Non-Neoplastic and Neoplastic Disorders of the Appendix

Congenital and Acquired Anatomic Anomalies of the Appendix

Abnormal Location, Size, and Absence of the Appendix

The appendix can have a host of anatomic abnormalities, including atypical location, duplication, and congenital absence. The position of appendix is determined by the rotation of the gut and position of the cecum during embryonic development. Retrocecal appendix is the most common abnormal location of the appendix. An abnormally long appendix (normal is 7–10 cm) has been linked to primary acute torsion, although torsion has also been reported in appendices of normal length. There can be complete or incomplete septa, which are seen principally in children and young adults and associated with acute appendicitis. Complete absence of appendix or atresia is extremely rare. This diagnosis in only made after a thorough search of the ileocecal region has failed to reveal an abnormally located appendix.

Diverticular Disease

Diverticula of the appendix can be congenital, in which case the muscularis propria is part of the diverticular wall, or acquired, in which case the diverticulum results from increased intraluminal pressure and mucosal herniation through a defect in the muscularis propria. This defect usually corresponds to the site of a penetrating artery. Acquired diverticula are more common than congenital diverticula and are seen in 1% to 2% of the population. However, acquired diverticula are greatly increased in patients with cystic fibrosis (CF), in whom they are found in up to 22% of appendectomy specimens. Patients may be completely asymptomatic or may present with signs and symptoms of acute appendicitis.

Grossly, the appendix may appear edematous and dilated. However, in most cases, diverticula cannot be easily identified. In case of perforation, the serosa shows purulent exudate. In the presence of dilated appendix, the lumen may be filled with mucin, and there may be evidence of extraappendiceal mucin. Histologically, there is outpouching of appendiceal mucosa through the muscularis propria, with or without periappendiceal fibrosis ( Fig. 8.1 ). The muscularis propria is usually attenuated. The epithelium may show reactive or hyperplastic epithelial changes that may be difficult to distinguish from low-grade appendiceal mucinous neoplasm. Diverticular disease can be associated with acellular mucin within the appendiceal wall, resulting in diagnostic mimicry with an appendiceal mucinous neoplasm. Preservation of the mucosal architecture with intact lamina propria and muscularis mucosae and lack of unequivocal cytologic dysplasia support a diagnosis of diverticular disease.

Fibrous Obliteration of the Appendiceal Lumen (Neural Hyperplasia)

Clinical Features

There are no specific features because this is typically an incidental finding in about one-third of appendices excised for a variety of reasons.

Fibrous Obliteration of the Appendiceal Lumen (Neural Hyperplasia)—Fact Sheet

Definition

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  A spindle cell proliferation that fills and "obliterates" the appendix lumen, usually at the tip

Incidence and Location

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  Found in about one-third of excised appendices

Morbidity and Mortality

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  None

Gender, Race, and Age Distribution

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  All ages, without race or gender predisposition

Clinical Features

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  Incidental finding in appendices excised for all reasons

Pathologic Features

Gross Findings

The tip of the appendix is usually affected. No definite lumen is identified. Instead, the cut surface appears tan to white.

Microscopic Findings

The appendiceal lumen is obliterated by a proliferation of bland spindle cells in a collagenous and myxoid background. The individual cells may have “wavy” or “buckled” nuclei ( Fig. 8.2 ). These cells consist of an admixture of fibroblasts, Schwann cells, and axons. The process may be confined to the mucosa (“intramucosal variant”) or may replace the entire lumen. These phenomena are believed to be overall proliferative, with attendant phases of growth, involution, and finally fibrosis. Immunohistochemical staining shows S-100 protein and neuron-specific enolase–reactive spindle cells (intermingled Schwann cells and axons, respectively), and scattered endocrine cells. The fibroblasts may be positive for CD34.

Fibrous Obliteration of the Appendiceal Lumen (Neural Hyperplasia)—Pathologic Features

Gross Findings

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  Normal appendix diameter with lumen being replaced by tan-white fibrous tissue

Microscopic Findings

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  Bland spindle cell proliferation amid fibromyxoid stroma

Immunohistochemistry

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  S-100– and neuron-specific enolase–positive cells with scattered endocrine cells

Differential Diagnosis

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  With benign mesenchymal tumors, the luminal location is the key

Differential Diagnosis

The differential diagnosis is with the host of spindle cell tumors of the gastrointestinal (GI) tract that are discussed in Chapter 7 . However, the location (with its epicenter in the lumen of the appendix) and nature of the spindle cell proliferation are helpful in distinguishing it from other mesenchymal neoplasms, especially those of neural origin.

Prognosis and Therapy

Fibrous obliteration is a benign and incidental lesion.

Acute Appendicitis

Clinical Features

Acute appendicitis most commonly affects children and adolescents (5–15 years) but occasionally may present in older individuals as well. The approximate incidence of acute appendicitis is 7% to 10%. It results from mucosal injury secondary to luminal obstruction by a fecalith, parasite, fragment of undigested food, or lymphoid hyperplasia followed by bacterial infection that progressively spreads from the mucosa to involve the appendiceal wall. Perforation is more common in the very young and in the older age groups. In older patients, the inflammatory process is often associated with neoplasms. Some observers believe that all appendices should be removed during surgery for suspected acute appendicitis, even when grossly normal, because nearly 20% of normal-appearing appendices may have acute inflammation on microscopic examination. A possible exception is patients who might require urologic surgery in the future because their appendices may later serve as urinary conduits.

Both ultrasound and computed tomography (CT) are useful in diagnosing acute appendicitis. The only sonographic sign that is specific for appendicitis is an enlarged, noncompressible appendix measuring greater than 6 mm in maximal diameter. CT signs of acute appendicitis include a distended appendix greater than 7 mm in maximal diameter, appendiceal wall thickening and enhancement, an appendicolith, circumferential or focal cecal apical thickening, pericecal fat stranding, adjacent bowel wall thickening, focal or free peritoneal fluid, mesenteric lymphadenopathy, and intraperitoneal phlegmon or abscess.

Acute Appendicitis—Fact Sheet

Definition

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  An acute inflammatory process attributed to local obstruction and infection involving the appendix

Incidence and Location

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  Involves the appendix

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  Incidences reported up to 7%

Morbidity and Mortality

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  Complications include wound infection, urinary retention, bowel obstruction, intraabdominal abscesses, urinary tract infections, and pneumonia, all more likely if the appendix has perforated

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  Overall mortality rate for appendectomy is about 0.3%; in individuals older than 65 years, this percentage is closer to 5%

Gender, Race, and Age Distribution

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  Peak presentation is from 5 to 15 years, but it occurs at any age

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  Male predominance in all races, but acute appendicitis is more common in whites than in African Americans and Asian Americans

Clinical Features

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  Classically, right lower quadrant pain accompanied by fever and elevated white blood cell count, but many variants occur

Prognosis and Therapy

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  Treatment is appendectomy

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  Preoperative antibiotics followed by appendectomy (“interval appendectomy”) have been advocated in patients with perforated appendices

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  Overall prognosis is good

Pathologic Features

Gross Findings

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. When the serosa is affected, the serosal aspect is initially dull and gray followed by a fibrinous or purulent exudate. Gangrenous appendicitis may show a purple, green, or blackish discoloration. Perforation secondary to mural necrosis can follow, which may lead to abscess formation. Cut surface shows edema and hyperemia of the wall, with or without intraluminal purulent contents. At times, 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 cause is rarely found.

Microscopic Findings

Early acute suppurative appendicitis (phlegmonous appendicitis) usually shows mucosal erosions and scattered cryptitis and crypt abscesses ( Figs. 8.3 and 8.4 ). Later, the inflammation extends to involve the appendiceal wall. Collection of neutrophils within the appendiceal lumen is considered insufficient for a diagnosis of acute appendicitis. Gangrenous appendicitis is associated with transmural necrosis extensive serosal fibroinflammatory reaction and can lead to perforation if left untreated.

As the appendix heals, two basic patterns may be seen. In the first, more typical pattern, there is a mixed inflammatory infiltrate ranging from patchy and mild to diffuse and transmural inflammation. Intramural or serosal foreign body–type giant cells surrounded by granulation tissue indicate prior rupture. Submucosal fibrosis, serositis, and fibrous adhesions can be present as well. In some cases, mucin extravasation may be a prominent feature and may lead to confusion with an appendiceal mucinous neoplasm. However, typical appendiceal mucinous neoplasms, even those that perforate, seldom show a prominent acute inflammatory component within the wall of the appendix and often display a dense fibrocollagenous stroma that is distinct from the acute edematous appearance of the stroma in acute appendicitis. A second pattern, which has been termed xanthogranulomatous appendicitis , consists of an inflammatory infiltrate rich in foamy histiocytes, multinucleate giant cells, abundant hemosiderin, and luminal obliteration with sparing of lymphoid follicles. These latter cases share features with Crohn’s disease but differ by lacking epithelioid granulomas, having fewer lymphoid aggregates, and having less profound subserosal fibrosis.

Commonly, patients who present with ruptured acute appendicitis are treated with antibiotic therapy and drainage followed by a delayed or “interval appendectomy” ( Figs. 8.5 and 8.6 ). In this setting, about two-thirds of patients have granulomas compared with fewer than 10% of acute appendicitis control participants. About one-third of interval appendectomy patients have xanthogranulomatous inflammation, and about half show a Crohn’s-like infiltrate. This is analogous to changes seen in sigmoid colon resections after antibiotic therapy for acute diverticulitis and should not be misinterpreted as manifestations of Crohn’s disease.

It is common for patients with neoplastic processes to present with clinical signs and symptoms of acute appendicitis only to reveal a neuroendocrine tumor (NET) or goblet cell neoplasm within the wall of the appendix. These cases require careful histologic evaluation to prevent misdiagnosis.

Acute Appendicitis—Pathologic Features

Gross Findings

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  Thickened diameter, depending on severity of process, with or without perforation. Serosa may be dull from periappendicitis

Microscopic Findings

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  Early lesions display mucosal erosions and scattered crypt abscesses; later, the inflammation extends into the wall of the appendix

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  When the inflammation extensively damages the muscularis propria, mural necrosis can lead to perforation

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  In appendectomies performed in patients with prior appendicitis, there are mixed inflammatory infiltrates ranging from patchy and mild to diffuse and transmural

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  In some appendices, there may be intramural or serosal foreign body–type giant cells surrounded by granulation tissue suggestive of prior rupture

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  Serositis and fibrous adhesions, as well as prominent submucosal fibrosis, may be present

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  Mucin extravasation is often seen but is admixed with a prominent inflammatory component, which is helpful in distinguishing this from a ruptured low-grade appendiceal mucinous neoplasm

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  Xanthogranulomatous appendicitis: features an infiltrate of foam cells, scattered multinucleated histiocytes, abundant hemosiderin, and luminal obliteration with spared lymphoid follicles

Differential Diagnosis

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  Interval appendectomy specimens share features with Crohn’s disease but differ by lacking epithelioid granulomas and having fewer lymphoid aggregates and less mural fibrosis, and these patients lack prior and concurrent clinical symptoms and endoscopic or radiologic signs of Crohn’s disease

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  Appendiceal involvement as part of an infectious enterocolitis and mechanical trauma associated with fecaliths. Both these conditions can cause superficial cryptitis and crypt abscesses. However, mural inflammation is typically present only in acute appendicitis. Inflammatory bowel disease involving the appendix is also in the differential (discussed later)

Prognosis and Therapy

The definite form of treatment is appendectomy. Complications include wound infection, urinary retention, bowel obstruction, intraabdominal abscesses, urinary tract infections, and pneumonia, all more likely if the appendix has perforated. Rarer complications include fistula formation, pylephlebitis, and liver abscesses. The overall mortality rate for appendectomy is about 0.3%. In individuals older than 65 years, the mortality rate approaches 5%.

Periappendicitis

Periappendicitis is characterized by serosal fibroinflammatory reaction with or without adhesions in the absence of mucosal or mural inflammation. Although intraoperative mechanical manipulation of the appendix alone may result in mild granulocytic infiltration of the serosa, the presence of fibrinous exudate is a potentially clinically significant finding. Periappendicitis is found in 1% to 5% of appendices resected for clinically acute appendicitis. The vast majority of cases are secondary to salpingitis. In two large series, the causes of periappendicitis included gonococcal and chlamydial salpingitis, yersiniosis, Meckel’s diverticulitis, and associated intraperitoneal abscess, urologic disorders, colon neoplasms, infectious colitis, abdominal aortic aneurysm, bacterial peritonitis, and GI perforation.

Grossly, the appendix is normal in size, and depending on the severity of periappendicitis, the serosal surface appears dull or tan to gray. The lumen and mucosa appear normal. Histologically, there is a serosa-confined (or possibly with extension into muscularis propria) inflammatory cell infiltrate consisting of neutrophils and fibrin if the process is acute ( Fig. 8.7 ) or with adhesions and chronic inflammation if the process is chronic. The lumen is unaffected. The pathologist’s finding of periappendicitis on an appendectomy specimen in the absence of luminal disease should alert the surgeon to take measures to identify the source of the serosal injury. If the patient is a woman, the genital tract is a likely source, but as noted previously, any abdominal process may result in periappendicitis. The treatment and prognosis depend on the inciting extraappendiceal lesion.

Ulcerative Colitis Involving the Appendix

The appendix has been shown to play a protective role in ulcerative colitis. The prevalence of prior appendectomy is lower in patients with ulcerative colitis than in the general population. Ulcerative appendicitis, the appendiceal counterpart of ulcerative colitis, is typically present in patients with pancolitis but is also common as a “skip lesion” in patients who have left-sided or rectal disease. It has an overall prevalence of 50% in patients with ulcerative colitis.

Grossly, the appendiceal mucosa appears erythematous and ulcerated. Ulcerative appendicitis shows the same histologic features as ulcerative colitis. Active mucosal inflammation is characterized by cryptitis and crypt abscesses. Chronic changes include crypt architectural distortion, basal lymphoplasmacytosis, and basal lymphoid aggregates. Ulcerative appendicitis is distinguished from early acute appendicitis partly on the basis of clinical history, although early acute appendicitis shows minimal crypt architectural distortion and basal plasmacytosis.

Crohn’s Disease Involving the Appendix

Most appendices resected in patients with Crohn’s disease are unremarkable. Appendiceal involvement by Crohn’s disease has been reported in up to 20% of patients and is typically associated with extensive ileocolonic involvement. Most patients who present with granulomatous appendicitis do not later manifest typical Crohn’s disease elsewhere in the GI tract.

Granulomatous Appendicitis

Granulomatous appendicitis was first described in 1953 by Meyerding and Bertram and was initially believed to be a manifestation of Crohn’s disease. However, studies that have appendiceal pathology in patients with documented idiopathic inflammatory bowel disease have shown that only a minority of patients with granulomatous appendicitis are a true manifestation of Crohn’s disease. Based on our current understanding, granulomatous appendicitis results from several conditions such as interval appendicitis, infections (bacterial— Yersinia spp., tuberculosis; parasitic—schistosomiasis, strongyloidosis; fungal— Candida spp., Histoplasma spp.), sarcoidosis, Crohn’s disease, and foreign body reaction. When a cause cannot be found, the condition is termed idiopathic granulomatous appendicitis . This histologic hallmark is the presence of granulomas that may involve any layer of the appendiceal wall. The presence of numerous granulomas, large-sized granulomas (>200 microns), and those with caseous necrosis or suppurative inflammation should prompt a search for infectious pathogens. The management of granulomatous appendicitis depends on the underlying cause, so appropriate ancillary infectious work-up and clinical information is essential.

Cystic Fibrosis