an atheromatous plaque, a vascular spasm, low-flow states, or obstruction of venous outflow. As a result, oxidative metabolism becomes impaired, leading to decreased adenosine triphosphate (ATP), increased glycolysis, acidosis, and changes in nuclear chromatin, as well as in other cellular organelles. The decreased ATP also leads to decreased functioning of the sodium-potassium pump with an influx of calcium ions and water and an efflux of potassium. As a result, the cells swell, as do intracellular organelles. As the organelles become damaged, ribosomes decrease and protein synthesis decreases, interfering with reparative processes.


Acute vascular occlusion

Arterial or venous thrombosis


Low-flow states (low cardiac output, hypotension/shock)






Necrotizing enterocolitis

Vasculitides and vasculopathies

Hypercoagulable states


Oral contraceptives


Digitalis and vasopressors

Potassium chloride

Vascular compression



Celiac axis compression


Collagen vascular diseases

Radiation damage

Diabetes mellitus

The hypoxia induces endothelial cells to produce various adhesion molecules, including integrins and selectins, which promote the adherence, transendothelial migration, and activation of leukocytes and platelets.

Acute mesenteric infarctions result from mesenteric arterial occlusion (Fig. 6.83), nonocclusive low-flow states, mesenteric vein thrombosis (Fig. 6.84), or vasculitis.

Ischemia in Low-Flow States (Nonocclusive Ischemia)

Low-flow states usually result from decreased cardiac output secondary to primary cardiac disease (infarction or arrhythmia), hypovolemia, shock, vascular shunting, or a combination of low mesenteric flow and mesenteric arterial vasoconstriction. A substrate of atherosclerotic vascular disease is frequently present. Patients with end-stage renal disease who undergo dialysis are at increased risk for nonocclusive ischemia due to the combined presence of hypertension, severe underlying heart disease, and the frequent removal of large volumes of fluid during ultrafiltration dialysis. Even though the blood supply to the superficial mucosa is fairly well maintained during shock, hypoxic injury still develops within 1 to 2 hours and is first seen at the villous tips (Fig. 6.85). Several pathogenic mechanisms account for the ischemic necrosis including vasoconstriction, redistribution of the blood flow away from the mucosa, and intestinal countercurrent mechanisms contribute to decreased perfusion of the villi (Fig. 6.86).

Arterial Occlusive Disease

Arterial occlusive disease occurs secondary to mesenteric artery thrombosis and embolization (Figs. 6.87 and 6.88) with about equal frequency. Thrombi almost invariably overlie atheromatous plaques occupying the proximal few centimeters of the vessel. In contrast, emboli lodge at bifurcation points or in a distal branch. Ischemia also complicates numerous other conditions that ultimately obliterate the intestinal vascular supply (Table 6.5). Atheromatous occlusion progresses slowly enough for collateral circulation to develop, and as a result, patients often have severe disease involving all the mesenteric arteries before they become symptomatic. Accordingly, intestinal infarction secondary to atheromatous occlusion of a single vessel is rare (134). The disease is likely to be most severe in patients with diabetes. The superior mesenteric artery is affected more commonly than is the inferior mesenteric artery. The most severe atherosclerotic lesions affect the proximal 2 cm of the superior and inferior mesenteric arteries.

Massive, acute, and often fatal embolism usually results from migration of an intracardiac mural thrombus complicating heart disease. Cholesterol emboli migrate from aortic plaques, especially following catheterization, resulting in localized or widespread intra-abdominal ischemia. Valvular endocarditis may shed small mycotic emboli.

Sudden occlusion of the superior mesenteric artery produces hemorrhagic infarction in the area supplied by the occluded vessel (as modified by the presence of a collateral blood supply). There is typically a sharp dividing line between the normal and hyperemic ischemic parts of the bowel (Fig. 6.89).

The most common clinical manifestation of bowel ischemia is the abrupt onset of poorly localized colicky abdominal pain that becomes constant and unremitting as the disease progresses. The pain starts and stops abruptly and results from spasm of the muscularis propria. Diarrhea develops and stools become overtly bloody. As the ischemic muscle loses its contractile functions, much of the colicky pain ceases, and the symptoms evolve into abdominal tenderness, positive rebound signs, and evidence of peripheral circulatory collapse. As the ischemia persists and infarction develops, the patients often develop an elevated white blood count, fever, abdominal distension, and signs of peritonitis. At this stage, the bowel is usually beyond recovery and requires surgical resection.

Mesenteric Venous Thrombosis

Mesenteric venous thrombosis is a relatively uncommon cause of mesenteric ischemia, primarily affecting the elderly in their sixth and seventh decades of life (135) (Fig. 6.90). Multiple etiologic factors, including a hypercoagulable state,
venous injury, and venous stasis, may contribute to thrombosis and may coexist in an individual patient. Twenty-five to fifty percent of cases have no predisposing cause; these are classified as primary venous thrombosis. Regardless of the cause of the thrombosis, egress of blood from the intestine becomes impaired, causing the mesenteric venous pressure to rise and arterial blood flow to slow, leading to the development of ischemia.

FIG. 6.82 During ischemia, cellular adenosine triphosphate (ATP) is converted to adenosine monophosphate and further catabolized to hypoxanthine, which serves as an oxidizable substrate for xanthine oxidase. The enzyme xanthine oxidase (XO) is the rate-limiting enzyme in nucleic acid degradation. XO generates H2O2 and O2- during the oxidation of hypoxanthine or xanthine. Free radicals are also generated via the Fenton reaction, especially during cell reperfusion. The free radicals recruit polymorphonuclear leukocytes (PMNs) to the reperfused area. The neutrophils adhere to the endothelial cells secondary to increased transcription of integrins and adhesion molecules on both neutrophils and endothelial cells. Free radicals also diffuse into the local tissues, causing abnormalities in the enterocytes with lipid peroxidation of membranes and damage to DNA, RNA, and proteins, and alterations in cellular transport mechanisms.

FIG. 6.83 Thrombosed superior mesenteric artery. The arrowhead points to the orifice of the superior mesenteric artery as it exits the aorta.

Approximately 95% of all mesenteric thromboses involve the superior mesenteric vein and lead to ischemia or infarction of the small bowel or proximal colon. In a small number of cases, the thrombosis develops over an extended period, permitting the development of collateral venous drainage from the involved intestinal segments. Depending on the cause, mesenteric venous thrombosis may begin in the portal vein and extend back into the mesenteric vein and its branches, or it may begin in smaller peripheral mesenteric
venous branches and proceed up into the portal vein. Propagating portal vein thrombosis causes portal hypertension. Predisposed patients may also develop Budd-Chiari syndrome.

FIG. 6.84 Intestinal infarction secondary to portal vein thrombosis. A: Gross photograph of the junction of the infarcted intestinal segment with normal mucosa. There is a sharp line of demarcation between the infarcted tissue (black tissue on the left) and the viable, noninfarcted tissue on the right. B: Dissection through the peri-intestinal fat showing a branch of the portal venous system, which has been opened and contains a long thrombus (arrows).

Patients with ischemia secondary to mesenteric venous thrombosis usually present with nonspecific signs and symptoms. The clinical presentation is characterized by gradually increasing colicky abdominal pain over a period of days or weeks. With increased blockage of the collaterals by new thromboses, the patient develops nausea and vomiting, an acute abdomen, and rectal bleeding. At this time, surgical intervention is required.

FIG. 6.85 Early ischemia demonstrating marked capillary congestion and loss of epithelium from the villous tips. One of these denuded villus tips is indicated by the star. Taken in isolation, the changes may resemble those seen in autolysis. No reperfusion has occurred and therefore acute inflammatory cells are absent.

The diagnosis of mesenteric venous thrombosis is usually made during laparotomy for an acute abdomen.

FIG. 6.86 Diagram of countercurrent mechanism demonstrating shunting that occurs at the villous base. It diverts oxygen from the villous tips to the base of the crypts during anoxic periods.

FIG. 6.87 Histologic section through the portal vein showing the presence of an organized thrombus.

Mechanical Obstruction of Venous Return

Venous return may become impeded when the bowel undergoes torsion, volvulus, or intussusception or when it is part of a strangulated hernia. External compression of the vasculature causes obstruction of the relatively thin-walled and low-pressure venous system without affecting arterial blood flow. As a result, the bowel becomes congested with blood, hemorrhagic, and edematous. Ischemic necrosis then develops rapidly. The histologic features resemble those of mesenteric venous thrombosis, except that thrombi are absent.

FIG. 6.88 Atheromatous emboli. A: Cross section through the superior mesenteric artery demonstrating the presence of a large atheromatous embolus. B: Emboli extend into the smaller vessels just beneath the muscularis mucosae (arrows).

Gross Features of Ischemic Injury

Ischemia characteristically appears segmental in nature. Early on, the ischemic bowel is edematous and pale with submucosal congestion, hemorrhage, and focal mucosal sloughing (Fig. 6.91). The mucosa appears necrotic, nodular, and ulcerated. Extensive submucosal hemorrhage may be present. In early lesions, only the mucosa and sometimes the submucosa are affected; the muscularis propria usually remains normal. As the necrosis progresses, all of the bowel wall layers become damaged and the serosa becomes dusky and purple or dark red, the intestinal wall thins and becomes friable, and membranous exudates form. Perforation may develop. Patients with chronic damage may have mural fibrosis and strictures. In cases of mesenteric venous thrombosis, the serosal and mucosal surfaces appear mottled, hemorrhagic, and discolored with fibrinous exudates deposited on them. The affected bowel appears thinned in areas of transmural hemorrhagic infarction. Adjacent areas show patchy ischemia. The mesentery usually appears thickened, hemorrhagic, and edematous, and it contains numerous cordlike thrombosed veins. The arteries usually appear normal.

Histologic Features of Ischemic Injury

The histologic features of ischemia depend on the severity and duration of the perfusion defect, and on whether reperfusion has occurred. Accordingly, the lesions range from patchy congestion and ulceration to extensive infarction, gangrene, and perforation.

Most pathologists encounter small intestinal ischemia when they examine large resected segments of necrotic
bowel. In this situation, it is easy to diagnose the ischemia. Diagnostic difficulties only occur when one encounters early lesions or when complications develop. Biopsies to establish a diagnosis of ischemia or to rule out other etiologies of enterocolitis are much less common than are colonic biopsies for the same purposes. Therefore, the biopsy features of intestinal ischemia are also discussed in Chapter 13.

FIG. 6.89 Small bowel ischemia. A: Hyperemic infarcted areas with adjacent friable pink-tan mucosa. B: Area of infarction with gradual hyperemia of adjacent lesser involved mucosa.

Because the mucosa is the layer of the intestinal wall most sensitive to hypoperfusion, it is damaged first (Fig. 6.92). Early epithelial damage results from loss of energy-dependent processes, causing intercellular edema and epithelial detachment. Membrane-enclosed cytoplasmic blebs develop on the basal side of the enterocytes where they attach to the basement membrane. This begins the epithelial detachment process. This process starts before the enterocytes display signs of irreversible damage. The process advances from the villous tips to the crypt bases. With more severe or more prolonged ischemia, or both, the epithelium lining the sides of the villi lifts off the basement membrane until the epithelial cells are lost completely (Fig. 6.93). Then, the villous core disintegrates. The crypt cells often remain intact with little histologic evidence of damage. Later, the crypt epithelial cells become markedly attenuated, and the crypts appear compressed and atrophic as the lamina propria swells and hemorrhages. Occasionally, degenerating sloughed goblet cells in ischemic partially viable mucosa may resemble signet ring cells (136). They typically lie within the crypt lumens along with inflammatory debris, in continuity with dying cells in the crypt.

In mesenteric venous thrombosis, recent, organizing, and partially recanalized thrombi are observable in the mesenteric venous vasculature, and the bowel wall shows intramural hemorrhage and variable degrees of edema and ischemic necrosis with ulceration and acute inflammation.

In cases of total occlusion, the capillaries appear congested with red cell extravasation and coagulation necrosis unaccompanied by acute inflammation. The presence of fibrin thrombi in mucosal capillaries serves as a useful diagnostic feature of ischemia (Fig. 6.94), but it only becomes evident once epithelial breakdown occurs. In cases of more prolonged injury (4 to 6 hours), the ischemic process extends into the submucosa and muscularis propria and serosa (Fig. 6.95), producing infarction and necrosis and potentially perforation.

If partial blood flow is maintained, then the effects of the reperfusion are superimposed on the ischemic damage. Early stromal changes consist of edema of the lamina propria, often associated with hemorrhage and emigration of neutrophils through the epithelial surface, especially at the villous tips. There is often prominent telangiectasia. A pseudomembrane composed of necrotic epithelium, fibrin, and inflammatory cells develops (Fig. 6.95).

It is unusual for the etiology of the ischemic damage to be evident from an intestinal resection or biopsy specimen, unless one finds evidence of vasculitis or thrombi. It is important to make a distinction between the damaged vessels that result from ischemia and ulceration and primary vascular disease. In trying to make this distinction, one must examine those parts of the intestine that are not ulcerated or show only minimal signs of ischemic damage to establish whether underlying vascular disease or another change is present.

Recovery from Ischemic Damage

Even when the villi are extremely damaged, healing begins quite rapidly if the tissues become adequately reoxygenated (137). If the ischemia only affects a small segment, collateral circulation may allow healing to begin even as the infarction is proceeding at a smaller focus, resulting in regenerative changes superimposed on degenerative ones. Recovery takes place in several phases. In the first phase, a new epithelial layer regenerates from the crypts and the lower third of the villi (Fig. 6.96). The cells proliferate and migrate upward to cover whatever residual villous core remains. If the villous cores are completely destroyed, the mucosa will become simplified, resembling colonic tissue, or even appear as an area completely lacking crypts. After 12 hours, a flat epithelium is present, but by 24 hours,

the epithelium and cells appear cuboidal or columnar and incipient development of small intestinal villi is apparent. After 8 days, the regenerated small intestinal mucosa shows a variably normal morphology, depending on the extent of the original injury and architectural loss. Areas that are recovering from severe injury and infarction may develop mural fibrosis, the extent of which matches the scope of prior ischemic damage.

FIG. 6.90 Portal vein thrombosis in a patient with protein S deficiency. The histologic features derive from the specimen illustrated in Figure 6.84. A: The patient developed ischemia with reperfusion injury. There is glandular dropout, loss of villous epithelium, villous congestion, and inflammation. B: Higher magnification of the submucosa showing the presence of a congested and a thrombosed (star) submucosal vein. C: Higher magnification of one of the vessels showing the lines of Zahn in the thrombus. D: The mesenteric fat contains numerous thrombosed branches of the portal vascular system.

FIG. 6.91 Gross features of intestinal ischemia. A: Unopened specimen with a perforation (arrow). B: Opened specimen showing a localized area of ischemia (arrow).

FIG. 6.92 Ischemic enteritis. A: Medium magnification showing loss of superficial epithelial lining from the villi. Large numbers of the crypts are identifiable only by residual cells at the base of the glands. B: Higher magnification of the superficial area showing edema, vascular congestion, and degeneration and sloughing of the epithelium from the tips (arrow).

Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) affects all age groups, ranging from premature neonates to the very elderly. The causes are poorly understood, although ischemia is felt to be a contributing factor. However, vascular occlusion is not usually demonstrable. Complications include bacterial infection and disseminated intravascular coagulation secondary to the presence of bacterial toxins.

Neonatal Necrotizing Enterocolitis

Neonatal NEC is a devastating disease with a rapid onset that affects approximately 10% of premature low birth weight (<1,500 g) infants (138). Fifty percent of cases are fatal. Surviving babies suffer from short bowel syndrome and/or malabsorption later in life. Stricture formation occurs as early as 5 weeks after the acute episode in infants who survive. Four major factors appear to contribute to the pathogenesis
of neonatal NEC, (a) prematurity, which results in immaturity of the intestinal mucosa; (b) establishment of enteral feeding; (c) intestinal mucosal ischemia, often secondary to reduced placental blood flow or postnatal hypoperfusion of the intestine; and (d) the presence of altered lumenal bacterial flora (Fig. 6.98).

FIG. 6.95 Acute ischemia. A: Early hemorrhagic necrosis of the tips of the folds is seen. The epithelium is extensively denuded. B: Extensive hemorrhagic infarction of the tip of the folds. The entire mucosal structure is completely infarcted. A pseudomembrane covers the surface of the bowel. The submucosal structures are edematous and hemorrhagic. C: Marked necrosis is seen in the small bowel. The mucosa appears hemorrhagic and telangiectatic. An organizing thrombus is seen in the underlying blood vessel. D: Severe extensive transmural infarction of the small bowel.

The neonatal intestine has a limited capacity to maintain oxygen uptake during periods of reduced perfusion pressure and arterial hypoxia, especially during feeding (198). Additionally, the enzymatic composition of the immature neonatal intestine does not allow complete digestion of fats, carbohydrates, and casein, leaving a large amount of protein in the intestinal lumen in the form of curd. This favors intestinal bacterial growth, particularly those organisms that produce potent toxins. Mucosal injury permits proteins and bacterial toxins to pass into the portal circulation and then into the liver, injuring hepatocytes and Kupffer cells. If liver function becomes sufficiently impaired, endotoxin enters the systemic circulation, causing shock. Gram-negative bacterial colonization also occurs, further intensifying the circulatory insufficiency and the shock. The terminal ileum and right colon are preferentially affected.

FIG. 6.96 Early regenerative changes following ischemic damage. The villi have become completely denuded. The crypts are lined by hyperchromatic cells that are beginning to proliferate and replace the previously destroyed epithelium.

The gross findings of neonatal NEC may be dramatic, with the affected bowel segments appearing dilated, necrotic, hemorrhagic, friable, and gangrenous (Fig. 6.99). The external surface shows shaggy serosal exudates and adhesions between adjacent loops of bowel. Because the injury is ischemic in nature, the changes are either diffuse or focal. Pneumatosis intestinalis may be present (Figs. 6.99 and 6.100).

FIG. 6.97 Ischemic stricture.

Tropical Necrotizing Enterocolitis

Tropical NEC affects patients of all ages in tropical and subtropical areas. Dietary factors and infections appear to contribute to its pathogenesis. Ischemia is always the initial insult. Pigbel, seen in Papua, New Guinea (Fig. 6.100), represents an example of this group of lesions. This entity is described further in a later section.

Celiac Axis Compression Syndrome

Celiac axis compression syndrome (mesenteric vessel compression) results in abdominal pain, vascular narrowing, and ischemia. It results from mesenteric vessel compression secondary to a variety of causes (Table 6.6). The intestines develop typical ischemic injury. If the inury results from a neoplasm compressing the vasculature, the tumors may also extend into the bowel wall.

FIG. 6.98 Pathogenesis of neonatal enterocolitis. Multiple factors play a role in the etiology of this pediatric disorder. Common to most cases is a period of hypoxia leading to ischemia. Coexisting hypovolemia leads to low-flow states and complicates the underlying anoxia. Umbilical vein catheterization may cause localized vasospasm and further compromise luminal flow. At the same time as anoxic injury is progressing, the small intestinal epithelium loses its normal barrier function and bacteria that are present gain access to the underlying tissues, leading to sepsis and shock.

FIG. 6.99 Necrotizing enterocolitis. A: Resection specimen from a child with severe necrotizing enterocolitis. The bowel is dusky in many areas, representing areas of hemorrhagic infarction. In addition, multiple areas of transmural gangrene with pseudomembrane formation are represented by the multifocal whitish areas. B: Pneumatosis intestinalis is present in area of stricture. C: Higherpower magnification demonstrates the bubbly quality of the mucosal surface representing entrapped air within the bowel wall.

FIG. 6.100 Necrotizing enterocolitis. A: The mucosa has regenerated. The villi are markedly shortened. The crypts are hyperplastic with a regenerative appearance. Some residual pseudomembranes are seen dissolving in the bowel lumen. Gas-filled cysts are present in the submucosa and correspond to pneumatosis intestinalis. B: Pigbel showing the patchy segmental involvement as seen from the serosal surface. C: Pigbel. Cross section of the bowel wall demonstrating submucosal edema. Brownish green spots coalesce to form larger area of necrosis. (B and C courtesy of Robin Cooke, M.D., Department of Pathology, Royal Brisbane Hospital, Brisbane, Australia.)


Retroperitoneal hematoma

Retroperitoneal fibrosis

Retroperitoneal tumors

Enlarged mesenteric lymph nodes

Metastatic carcinoma


Infectious processes

Intestinal Ischemia Secondary to Atheromatous Embolization

Cholesterol emboli arising from complicated atheromatous plaques in the aorta of patients undergoing abdominal aortic catheterization. Patients present with abdominal pain and melena secondary to intestinal ischemia. Because the entire abdominal arterial circulation is potentially affected, involvement of the spleen, kidneys, and adrenals is not uncommon. Affected vessels are initially plugged by atheromatous emboli, cholesterol crystals, or amorphous debris. This elicits a foreign body giant cell reaction followed by concentric intimal fibrosis, luminal reduction, and variable degrees of recanalization (Fig. 6.101). Because the emboli most commonly lodge in small vessels, it is rare for full-thickness infarction to develop due to the presence of collateral circulation. Patients with healed disease develop strictures.

FIG. 6.101 Ischemia due to atheromatous emboli. A: A portion of ischemic small intestine with focal complete loss of the epithelium (arrows). The vessels are extremely dilated. One vessel contains an embolus with slitlike spaces corresponding to cholesterol emboli (arrow). B: Higher magnification of the cholesterol clefts in the emboli in a medium-sized vessel.

Intestinal Ischemia Secondary to Vasculitis

Vascular inflammation (vasculitis) is a feature of many systemic rheumatologic disorders and may result in ischemic enteritis and infarction. Either the small or large intestine may be involved. Vasculitides are often classified based on the size of the vessels that are involved as shown in Table 6.7. The intestines are also affected by other forms of vasculitis, including Henoch-Schönlein disease, Wegener granulomatosis, and Churg-Strauss disorder. Venous disease leading to ischemia not caused by primary thrombotic processes may occur in systemic lupus erythematosus (139), Behçet disease (140), enterocolic lymphocytic phlebitis (ELP) (141), and idiopathic myointimal hyperplasia of mesenteric veins (142).

Polyarteritis Nodosa

Larger vessel disease is exemplified by polyarteritis nodosa, and intestinal symptoms (affecting 25% to 79% of patients) are secondary to involvement of the small- to medium-sized mesenteric arterial branches. Males are afflicted four times more often than women, most commonly between the ages of 20 and 40. Patients often have other autoimmune diseases, with rheumatoid arthritis and systemic lupus erythematosus being the most common. However, approximately 30% to 35% of patients with PAN exhibit only GI manifestations. Symptoms attributable to intestinal involvement include
abdominal pain, diarrhea, positive fecal occult blood, nausea, vomiting, and hematemesis (143). Ulceration, perforation, strictures, and intussusception may all occur (144). Deposition of immune complexes in the blood vessels leads to fibrinoid necrosis and the development of microaneurysms and vascular stenosis.


Affecting large vessels

Takayasu arteritisa

Giant cell arteritisa

Polyarteritis rheumaticaa

Predominantly affecting large and medium-sized vessels

Crohn disease

Predominantly affecting small and medium-sized blood vessels

Radiation damage

Polyarteritis nodosa

Kawasaki diseasea

Arterial fibromuscular dysplasia of childhood

Buerger disease

Fungal vasculitis

Danlos-Ehlers syndrome

Predominantly affecting small-sized vessels, ANCA associated

Wegener granulomatosis

Churg-Strauss syndrome

Microscopic polyangiitis

Predominantly affecting small vessels

Henoch-Schönlein syndrome

Behçet syndrome

Hypersensitivity vasculitis

Thromboangiitis obliteransa

Leukocytoclastic vasculitis

Systemic lupus erythematosus

Rheumatoid arthritis

Hypocomplementemic vasculitis

Cytomegalovirus vasculitis

Rickettsial vasculitis


Predominantly affecting veins and venules

Mesenteric inflammatory venoocclusive disease

Diffuse hemorrhagic gastroenteropathy

a Very rarely affects the gastrointestinal tract ANCA, antineutrophil cytoplasmic antibody.

A resection specimen often shows patchy necrosis, welldemarcated mucosal ulcers along the antimesenteric border, strictures, and possibly perforation. The major histologic findings usually remain confined to the smaller mesenteric arteries as well as small and medium-sized submucosal arteries. Vascular edema occurs first, followed by acute inflammation of all layers of the vessel walls (Fig. 6.102). Fibrinoid necrosis of the media and elastic intima occurs later, causing stretching and fragmentation. This predisposes the abnormal vessel to undergo thrombosis and luminal narrowing. Elastic tissue destruction results in aneurysmal dilation or rupture. The whole circumference of the artery may be involved, but more often the involvement is eccentric or segmental in nature. Elastic tissue stains demonstrate disruption and dissolution of the elastic fibers. Lymphocytes, histiocytes, polymorphonuclear cells, and eosinophils infiltrate the intestinal wall in response to the vasculitis. Giant cells are absent.

FIG. 6.102 Polyarteritis nodosa. The vessels are inflamed.

Henoch-Schönlein Purpura

Henoch-Schönlein purpura (HSP) is a multiorgan disorder characterized by a symmetric, nontraumatic, nonthrombotic, painless purpuric rash largely involving the skin of the legs and buttocks with arthritis, nephritis, hematuria, and GI injury (145). The disorder is primarily a pediatric disease characterized by IgA immune complex deposition beneath the vascular basement membranes. Antigenic stimulation may result from respiratory tract infections, insect stings, immunizations, and drugs. The gut is involved in up to 85% of patients. Patients may initially manifest isolated GI disease, but subsequently other organs become involved. Any bowel segment may be involved but the jejunum and ileum are most frequently affected. Patients present with acute abdominal symptoms, including pain and GI bleeding.

Grossly, the bowel exhibits small, superficial infarcts with diffuse edema, mottling, congestion, and hemorrhage. A white purulent exudate covers an erythematous mucosa (146). Erosions and ulcers may be present. Several ischemic areas of varying ages may be present. Transmural infarctions and perforations are rare. The mesentery may appear focally congested.

Histologically, there is vascular congestion, hemorrhage, and necrosis (Fig. 6.103). The necrotizing small vessel vasculitis predominantly affects capillary venules in the mucosa
and upper submucosa, sparing larger mesenteric vessels. The venules of involved portions of the bowel demonstrate an acute leukocytoclastic vasculitis, fibrinoid necrosis of the vascular walls, and neutrophilic infiltrates in surrounding tissues (Fig. 6.104). The demonstration of IgA deposits in the vascular walls by immunofluorescence is diagnostic.

FIG. 6.103 Henoch-Schönlein purpura. A: A leukocytoclastic vasculitis is seen in a submucosal vessel. B: Low-power photograph demonstrating the presence of mucosa on the right side of the photograph and distorted, penetrating vessels with fibrosis and inflammation. C: Higher magnification of the penetrating vessel.

Hypersensitivity Vasculitis

Hypersensitivity vasculitis is one of the most common types of vasculitis and represents an allergic response to a precipitating antigen such as a drug, vaccine, microorganism, or foreign protein (147). Immune complexes deposit in the walls of small vessels, activating the complement cascade. Biopsies usually show ischemia, fragmentation of white cells (leukocytoclasis), and fibrinoid necrosis of the walls of the small blood vessels. Specific involvement of small vessels in contrast to medium-sized muscular arteries distinguishes hypersensitivity vasculitis from polyarteritis nodosa.

Wegener Granulomatosis

Wegener granulomatosis is characterized by a granulomatous vasculitis involving small or medium-sized arteries and veins. The disease, which affects males and females equally, classically involves the upper and lower respiratory tracts and the kidney, but it may affect any organ system, although GI tract involvement is relatively uncommon compared to other vasculitides. Persistent inflammatory sinonasal disease coexisting with systemic fevers, malaise, and migratory arthritis typifies the clinical presentation. The granulomatous inflammation consists of palisading epithelioid histiocytes arranged around necrotic foci (148). Multinucleated giant cells constitute a prominent feature of the vascular inflammatory infiltrate. Antineutrophilic cytoplasmic antibodies (c-ANCAs) are diagnostic, especially in patients with concomitant renal disease.

FIG. 6.104 Henoch-Schönlein purpura. Vessel demonstrating fibrinoid necrosis.

Rheumatoid Arthritis and Other Collagen Vascular Diseases

Patients with vasculitis secondary to rheumatoid arthritis (RA) usually have severe arthritis, rheumatoid nodules, and high titers of rheumatoid factor. They usually display signs of cutaneous vasculitis. RA may also manifest as polyneuropathy, cutaneous vasculitis with ulceration, and digital gangrene. In severe cases, the vasculitis affects virtually any organ. GI tract involvement, affecting the mesenteric or intramural vessels (Fig. 6.105), is uncommon (˜10% of patients) but potentially catastrophic when it occurs. Occasionally, RA patients also have proliferative endarteritis characterized by intimal proliferation without vascular wall necrosis or inflammation. GI bleeding, intraperitoneal bleeding, ischemic mucosal ulceration, small and large bowel infarction, bowel perforation, and pancolitis have all been reported. Patients may also develop complications from their NSAID or gold therapy.

Arteritis and venulitis in systemic lupus erythematosus may result in massive lower intestinal hemorrhage, potentially complicated by infarction. Histologic examination shows mucosal ulceration with necrotizing vasculitis with fibrinoid necrosis.

FIG. 6.105 Vasculitis in rheumatoid arthritis. A and B come from the same resection specimen that was removed for ischemic enterocolitis. A: Cross section through a small arteriole demonstrating the presence of prominent, predominantly concentric perivascular inflammation with a necrotizing vasculitis. Prominent fibrin deposition is present within the lumen. Desquamating cells are seen. B: Another vessel with an endoluminal proliferation and occlusion by proliferating reactive cells. Inflammatory cells surround the bottom portion of the photograph.

Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome is an autosomal dominant disorder resulting from a deficiency in type III collagen, affecting the cardiovascular, gastrointestinal, and respiratory systems. GI vascular involvement presents with intramural hemorrhage, massive bleeding, ischemic necrosis, and perforation (149). The cardinal histologic features include arterial dilation with aneurysm formation and aneurysmal rupture of medium-sized and smaller muscular arteries, including those in the mesentery. The affected arterial media displays disorderly and loose collagen fibers, acid mucopolysaccharide deposition, and hemorrhage. Muscular and collagen fiber abnormalities also lead to disintegration of the muscularis mucosae, which becomes practically unrecognizable, especially in the small intestine, and diverticula may develop.

Segmental Mediolytic Arteriopathy

GI segmental mediolytic arteriopathy (SMA) is a rare noninflammatory disorder affecting the abdominal muscular arteries and arterioles in the serosa and bowel wall of elderly patients. It can present with hemoperitoneum and is
often fatal. It may mimic vasculitic syndromes such as PAN radiologically. The etiology is unknown, though a relationship to fibromuscular dysplasia has been proposed (150). Histologically, SMA is characterized by transformation of the arterial smooth muscle cytoplasmic contents into a maze of dilated vacuoles containing edema fluid with disruption of the medial smooth muscle, fibrin deposits and hemorrhage at the adventitial-medial junction, and microaneurysm formation. Inflammation is inconstant and limited to the periadventitial tissues, distinguishing this disorder from a true vasculitis.

Enterocolic Lymphocytic Phlebitis

ELP is an uncommon inflammatory disorder affecting the small or large intestinal veins that causes ischemia and often requires surgical intervention. The patients are typically elderly (median age 63 years) and present with acute abdominal pain, nausea and vomiting, diarrhea, or rectal bleeding (151). The etiology is unknown, though a subset have been associated with cardiovascular disease, medication use and systemic IgG4 disease (152). Patients often recover following surgery, suggesting that the process is self-limited or indolent in nature. The disorder selectively affects veins and venules in the submucosa, subserosa, and peri-intestinal tissues. Arteries and arterioles remain completely unaffected. The phlebitis exhibits various histologic stages of progression. Some veins have lymphocytic infiltrates in their walls without luminal compromise; others have intense transmural lymphocytic infiltrates accompanied by subintimal, focally occlusive fibroproliferative lesions and intraluminal thrombi (Fig. 6.106). Some veins recanalize or develop myointimal hyperplasia. Sparse neutrophilic or eosinophilic infiltrates, necrosis, or granulomas may accompany the lymphocytes. The differential diagnosis of ELP includes a drug-induced hypersensitivity reaction, vasculitis affecting small veins as seen in systemic lupus erythematosus and Behçet disease, though the clinical scenario should help to distinguish these possibilities, and ELP lacks the characteristic clinical scenario, serologic findings, and histologic necrosis and leukocytoclasis of the latter.

FIG. 6.106 Lymphocytic venulitis. A: Low magnification showing the mucosa to the right and a prominent submucosal vessel with intense basophilia due to mononuclear cell infiltration. B: Higher magnification showing complete obliteration of the vascular wall by a mixed mononuclear cell infiltrate.

Cryptogenic Multifocal Ulcerating and Stenosing Enteritis

Cryptogenic multifocal ulcerating stenosis enteritis (CMUSE) is a very rare ulcerating and stricturing disorder of the intestines (153). Its pathogenesis is poorly understood, although deletion mutations in cytosolic phospholipase A2-&agr; have been identified in two individuals (154). Patients experience anemia, weight loss, and partial bowel obstruction. Characteristic intestinal lesions include variable areas of stenosis in the jejunum or proximal ileum, and sharply demarcated superficial (mucosal and submucosal) ulcers. The remainder of the small intestine appears normal. Some cases exhibit vascular wall degeneration with fibrous obliteration,
though true vasculitis is not present. Patients who undergo surgical resection may experience a complete recovery. However, many patients require steroid therapy. CMUSE can be distinguished from Crohn disease by the absence of transmural inflammation, granulomas, and extraintestinal manifestations of IBD. Other considerations include NSAIDrelated strictures, infection, and malignancies, which can be excluded by clinical correlation and examination of resection specimens.

Thromboangiitis Obliterans

Thromboangiitis obliterans (Buerger disease) is a thrombotic disorder of small and medium-sized arteries and veins of the upper and lower extremities. GI vascular lesions affect the smaller submucosal and serosal vessels of either the small intestine or colon. Most patients are males with a history of smoking who present with progressive peripheral arteriolar disease and migratory thrombophlebitis. Buerger disease has a worldwide distribution, but it is more prevalent in the Middle East and Far East than in North America or Western Europe (155). Larger mesenteric vascular involvement, although less common, can cause low-grade intestinal ischemia with clinical presentation ranging from crampy abdominal pain to acute abdominal emergency secondary to bowel infarction (156).

During the acute phase of disease, the thrombosis is accompanied by angiitis and microabscesses within the thrombus, with relative sparing of the vessel wall. GI lesions demonstrate endothelial cell proliferation, concentric vascular intimal thickening, mild fibrosis, or transmural inflammation (Fig. 6.107). Subacute lesions appear less distinctive than the acute ones, and end-stage lesions may be difficult to distinguish from old organized thrombi. There may be mild perivascular inflammation. The internal elastic lamina is intact (distinguishing the lesion from other forms of vasculitis), and it and the media lack atheromas or calcification. Patients may have superimposed areas of acute and/or chronic ischemia. The absence of medial necrosis and the involvement of medium-sized vessels distinguish these lesions from those seen in polyarteritis nodosa.

FIG. 6.107 Buerger disease. A through C show portions of a medium-sized vessel from a small intestinal resection in a patient with Buerger disease. A: Complete obliteration of the lumen by loose, edematous tissue. B: Cross section through another vessel demonstrating almost complete occlusion (van Gieson stain). It shows reduplication of the internal elastic membrane. The material within the vascular lumen represents an area of recanalizing thrombus. Several dilated vascular structures are seen (arrows). C: Higher magnification of the material within the central portion of the vessel shown in A demonstrating the presence of a loose reparative tissue containing numerous proliferating capillaries.

Vascular Diseases Caused by Infections

Several infections involve the GI vasculature, damaging the vessel walls and inducing secondary ischemia. Fungi and cytomegalovirus (CMV) are the most frequent offenders. Debilitated patients with Aspergillosis and Candidiasis may develop fungal vascular invasion and mycotic aneurysms. The fungi completely occlude the vascular lumens, becoming coated with platelets and fibrin, and eventually the vessels thrombose. The intravascular fungi induce an inflammatory response that leads to secondary damage of the vascular wall and extravasation of red blood cells and vasculitis.

CMV is notorious for its ability to infect endothelial cells, causing endothelialitis and predisposing the vessels to thrombosis (Fig. 6.108). A granulomatous lesion characterized by histiocytic collections without giant cells may surround the vascular wall (Fig. 6.109). Viral inclusions may be highlighted by immunostains, but may be scarce and thus are not always identifiable within the endothelium of the affected vessels on a given section.

FIG. 6.108 Severe cytomegalovirus infection in a renal transplant patient. A: Low-power photomicrograph demonstrating extensive ischemic injury to the small intestine. B: Numerous cytomegalovirus inclusions are present in endothelial cells lining the submucosal vessels.

Diabetic Microangiopathy

The most consistent morphologic feature of diabetic microangiopathy is the presence of arteriolosclerosis (Fig. 6.110) and hyalinized PAS-positive thickened vessel walls with variable degrees of luminal narrowing in smaller caliber submucosal vessels (157). The vascular thickening is secondary to the deposition of basement membrane material. The small bowel may be extensively involved, resulting in diarrhea and malabsorption. The vessels are uninflamed and Congo red stains are negative. There is no endothelial proliferation.

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Oct 28, 2018 | Posted by in GASTROENTEROLOGY | Comments Off on The Nonneoplastic Small Intestine

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