Nonneoplastic Diseases of the Appendix

Amy E. Noffsinger

▪ NORMAL EMBRYONIC DEVELOPMENT

The cecum appears during the 5th fetal week, arising as a diverticulum from the distal primitive intestinal loop before it differentiates into the small and large intestine. The appendix develops from the cecum and matures in the second trimester (1). As the appendix lengthens, the junction between the appendix and the cecum becomes increasingly more distinct. Longitudinal folds and ridges form, producing a segmented appearance; villi form (Fig. 8.1) that eventually involute. The epithelium appears clear due to large amounts of intracytoplasmic glycogen. Endocrine cells develop in the subepithelial connective tissue around the 9th fetal week when the epithelial basement membrane is not fully formed and the muscularis mucosae has not yet developed. Lymphoid stem cells migrate into the appendiceal mesenchyme. Mature lymphocytes appear when the fetus measures approximately 100 mm in length (2); lymphoid aggregates appear by the 17th week. The apical poles of incipient lymphoid follicles impinge on the surface epithelium by the time the fetus reaches 150 mm in length, and lymphoid cells invade the epithelium. Germinal centers develop between the 3rd and 6th postnatal weeks after the introduction of foreign protein (by eating) into the gut. Macrophages appear shortly after the lymphocytes (3). Primitive neural structures develop in the first trimester.

▪ NORMAL GROSS ANATOMY

The appendix usually arises from the posteromedial cecal wall, 2.5 to 3.0 cm below the ileocecal valve at the convergence of the taeniae coli (Fig. 8.2). The adult appendix averages 7 cm in length; lengths up to 20 cm have been reported. The appendix is longer in adults than in children. Its external diameter ranges from 0.3 to 0.8 cm. The appendiceal lumen measures from 1 to 2 mm in diameter appearing round, oval, irregular, or slitlike. The distal tip may be obliterated in adults. The appendix is suspended from the mesoappendix and attaches to the cecum in several ways (4). In 65% of adults, the appendix lies behind the cecum with its orifice opening into the cecum near the ileocecal valve. It may also lie to the side of the ascending colon, in front of, or behind, the ileum, lying on the psoas muscle or hanging over the pelvic brim (4). The appendix receives its blood supply from a branch of the posterior cecal artery; its venous drainage is to the portal system, explaining the coexistence of hepatic inflammation in the setting of appendicitis. The lymphatics first drain into the nodes of the mesoappendix and then to the right pericolic lymph nodes as well as to the ileocecal lymph nodes.

▪ HISTOLOGY OF THE APPENDIX

The appendiceal mucosa resembles that of the large intestine, except for the prominent circumferential arrangement of lymphoid follicles. Lymphoid aggregates (Fig 8.3) are most prominent in children, decreasing in size with age. They are markedly diminished or absent in the elderly. The appendiceal epithelium over the dome of each lymphoid follicle contains M cells with a structure similar to that seen in the small intestine (see Chapter 6). Nonbranching crypts are lined by tall mucussecreting goblet cells that extend from the luminal surface to the crypt bases. The crypts also contain endocrine cells, Paneth cells, and small numbers of intraepithelial lymphocytes. The muscularis mucosae is often absent, sometimes making it difficult to determine the mucosal-submucosal boundary.

The regularly arranged lymphoid follicles lie at the mucosal -submucosal junction (Fig. 8.3), and a well-defined lymphatic sinus surrounds both the lateral and basal parts of the follicle. These lymphatic sinuses empty into the submucosalcollecting lymphatics. Lymphocytes that proliferate in the gut-associated lymphoid tissues migrate into the surrounding lymphatic sinus or capillaries and enter the systemic circulation to be redistributed to other lymphoid tissues and organs. The endocrine cell population is discussed in Chapter 17.

FIG. 8.1 Fetal appendix. A: Differentiation of the ileum, cecum, and appendix is not easy at this time since villi are present in all three areas. B: Higher magnification of the fetal villi showing a glycogenated epithelium, proliferating crypts and villi. The section comes from the blind distal end of the specimen shown in (A).

FIG. 8.2 The normal appendix arises at the junction of the three taenia coli.

FIG. 8.3 Appendix from a 1-year-old boy. A: Lowpower magnification showing the regular arrangement of the lymphoid follicles and the straight tubular crypts. B: Higher magnification showing a single follicle.

FIG. 8.4 Hypoplastic appendix. A: The lamina propria blends into the underlying submucosa and muscularis propria. No muscularis mucosae is present. Numerous cystically dilated glands are present in the submucosa. B: Higher magnification showing the lack of a distinction between the lamina propria and the underlying submucosa.

▪ CONGENITAL ABNORMALITIES OF THE APPENDIX

Congenital appendiceal anomalies are rare (5). They include appendiceal agenesis (6), hypoplasia, duplications, horseshoe shape (7), heterotopia, and diverticula. These occur in the presence of either a normal cecum or in association with cecal dysgenesis.

Appendiceal Agenesis

Appendiceal agenesis (or absence) differs from appendiceal hypoplasia in that in the latter condition, the appendix is present but underdeveloped with a simplified structure and with mucosal cysts (Fig. 8.4). There are five types of appendiceal agenesis (Fig. 8.5) (6). All but one type (type 4) results from failure of the primitive cecal diverticulum to differentiate into the appendix. The fourth type results from intrauterine atrophy of a previously well-formed appendix. Appendiceal agenesis sometimes accompanies ileal atresia (8), thalidomide ingestion (9), or trisomy 18. Patients with trisomy 18 usually have multiple gastrointestinal and extragastrointestinal congenital abnormalities (6).

Positional Abnormalities

The appendix may lie in unusual locations, usually because of cecal mobility, excessive appendiceal length, situs inversus, or intestinal malrotation. This may cause an otherwise typical appendicitis to present in atypical ways.

FIG. 8.5 Forms of appendiceal agenesis. A: Normal appendix. B: Absent cecum and appendix. C: Rudimentary cecum and absent appendix. D: Normal cecum and absent appendix. E: Normal cecum and rudimentary appendix. F: Enlarged deformed cecum distal to the ileocecal valve and absent appendix.

Duplications

Three patterns of appendiceal duplication exist: double barreled, paired, and accessory (10). In “double-barrel” appendix, two separate tubes, each lined by a mucosa and separated by a submucosa, lie within a single muscular coat. Two symmetrically placed appendices lie on either side of the ileocecal valve in the paired form of duplication. This only occurs in infants with multiple congenital anomalies. A normalappearing appendix lying in its usual position and a second rudimentary appendix arising from the cecum represent the accessory type of duplication. Triplication of the appendix can also occur (11).

Heterotopias

Heterotopic tissues rarely affect the appendix. However, heterotopic gastric, esophageal, ileal, and pancreatic tissues can all occur in this location.

▪ DIVERTICULOSIS

Diverticula affect 0.004% to 2.8% of histologically examined appendices (5,12). They can be congenital or acquired; both types may be single or multiple. Congenital diverticula present as antimesenteric outpouchings with complete muscular walls, contrasting with acquired diverticula that lack the muscularis propria (Fig. 8.6). Some congenital diverticula are attached to the umbilicus by a fibrous band, resembling Meckel diverticulum.

FIG. 8.6 Appendiceal diverticulosis associated with an appendiceal adenoma. There are multiple diverticula extending through the appendiceal wall. They lack the muscularis propria as is typical of acquired diverticula.

Acquired diverticula are 10 times more frequent than their congenital counterparts (5). They affect both sexes equally and develop along the area of the penetrating arteries, often secondary to inflammation or tumors. Associated neoplasms, particularly low-grade mucinous neoplasms, are present in some patients (Fig. 8.6) (13). Diverticula develop due to the increased pressure of the accumulated intraluminal mucin. A similar mechanism may be responsible for the relatively high incidence (14%) of appendiceal diverticula in patients with cystic fibrosis.

Acquired diverticula are commonly multiple (Fig. 8.6), lying along the mesenteric and antimesenteric borders. They usually involve the distal appendix, giving the appendix a beaded appearance. Their size varies from 2 to 5 mm. Like colonic diverticula, they are subject to inflammation or perforation. Inflammation may distort, obliterate, or disrupt a diverticulum. When the inflammatory process spreads into the periappendiceal tissues, an abscess results.

▪ APPENDICEAL INTUSSUSCEPTION, AUTOAMPUTATION, AND INVERTED APPENDICEAL STUMP

Appendiceal intussusception is rare, usually affecting young boys (14). Patients range in age from 8 months to 75 years. Predisposing factors to intussusception include the presence of a fetal cone-shaped appendix, an unusually thin mesoappendix, or the presence of a mass lesion, most typically endometriosis, adenoma, endocrine tumor, or the lymphoid hyperplasia associated with viral infection. The presenting signs and symptoms resemble those of acute appendicitis. The lesions may also remain asymptomatic only to be discovered incidentally.

There are four types of appendiceal intussusception (Table 8.1). In some cases, the distal appendix intussuscepts into the proximal appendix; in other cases, the proximal appendix intussuscepts into the ceco-appendicular opening or the whole appendix intussuscepts into the cecum (Fig. 8.7) presenting as an edematous or infarcted cecal “polyp.” Intussusception can also appear as an umbilicated area at the junction of the taeniae coli on the cecal serosal surface. The mucosa may appear normal, hyperplastic, inflamed, eroded, or ischemic. The latter occurs if the vascular supply has been compromised. If there have been recurrent episodes of intussusception, the mucosa and muscular layers may become hyperplastic. In intussusception, the histology may also appear to be reversed from normal, with the epithelium lying on the external surface of tissue and the submucosa and muscularis propria lying inside the mucosa (Fig. 8.8). The submucosa becomes edematous, and the muscularis propria may appear hyperplastic, fibrotic, or splayed (Fig. 8.9). The muscular layers maintain a normal relationship with one another and with the submucosa and mucosa. It is important that the appendix be examined carefully in this setting to exclude the presence of an underlying neoplasm or other lesion such as endometriosis that may have been the lead point for the intussusception. Treatment of the intussusception is surgical resection.

TABLE 8.1 TYPES OF APPENDICEAL INTUSSUSCEPTION

Intussusception	Intussuscipiens
Appendix tip	Proximal appendix
Appendix base	Cecum
Proximal appendix	Distal appendix
Complete inversion (inside-out appendix)

Occasionally, the appendix autoamputates following intussusception or volvulus. The presence of cecal scarring and hemosiderin in the absence of other cecal abnormalities provides clues that the appendix was present at birth. Inverted appendiceal stump follows appendiceal autoamputation or postsurgical resection and may appear
as a cecal polyp grossly or endoscopically. One of the complications of an appendiceal stump is a vascular malformation. Patients may present with massive bleeding from cecal ulcerations. Histologically, massively dilated vessels are present.

FIG. 8.7 Appendiceal intussusception. Double-contrast barium examination demonstrating inverted appendiceal stump.

FIG. 8.8 Diagram of appendiceal intussusception. A: The tip of the appendix begins to move toward the junction of the appendix with the cecum. A section taken through the appendix (indicated by the black line) demonstrates essentially normal histological features. B: Once the appendix intussuscepts into the cecum, it may produce a small polyp. A cross section through the lesion taken at the level of the black line shows the inverted histology.

FIG. 8.9 Appendiceal intussusception. A: The lesion presented as a cecal polyp. One can see the cautery margin (arrows) of the “polypectomy” specimen. The center of the “polyp” consists of hyperplastic muscularis propria. External to this is an edematous submucosa. The surface of the polyp is covered by appendiceal type mucosa with prominent lymphoid follicles. B: Higher magnification showing the presence of the submucosal edema and marked lymphatic dilatation.

▪ TORSION

Appendiceal torsion is rare, and when it occurs, it causes ischemic appendicitis (Fig. 8.10). Histologically, one sees distal inflammation with areas of hemorrhage and necrosis. As with intussusceptions, a careful examination for the presence of an underlying neoplasm, as well as the assessment of the adequacy of the resection of the appendix if a neoplasm is present, is important.

▪ SEPTATED APPENDIX

Single or multiple, complete or incomplete septa consisting of mucosa and submucosa may divide the appendiceal lumen into compartments (Fig. 8.11), predisposing the appendix to develop appendicitis. The inflammation usually remains confined to one compartment of the septated lumen. These lesions present most often in the 15- to 19-year age group with a clear-cut male predominance. They represent residual fetal septations.

▪ “ABSENT APPENDIX”

The appendix may appear to be absent for several reasons: (a) agenesis; (b) previous resection; (c) obliteration from previous episodes of acute appendicitis, intussusception, or torsion; or (d) its presence in an abnormal location. Retrocecal, retrocolic, and retroileal appendices are uncommon but can cause clinical confusion, especially in the individual who presents with acute abdominal pain. Acute appendicitis can resolve, leaving only a thin fibrous cord. Resection of the appendix should be suspected in individuals who have undergone previous
surgical procedures. The confluence of the three cecal taeniae are the only consistent landmarks for the appendiceal origin.

FIG. 8.10 Appendices that undergo torsion usually show some evidence of ischemia.

FIG. 8.11 Septated appendix. A: Several cross sections through areas showing incomplete septa. The lumen contains projections of tissue covered by atrophic appendiceal mucosa. Extensions of the submucosa form the core of the septum. B: Higher magnification of the septum.

▪ APPENDICITIS

Demographic Features

Appendicitis develops at any age, with a peak incidence in the second and third decades. Over their lifetime, 7% to 12% of the US population develops appendicitis. Appendicitis occurs more commonly in Western cultures than in Eastern cultures likely due to dietary differences between these populations (15). Heredity may also play a role in the pathogenesis of appendicitis. Patients with a family history of appendicitis have approximately three times the risk for developing appendicitis than those with no family history (16). Appendicitis affects males slightly more commonly than females, particularly during early childhood (17).

Acute appendicitis may also develop in neonates. Although this is rare, it is associated with high morbidity and mortality rates (18,19). Neonatal appendicitis usually results from the presence of neonatal necrotizing enterocolitis, cystic fibrosis, Hirschsprung disease, or from bacteremia associated with maternal chorioamnionitis (18).

Despite the proclivity of appendicitis to involve younger individuals, it also affects the elderly and other age groups. The incidence of appendicitis in the elderly may be increasing due to longer life expectancy. Appendicitis in the elderly also has a high mortality and complication rate (20), perhaps due to concomitant NSAID use. NSAIDs may impair the inflammatory processes and suppress white cell responses
increasing the risk of developing appendicitis (20). Additionally, NSAIDs mask the symptoms so that patients present with late-stage disease.

TABLE 8.2 CAUSES OF APPENDICEAL OBSTRUCTION LEADING TO APPENDICITIS

Stones (fecaliths)

Food

Mucus—most often in cystic fibrosis

Kinks (angulated appendix)

Parasites

Tumors in the appendix or cecum

Endometriosis

Foreign objects

Lymphoid hyperplasia—usually secondary to viral infection

Pathophysiology

The etiology of appendicitis is multifactorial. It may involve obstruction, ischemia, infection, and hereditary factors. Direct luminal obstruction can result in appendicitis, but this is not a universal occurrence. When luminal obstruction does occur, it may be due to any of the factors listed in Table 8.2. The obstruction is followed by loss of mucosal integrity, ischemia, and bacterial invasion. Secretions accumulate under pressure behind the obstruction.

The mucosa can also be primarily involved by infections, as in the rest of the intestines without antecedent obstruction, or it may be affected by inflammatory bowel disease (IBD). Bacterial, viral, fungal, and parasitic diseases may all cause specific forms of acute appendicitis. However, microbiological studies generally show that no single organism is identified; rather, a mixed aerobic and anaerobic bacterial population is present in most cases. The most commonly isolated bacteria are Bacteroides fragilis and Escherichia coli (21). Streptococcus milleri can also be detected and may be associated with an increased risk for abscess formation (22). Similarly, Fusobacterium species may be associated with an increased risk of severe disease, including perforation (23). Campylobacter jejuni is also an important cause of acute appendicitis (24).

FIG. 8.12 Fecalith and acute appendicitis. A: Gross photograph. The proximal bulge is due to the presence of an intraluminal fecalith. Marked vascular engorgement is seen and a fibropurulent exudate covers the appendix (curved arrows). B: Specimen radiograph showing a radiopaque fecalith.

Once an infection becomes established, pressure from inflammation and edema predisposes to the rapid development of gangrene, perforation, and peritonitis. Infections may also cause fibrin thrombi, which can block the small appendiceal vessels, causing secondary ischemia. The appendix is particularly prone to ischemia, since the appendiceal artery is an end artery. The enteric nervous system may also play a role in the pathogenesis of acute appendicitis. Increased numbers of nerve fibers, Schwann cells, and enlarged ganglia have all been found in patients with acute appendicitis (25).

Clinical Features

The diagnosis of appendicitis is straightforward when it presents classically with right lower quadrant abdominal pain of short duration, abdominal rigidity, and anorexia. Appendicitis also causes acute periumbilical, colicky pain, or vomiting. Fever and leukocytosis develop early. However, there are many examples of appendices that are removed for suspected acute appendicitis in which histologic evidence of an acute appendicitis is lacking.

Pathologic Features

Normally, the appendiceal mucosa appears smooth, light yellow-tan; the serosa appears pink-tan, smooth, and glistening. When the inflammation is restricted to the mucosa, the exterior of the appendix may grossly appear normal. Dilatation and congestion of serosal vessels produces localized or generalized hyperemia and constitutes the earliest visible external change (Figs. 8.12, 8.13 and 8.14). Well-developed acute appendicitis shows marked congestion with a dull (rather than glistening) serosal surface or there may be a serosal granular, fibrinous, or purulent coating and vascular engorgement reflecting severe necrosis and inflammation.
The mesoappendix appears edematous, and contiguous structures may become inflamed. The appendix often exudes purulent material from the cut surface; one may sometimes identify an impacted intraluminal fecalith. Mucosal necrosis and ulceration are usually present. The acute inflammation can localize to one segment of the organ, or the entire appendix may be affected. There may be the appearance of a mucocele. If so, the appendix should be well sampled to exclude the presence of a coexisting mucinous neoplasm.

FIG. 8.13 Acute appendicitis showing vascular engorgement and serosal erythema. A white purulent membrane covers the serosal surface.

By the time full-blown gangrenous appendicitis develops, the organ appears soft, purplish, and hemorrhagic or even greenish black, sometimes with visible thrombi in the mesoappendix. These may spread along the ileocecal and upper mesenteric veins. Perforation may be present. In complicated cases, abscesses may form around a site of perforation, and inflammation may extend into the mesoappendix (Fig. 8.15).

Histologic changes associated with appendicitis reflect disease duration and severity, and some changes may not reflect clinical disease at all. The term “acute intraluminal appendicitis” has been used when there are neutrophils in the appendiceal lumen, but they have not yet infiltrated the mucosa (26). This may not be of any significance since this finding can be seen in incidental appendectomy specimens. Other minimal changes may consist of focal neutrophilic collections in the lumen and lamina propria. This is sometimes referred to as “mucosal” or “early” appendicitis. The term mucosal appendicitis has been used both in the presence and the absence of ulcers if the inflammation is restricted to the mucosa (27,28,29). The clinical significance of pure mucosal inflammation in the absence of ulcers is uncertain. Since these changes may reflect sampling error, more sections should be taken of the appendix to be certain that there is not more extensive inflammation elsewhere in the appendix.

FIG. 8.14 Gangrenous appendicitis. The external surface of the appendix is hemorrhagic and reddened with a well-developed fibropurulent membrane.

FIG. 8.15 Diagram illustrating the complications of acute appendicitis.

In better developed disease, focal erosions, cryptitis, and crypt abscesses develop. The inflammation then extends to the submucosa. After the inflammatory process reaches the submucosa, it spreads quickly to involve the remaining appendix. Eventually, the mucosa erodes, the wall becomes necrotic, and the vessels may thrombose. Submucosal abscesses, edema, and congestion follow. Some appendices contain prominent eosinophilic infiltrates. Extravasated mucin in the bowel wall may induce a foreign body reaction or even small mucin granulomas.

Gangrenous appendicitis shows extensive suppuration, often extending deep into or through the appendiceal wall with complete mural destruction (Figs. 8.16 and 8.17) with or without rupture. If perforation occurs, an intense nonspecific inflammatory process ensues. Perforation may be suspected clinically, but it is often difficult to see in the resected specimen due to the extensive inflammation. Resolving appendicitis is characterized by the presence of a predominantly lymphocytic infiltrate involving the subserosa and muscularis propria or the subserosa. When appendicitis heals, it assumes one of two basic patterns: the “usual” pattern, sometimes with an intraluminal cord of granulation tissue, and a xanthogranulomatous pattern (30). Fibrosis may develop.

FIG. 8.16 Acute appendicitis. A: Cross section through the appendix showing the transmural inflammation. B: High magnification of the surface exudate that contains necrotic debris and bacteria. C: Below the surface of the debris shown in (B), there is acute and chronic inflammation. D: Acute and chronic inflammation with small thrombi within the dilated and congested veins. E: Cross section through a larger vessel containing an organizing thrombus at the base of the vessel (arrow). Overlying the vessel is necrotic and inflammatory debris. Under the vessel is a zone of acute and chronic inflammation. F: Cross section through a small vessel demonstrating with fibrinoid necrosis and acute and chronic inflammation. G: The serosa shows marked vascular engorgement and small thrombi in the dilated vessels (arrow). H: Lower magnification showing the extension of fibrosing stands of tissue extending into the mesoappendiceal fat. The vessels on the serosal surface are markedly engorged. The lumen of the appendix at this level is completely necrotic (star).

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