Inflammatory Disorders of the Appendix
Leona A. Doyle
Robert D. Odze
Normal Histology
In humans, the appendix is a vestigial organ. It has no proven significant physiologic function.
The vermiform appendix arises from the medial aspect of the cecum, inferior and posterior to the ileocecal orifice. It is approximately 8 cm long (range 2 to 20 cm) and 0.7 cm in diameter.1 The anatomic location of the appendix varies among individuals. It may be located behind the cecum and ascending colon (most common location), behind the ileum and mesentery, along the pericolic gutter, in the subhepatic region, or in the lesser pelvis. The appendix is maintained in its position by a fold of peritoneum that invests mesoappendiceal fat throughout the length of the appendix. The appendiceal artery is derived from the ileocolic artery, which is derived from the superior mesenteric artery, and it is located at the free edge of the peritoneal fold.
The layers of the appendix are similar to those in other portions of the large bowel, consisting of mucosa, submucosa, muscularis propria, and serosa. However, the mucosa has abundant, organized lymphoid tissue circumferentially arranged. It closely resembles mucosa from the terminal ileum, particularly in young individuals. The epithelium of the appendix contains goblet cells, absorptive cells, neuroendocrine cells (predominantly Kulchitsky type and basally located), and scattered Paneth cells.2 Unlike the colon, in which crypts are uniformly aligned, appendiceal crypts tend to be irregularly spaced and can be entirely absent in areas of mucosa adjacent to lymphoid aggregates.
In addition to lymphoid tissue, abundant immunoglobulin A (IgA)–secreting plasma cells are normally present in the lamina propria. The muscularis propria consists of an inner circular and outer longitudinal layer of smooth muscle, similar to other parts of the gastrointestinal (GI) tract. The appendix is enveloped by serosa up to the point of attachment of the mesoappendix, where the serosa envelops the mesoappendiceal fat up to the peritoneal fold. Under normal circumstances, neutrophils and eosinophils are absent from the mucosa and wall of the appendix.
Congenital, Developmental, and Acquired Anatomic Abnormalities
The appendix may exhibit a variety of anatomic abnormalities, including an atypical location,3 duplication,4,5 congenital absence,6 and luminal septal formation.7 An abnormally long appendix (>7 to 10 cm) has been linked to the development of torsion, although this complication has also been reported for appendices of normal length.8
Abnormal Location
The anatomic location of the appendix varies among individuals. The position of the appendix is determined mainly by changes in the position and shape of the cecum that occur during organ development, growth, and rotation. If the cecum does not descend fully, the appendix becomes located retroperitoneally in an ascending retrocecal position anterior to the right kidney. The frequency of a retrocecal location ranges from 26% to 65%.9,10 If the appendix is in a retrocecal position, it may be positioned intraperitoneally in a paracecal pouch of peritoneum or retroperitoneally with or without a paracecal fossa formed by the peritoneum.11
The clinical manifestations of acute appendicitis depend on the location of the appendix in the abdomen. If the appendix is located retrocecally, it may give rise to an abscess in the pararenal space, or infection may spread along the right paracolic gutter up to the right posterior subhepatic and right subphrenic spaces.12,13 More than 50% of patients with ascending retrocecal appendicitis have an atypical clinical presentation. They may have right upper quadrant pain or nonlocalizing abdominal pain instead of the more common presentation of central periumbilical pain followed by localization to the right lower quadrant, signs that are more often seen in cases of appendicitis when the appendix is in its normal anatomic location.14,15 Because of the atypical clinical presentation, retrocecal appendicitis is more likely to be diagnosed later in its course, resulting in a higher incidence of perforation and more serious complications.14 However, some studies have not shown an association between retrocecal location and perforation at the time of presentation.16
Duplication
Duplication of the vermiform appendix is rare. It occurs in approximately 1 of 25,000 patients (0.004%) who have undergone surgery for acute appendicitis.17 The clinical presentation depends on the location of the appendices in the colon.17,18 Cave and Wallbridge classified appendiceal septal formation as three types.19,20 Type A has incomplete duplication, with both appendices having a common base. Type B has complete duplication, with the first appendix arising from its usual location at the confluence of the teniae coli and the second located at various sites along the colon. Type C has complete duplication of the cecum, with each part having its own appendix.19,20
In one report, duplication of the appendix was associated with duplication of the colon in a 28-year-old man who was evaluated for an abdominal mass.21 He also had hydronephrosis and atrophy of the right kidney resulting from pressure atrophy from an inflammatory cecal mass.21
Absence and Atresia
Agenesis and atresia of the vermiform appendix are rare, occurring at an estimated frequency of 1 case per 100,000 resected appendices.6,22 Congenital absence should be diagnosed only after thorough examination of the entire ileocecal region to exclude the possibility of an abnormally located appendix.
Atresia of the appendix may be associated with atresia of the entire ileocecal region23 or with atresia of other sites in the small intestine.24 Congenital absence of the appendix has been associated with other congenital malformations, such as congenital diaphragmatic hernia.25 Acute appendicitis may occur in an atretic appendix, but the diagnosis of atresia is usually made only after pathologic examination of the resection specimen, because radiologic findings are often nonspecific and may be obscured by periappendiceal inflammation.26
Appendiceal Septa
The appendix can have complete or incomplete septa formation within the appendiceal lumen, a finding that is principally seen in children and young adults, who usually have acute appendicitis at clinical presentation.7 Possible contributing factors to the formation of septa include congenital abnormality, postinflammatory fusion of mucosal folds, and ischemia caused by thrombosed vessels.
Diverticular Disease of the Appendix
Diverticular disease of the appendix is rare. It has a reported incidence of 1 case (0.77% to 2%) per 50 to 130 appendectomies, or 1 case (0.004%) per 25,000 for true congenital diverticula.22,27 Diverticula may be congenital, in which case the muscularis propria represents a component of the diverticular wall, or it may be acquired, in which case the diverticulum results from increased intraluminal pressure and subsequent mucosal herniation through a defect or weak area of the muscularis propria, often at the site of a penetrating artery.
Acquired diverticula are more common than congenital diverticula. They occur most often in older adult males. Acquired diverticula are usually located in the distal third of the appendix (60%) on the mesenteric border and usually have a diameter of less than 5 mm.27 The incidence of acquired diverticula is greatly increased among patients with cystic fibrosis in whom mucosal secretions are markedly thickened. In this patient population, diverticular disease may be identified in as many as 22% of appendectomy specimens (Fig. 18.1).28
The disease may be asymptomatic or may manifest with acute or chronic pain, mimicking acute appendicitis.27,29 Computed tomography (CT) may help to visualize inflamed diverticula, which may appear as small, cystic outpouchings, but there is a high rate of false positives with this method of imaging.30 During the acute phase of illness, the incidence of perforation is approximately three times higher than that for patients with classic appendicitis (33% versus 10%).31 Because acquired diverticula lack a muscular wall, perforation is not surprising. The morbidity and mortality rates are greater than those for patients with classic acute appendicitis.27
Pathologically, the appendix may appear edematous, but diverticula may not necessarily be easily appreciated. If perforation has occurred, the serosa may appear dusky and have a yellow-tan exudate. Histologic findings include an outpouching of appendiceal epithelium through the muscularis propria of the appendix, with or without associated acute suppurative appendicitis, and chronic changes such as muscular hypertrophy and transmural, periappendiceal fibrosis, and lymphoid atrophy.29,32 In some cases, fibrous obliteration of the lumen may be seen.
Chronic changes suggest prior rupture or inflammation of a diverticulum. A ruptured appendiceal diverticulum can mimic a low-grade appendiceal mucinous neoplasm (LAMN) (see Chapter 28),29 as mucin extravasation onto the serosal surface or into periappendiceal tissue mimics mucin dissection of LAMN. Less commonly, detached fragments of benign-appearing epithelium may be associated with mucin as a result of perforated diverticula, mimicking localized pseudomyxoma peritonei. Occasionally, identification of diverticula is made grossly, but in most cases it is apparent only on microscopic examination of the tissue. In some instances, communication between the diverticulum and the appendiceal lumen is not seen in the original histologic plane of section, but it may become apparent after deep tissue sectioning.
Differentiation of hyperplastic or regenerative epithelial changes associated with diverticular disease from LAMN may be difficult. Mucosal regeneration shows architectural changes that are more pronounced in the superficial than in the basal portion of the mucosa. Gland serration, crypt disarray, and increased mucin-producing cells are seen in the upper half of the mucosa. The crypts are usually separated by lamina propria and show little or no crowding. In contrast, LAMN shows back-to-back crypts with minimal intervening lamina propria and slender, elongated, and filiform villi.29 In some cases, this distinction can be extremely difficult, and examination of the entire appendix is recommended. Preserved mucosal architecture, multiple diverticula, mucosal neuromas, and other chronic changes are clues to the diagnosis of diverticular disease rather than LAMN (Table 18.1).
Table 18.1
Features Differentiating Diverticular Disease from Low-Grade Mucinous Neoplasms of the Appendix
| Feature | Diverticular Disease | Low-Grade Mucinous Appendiceal Neoplasm |
| Extraappendiceal mucin | May be present Almost always acellular |
Frequently present May be cellular or acellular |
| Crypt architecture | Preserved | Crowded |
| Epithelial morphology | Bland, reactive hyperplastic changes | Dysplastic, usually low-grade |
| Filiform growth pattern | No | Yes |
| Acute inflammation | Usually present | May be present or absent |
| Mural fibrosis | Usually present | May be present (usually mild) or absent |
| Fibrous obliteration | Often present | May be present or absent |
| Muscular hypertrophy | Usually present | Not usually present |
| Diffuse pseudomyxoma peritonei | No | May be present or absent |
Fibrous Obliteration of the Appendiceal Lumen
Obliteration of the appendiceal lumen (also known as neuroma or neural hyperplasia) by spindle cells located within a collagenous and myxoid background is seen in approximately one third of excised appendices. It is usually an incidental finding. The frequency of occurrence increases with patient age.
The tip of the appendix is usually affected, but the whole appendix may be progressively involved. Grossly, the appendix may appear narrow and white in areas of obliteration compared with adjacent normal appendix. Lesional cells include fibroblasts, Schwann cells, and axons. Admixed mast cells, eosinophils, and scattered endocrine cells may also be present. The infiltrate may be confined to the mucosa, but more commonly, it replaces the entire lumen and underlying crypts (Fig. 18.2).
Immunohistochemical staining shows a mixed population of S100 protein–reactive and neuron-specific enolase–reactive spindle cells corresponding to intermingled Schwann cells and axons, respectively. Admixed fibroblasts may be positive for CD34. The finding of lesions with a predominantly neural composition has led to the alternative designation of appendiceal neuroma.33 This phenomenon is thought to be a reactive process, either as a normal part of aging or as a response to prior acute appendicitis, with progressive phases of growth, involution, and fibrosis.33,34 The common occurrence of fibrous obliteration and neuromatous changes in appendices with ruptured diverticula supports the hypothesis that this phenomenon is a reactive process.29
Acute Appendicitis and Associated Disorders
Clinical Features and Pathogenesis
Acute appendicitis is predominantly a disease of children and young adults. It occurs in children and adolescents between 5 and 15 years old, although no age group is exempt from this condition.35,36 One crude estimate of the incidence of acute appendicitis in the United States is 11 cases per 10,000 population.37 Acute appendicitis is more common in Western countries than in Asia or Africa.
The pathogenesis of acute appendicitis is thought by some to reflect an initial insult to the mucosa resulting from luminal obstruction by a fecalith, a fragment of undigested food, lymphoid hyperplasia, or a tumor, followed by bacterial infection that progressively spreads outward from the mucosa and into and through the wall of the organ. However, the evidence for this mechanism is circumstantial at best. Some authorities believe that acute appendicitis represents one manifestation of a range of injuries that include hypersensitivity reactions, infections, and ischemic lesions. The potential causes of acute appendicitis are listed in Box 18.1.
The classic symptom triad of acute appendicitis consists of periumbilical pain, which eventually localizes to the right lower quadrant of the abdomen, accompanied by anorexia and nausea. Mild fever, leukocytosis, elevated C-reactive protein level, and right lower quadrant tenderness are usually present. If perforation has occurred, signs of peritonitis may be present. Common clinical mimics of acute appendicitis include mesenteric lymphadenitis (particularly in children), ovarian cysts, appendiceal or colonic diverticulitis, and Meckel diverticulitis.
Imaging methods, particularly CT, used to detect acute appendicitis have improved.38,39 Laparoscopic appendectomy has emerged as a relatively safe technique.40 CT findings suggesting acute appendicitis include distention, wall thickening and enhancement, periappendiceal fat stranding, cecal thickening, and free peritoneal fluid. Approximately 70% of patients suspected of having appendicitis by clinical or imaging methods are found to have acute appendicitis at the time of surgery.41,42 Some authorities believe that all appendices, even when grossly normal, should be removed when the indication for surgery was suspected acute appendicitis, because almost 20% of grossly normal-appearing appendices may contain acute inflammation on microscopic examination of the tissue.41,42 One possible exception is for patients who may require urologic surgery in the future, because their appendices may prove useful as a urinary conduit.43 Patients with appendicitis in the setting of human immunodeficiency virus (HIV) infection have a similar clinical presentation, although sometimes with a less striking elevation in the peripheral white blood cell count. In one surgical series of appendicitis in patients with HIV infection, delay before operation increased the likelihood of perforation.44
Pathologic Features
The appendix may appear grossly normal when inflammation is limited to the mucosa and submucosa. However, when inflammation extends into the muscularis propria, the appendix frequently becomes swollen and erythematous due to dilation of the serosal vessels. When the serosa is affected, the peritoneum is initially dull and gray, and a purulent exudate then develops. In approximately one third of cases, a fecalith is identified. Perforation from mural necrosis (i.e., gangrenous appendicitis) can follow, which may lead to abscess formation. Sometimes, an appendix resected in the clinical setting of acute appendicitis is grossly and histologically normal, even after submission of the complete specimen for histologic examination. In these cases, a specific cause is rarely found. Possible causes are listed in Box 18.2.
On microscopic examination, early lesions may reveal mucosal erosions and a neutrophilic infiltrate resulting in cryptitis and crypt abscesses (Fig. 18.3). Later, the inflammation extends into the submucosa and muscularis propria. Collections of neutrophils may be seen in the lumen. However, luminal neutrophils alone are not sufficient for a diagnosis of acute appendicitis. When inflammation extensively damages the muscularis propria, mural necrosis can lead to perforation (see Fig. 18.3). Thrombosed vessels may be seen. When periappendiceal inflammation occurs in the absence of mural involvement, other causes of peritonitis should be sought clinically (see “Periappendicitis”). Anaerobic bacteria are detected in approximately 50% of cases, but they may represent secondary colonization rather than being the primary cause of appendicitis.45
The morphologic differential diagnosis, at least for very early lesions, includes infectious gastroenteritis and trauma from fecaliths, both of which may result in mild superficial neutrophilic inflammation. If inflammation is limited to the mucosa, additional sections may reveal mural inflammation, supporting a diagnosis of acute appendicitis. The differential diagnosis also includes inflammatory bowel disease involving the appendix (discussed later).
Natural History and Outcomes
Two basic patterns of progression may occur in patients with acute appendicitis.46,47 In the first and more common pattern, there is a mixed inflammatory infiltrate ranging from patchy and mild, to diffuse and transmural. In some appendices, there may be intramural or serosal foreign body–type giant cells surrounded by granulation tissue, suggesting prior rupture. Serositis, fibrous adhesions, and prominent submucosal fibrosis can occur. Mucin extravasation is often seen. A second pattern, which has been called xanthogranulomatous appendicitis, consists of an infiltrate of foam cells and multinucleate histiocytes, with hemosiderin deposition, luminal obliteration, and sparing of lymphoid follicles (Fig. 18.4). This reaction pattern shares features with Crohn’s disease (CD) but lacks epithelioid granulomas, has fewer lymphoid aggregates, and has less subserosal fibrosis. However, in one study, a patient exhibiting this pattern of inflammation was found to have CD on follow-up.48 Careful clinical correlation is important in such cases.
The most common complications of acute appendicitis are perforation with the development of peritonitis and abscess formation. Young children and elderly adults have the highest risk of perforation. For some patients in whom the appendix has already ruptured at the time of presentation, the surgeon may elect to treat the condition initially with antibiotics and drainage, followed by an appendectomy 4 to 8 weeks later. This approach is called an interval appendectomy (see Chronic Appendicitis).
Periappendiceal abscesses may result in an inflammatory mass that may mimic a neoplasm clinically. If not surgically treated, an abscess may fistulize into the small intestine or colon or onto the skin surface. In women, obstruction of an adjacent fallopian tube may lead to infertility. Inflammation of adjacent blood vessels may result in pylephlebitis. Early diagnosis and surgical intervention (i.e., appendectomy) combined with antibiotic therapy has drastically reduced the mortality rate associated with acute appendicitis since the early 1900s. The overall mortality rate for acute appendicitis is now less than 0.5%.
Stump Appendicitis
Stump appendicitis is an uncommon late complication of appendectomy. It is defined as residual or progressive acute inflammation in the remaining stump of the appendix after surgery.49–51 A diagnosis of stump appendicitis is often delayed because of its relatively infrequent occurrence, but a high level of suspicion should be maintained for patients who have signs and symptoms of appendicitis and have had a prior appendicectomy.52–54 A history of colicky central abdominal pain that localizes to the right lower quadrant does not often occur in patients with stump appendicitis. Other signs and symptoms include generalized abdominal pain and tenderness, nausea, vomiting, fever, and peritonitis. Abdominal CT findings that reveal a distended appendicular stump, fecalith, pericecal fat stranding, or abscess help to confirm the diagnosis.49 The consequences of delayed diagnosis include stump necrosis, gangrene, and perforation, which occur in as many as 40% of patients.49
Complete pathologic features of stump appendicitis have not been described. However, in most cases, findings are similar to those of classic acute appendicitis, consisting of neutrophils, cryptitis, and some degree of transmural inflammation. Transmural necrosis and perforation can occur in patients with late-stage disease. Granulomatous inflammation has been described in one patient with stump appendicitis.55
Management usually requires surgical resection of the inflamed residual appendix and antibiotic therapy. It is unclear whether the increasing use of laparoscopic instruments for appendectomy is associated with an increase in the incidence of stump appendicitis.
Periappendicitis
Preoperative mechanical manipulation of the appendix may cause mild, diffuse neutrophilic infiltration of the periappendiceal serosa.56 However, when inflammation in the serosa is accompanied by fibrin deposition or adhesions, it is a potentially significant clinical finding. Periappendicitis without mucosal or mural involvement occurs in 1% to 5% of appendices resected for clinically suspected acute appendicitis. Most cases are caused by salpingitis.57
A clinical review of cases of periappendicitis showed that there were significant clinical differences, including longer duration of pain, localization less often in the right lower quadrant, and fewer peritoneal signs, compared with patients with classic acute appendicitis.58 In two large series, suspected “periappendicitis” was attributable to a variety of processes: gonococcal and chlamydial salpingitis, yersiniosis, Meckel diverticulitis and associated intraperitoneal abscess, urologic disorders, colonic neoplasms, infectious colitis, abdominal aortic aneurysm, bacterial peritonitis, and GI perforation.57,59
Grossly, the serosal surface of the appendix and mesoappendix may appear dull and coated with a fibrinous exudate. Microscopically, a neutrophilic infiltrate is seen within the serosa. The inflammation may extend into the subserosa and rarely into the muscularis propria. Fibrinous adhesions may also be identified. By definition, the mucosa of the appendix is uninvolved. Because the serosal findings are common in patients with acute appendicitis, examination of the entire appendix is recommended to exclude this diagnosis completely. The management of periappendicitis depends on the underlying cause.
Chronic Appendicitis
The criteria and definition of chronic appendicitis as clinical or pathologic diagnostic entities are controversial. For instance, the term chronic appendicitis has been used to describe fibrous replacement of the appendiceal wall after severe or recurrent bouts of acute appendicitis. This process also has been referred to clinically as subacute appendicitis. The term has also been used for patients who have had an interval appendectomy, when resection of a perforated appendix was delayed as a result of initial conservative management with antibiotics and drainage. Chronic appendicitis is an umbrella diagnosis that encompasses any type of potentially chronic inflammatory condition of the appendix other than classic acute appendicitis.
Recurrent episodes of acute appendicitis (i.e., subacute appendicitis), ulcerative colitis (UC) and CD of the appendix, granulomatous appendicitis (and its many causes), interval appendicitis, and cystic fibrosis are potential causes of chronic appendicitis. The causes of chronic appendicitis are summarized in Box 18.3 and discussed in more detail later.
Ulcerative Colitis
The appendix plays an interesting but poorly defined role in patients with UC or CD. For instance, appendectomy is a protective factor in UC. The prevalence of prior appendectomy is lower among patients with UC compared with the general population.60–62
Ulcerative appendicitis, which represents appendiceal involvement in patients with UC, is typically seen in patients with pancolitis,63 but it may also occur as a skip lesion in patients with subtotal, left-sided, or rectal-only disease. It has an overall incidence of 50% among patients with UC.63–65
Grossly, erythema and ulceration at the appendiceal orifice may be seen endoscopically. Ulcerative appendicitis shows histologic features similar to those of the colon in UC (see Chapter 17). Active mucosal inflammation is characterized by cryptitis, crypt abscesses, and suppurative luminal exudate. Chronic changes include lamina propria lymphoplasmacytosis, basal lymphoid aggregates, crypt architectural distortion, and Paneth cell hyperplasia (Fig. 18.5). Early acute appendicitis in non-UC patients exhibits less crypt distortion and plasmacytosis than in UC-associated appendicitis. In UC, immunostains may show prominent S100 protein–reactive and MAC387-positive dendritic cells, which are not present in non-UC cases of acute appendicitis.66 The prognostic implication of appendiceal involvement in UC is dictated by the degree and extent of colonic involvement, but there is little outcome data in this regard.
Crohn’s Disease
Unlike UC, the relationship between appendectomy and CD is not well established. However, one study did find a protective effect of appendectomy on the occurrence of disease after the bias of appendectomy at the time of diagnosis of CD was removed from the analysis.61 Most appendices removed from patients with CD of the small and large intestine are histologically normal. Patients with appendiceal involvement in CD usually have extensive ileocolonic involvement. Many cases labeled granulomatous appendicitis in the past were thought to represent CD, but many of these cases instead represent a variety of different disorders, all of which feature granulomatous inflammation in the appendix. A crude estimate of the incidence of appendiceal involvement in CD from the recent literature is approximately 20%.67
In patients with appendiceal involvement, the histologic features are similar to those seen in other sites of the GI tract. Mucosal ulceration, active inflammation with cryptitis and crypt abscesses, fissures, transmural inflammation, transmural lymphoid aggregates, fissures, and fistulas are characteristic features. Paneth cell hyperplasia may also occur. Scattered non-necrotizing granulomas are identified in approximately 50% to 80% of cases (Fig. 18.6).46,68
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