Primary cytomegalovirus (CMV) infections in immunocompetent persons are usually asymptomatic. CMV infection may develop anywhere in the GI tract, from mouth to anus, in both immunocompromised and immunocompetent persons. CMV is best known as an opportunistic pathogen in patients with a suppressed immune system, most commonly in those with the acquired immunodeficiency syndrome (AIDS) and in patients who have undergone solid organ or bone marrow transplantation.² In fact, CMV remains the most common GI pathogen overall in patients with AIDS.

Primary infections in healthy persons are typically asymptomatic. When symptomatic disease does occur, it is usually self-limited and may manifest as a mononucleosis-like syndrome. In most of these cases, GI involvement is subclinical. Symptomatic GI infection has been reported occasionally in immunocompetent patients,^3,4 although many of these were elderly or were eventually found to have underlying malignancies or hematologic disorders and therefore may not have had entirely competent immune systems.

Symptoms vary with site of infection. The most common clinical symptoms are diarrhea (either bloody or watery), abdominal pain, fever, and weight loss.² Patients with esophageal infection often have dysphagia and odynophagia.⁵ A rare, but important, entity associated with pediatric CMV infection is hypertrophic gastropathy and protein-losing enteropathy resembling Ménétrier disease.^6,7

In addition, secondary CMV infection may be superimposed on chronic GI diseases such as ulcerative colitis and Crohn’s disease. In such cases, CMV superinfection is associated with exacerbations of the underlying disease, steroid-refractory disease, toxic megacolon, and a higher mortality rate. Some authorities recommend immunohistochemical evaluation for CMV as part of the routine evaluation of biopsies in patients with steroid-refractory ulcerative colitis.^8,9

Pathologic Features

CMV causes a remarkable variety of gross lesions.^2,10 Ulceration is the most common; the ulcers may be single or multiple, and superficial or deep. They can be quite large (>10 cm), and often have a well-circumscribed, “punched-out” appearance. Segmental ulcerative lesions and linear ulcers may mimic Crohn’s disease. Other gross lesions include mucosal hemorrhage, pseudomembranes, and inflammatory polyps or masses.^11,12

The histologic spectrum of CMV infection is extremely variable, ranging from minimal inflammation to deep ulcers with prominent granulation tissue and necrosis. Frequently observed histologic features include mucosal ulceration, a neutrophil-rich mixed inflammatory infiltrate, and cryptitis of glandular epithelium.² Crypt abscesses, crypt atrophy and loss, and numerous apoptotic enterocytes may be seen as well.¹⁰ CMV may also cause a vasculitis featuring numerous endothelial viral inclusions with associated inflammation, necrosis, and thrombosis of the affected vessel and resultant mucosal ischemia.¹³

Infected cells show both nuclear and cytoplasmic enlargement (hence the name, “cytomegalovirus”) (Fig. 4.1, A). Characteristic “owl’s-eye” intranuclear viral inclusions and basophilic granular intracytoplasmic inclusions may be seen on routine hematoxylin and eosin (H&E) preparations (see Fig. 4.1, B and C). Inclusions are preferentially found in endothelial cells, stromal cells, and macrophages, and, rarely, in glandular epithelial cells. In contrast to adenovirus or herpes, CMV inclusions are often found deep within ulcer bases rather than at the edges of ulcers or in the superficial mucosa. Adjacent nuclei may be enlarged, appear smudged, or have a “ground-glass” appearance, but they lack typical inclusions. Characteristic inclusions with virtually no associated inflammatory reaction may occur in severely immunocompromised patients.

In biopsy specimens, the diagnosis are easily missed when only rare inclusions are present. Examination of multiple levels and use of immunohistochemistry can be invaluable in detecting the rare cells containing an inclusion. Other diagnostic aids include viral culture, polymerase chain reaction (PCR) assays, in situ hybridization, serologic studies, and antigen tests. Serologic studies often have limited usefulness because of the persistence of latent CMV infection. In addition, isolation of CMV in culture does not imply active infection, because the virus can be excreted for months to years after a primary infection.²

Herpetic infection can occur throughout the GI tract but is most common in the esophagus and anorectum. Although herpes infection of the gut is often seen in immunocompromised patients and remains one of the most common infections in patients with human immunodeficiency virus (HIV), it is not limited to this group. In immunocompetent patients, infection is often self-limited.¹⁴ Immunocompromised patients, however, are at risk for disseminated infection and life-threatening illness.

Patients with herpetic esophagitis are seen with odynophagia, dysphagia, chest pain, nausea, vomiting, fever, and GI bleeding. Many have disseminated herpes infection at the time of diagnosis.¹⁵ Herpetic proctitis is the most common cause of nongonococcal proctitis in homosexual men. Patients typically are seen with severe anorectal pain, tenesmus, constipation, discharge, hematochezia, and fever. Concomitant neurologic symptoms (difficulty in urination and paresthesias of the buttocks and upper thighs) are also well described, as is inguinal lymphadenopathy.¹⁵

Pathologic Features

Ulcers are the most common gross finding in the esophagus, and these are usually associated with an exudate. The ulcers are often shallow and well-circumscribed. Some patients have vesicles surrounding the ulcers. Many patients have a nonspecific erosive esophagitis without discrete ulcers, however. In herpetic proctitis, the presence of perianal vesicles is common, often in association with pustules or shallow ulcers. Proctoscopic findings include ulceration and mucosal friability. Vesicles may extend into the rectum or anal canal.^15,16

Typical histologic findings, regardless of site, include ulceration, neutrophils in the lamina propria, and an inflammatory exudate that often contains sloughed epithelial cells (Fig. 4.2, A). Prominent aggregates of macrophages may also be present.¹⁷ In the anorectum, perivascular lymphocytic cuffing and crypt abscesses may be seen as well.

Characteristic viral inclusions and multinucleate giant cells are present in only a minority of biopsy specimens (see Fig. 4.2, B and C).⁷ The best place to search for viral inclusions is in the squamous epithelium at the edges of ulcers and in sloughed cells in the exudate. Two types of nuclear inclusions may be found: the homogeneous ground-glass inclusions and the acidophilic inclusions with a surrounding clear halo and peripheral chromatin margination (Cowdry type A inclusions). Inclusions may be single or multinucleate. The histologic findings for herpes simplex virus 1 (HSV-1) and HSV-2 are indistinguishable.

Differential Diagnosis

The differential diagnosis predominantly contains other viral infections, including CMV and varicella-zoster, that may infect the GI tract (see Table 4.1).¹⁸ Varicella produces histologic findings identical to those of HSV, but patients often have a rash.¹⁸ Mixed infections are common in many situations in which herpetic infection is found. Immunohistochemistry and in situ hybridization are very useful, and viral culture is a valuable diagnostic aid as well. Serologic studies may be useful if there is a very high or rising antibody titer, but serologic testing has limited use because latent infections can persist for years.

Adenovirus

Adenovirus infection is second only to rotavirus as a cause of childhood diarrhea, and it is associated with a broad spectrum of diseases in both children and adults. It has gained more attention in recent years as a cause of diarrhea in immunocompromised patients, especially those with AIDS and those who have received bone marrow or solid organ transplants.^19–21 Virtually all patients are seen with diarrhea, sometimes accompanied by fever, weight loss, and abdominal pain. Characteristic inclusions may be seen, especially in immunocompromised patients, in the nuclei of surface epithelial cells (particularly goblet cells); these are often accompanied by apoptotic epithelial cells and epithelial degenerative changes.^19,24 Adenovirus is also one of the associated with ileal and cecal intussusception in children.^22–24 The characteristic nuclear inclusions are known as “smudge cells” because of their enlarged, homogeneous, basophilic characteristics (Fig. 4.3; see Table 4.1). Useful aids to help in the diagnosis of adenovirus infection include immunohistochemistry, stool examination by electron microscopy, molecular studies, and viral culture. This entity is discussed further and illustrated in Chapter 5.

Other Enteric Viruses

Acute viral gastroenteritis is one of the most common causes of illness worldwide. Although most infections are self-limited, viral gastroenteritis can cause severe dehydration (particularly when caused by rotavirus), as well as chronic diarrhea in children with immunodeficiency syndromes such as severe combined immunodeficiency. Enteric viral infections are a significant cause of diarrhea in patients with AIDS. Rotavirus and enterovirus, like adenovirus, are associated with intussusception in children. Many enteric viruses do not cause disease in humans; others seldom cross the stage of the surgical pathologist because they are detected in stool samples rather than biopsy specimens. Common enteric viruses known to cause diarrhea in humans include, but are not limited to, adenovirus, rotavirus, coronavirus, astrovirus, Norwalk virus and other enteric caliciviruses, and echovirus and other enteroviruses.^25–30 Enteric involvement was documented in the coronavirus-associated severe acute respiratory syndrome (SARS), and diarrhea was a common presenting symptom in that outbreak.²⁵

Small bowel biopsy findings include villous fusion, broadening, and blunting; crypt hypertrophy; and an increased mononuclear cell infiltrate within the lamina propria with variably present neutrophils (Fig. 4.4). There may also be an increase in intraepithelial lymphocytes. Reactive and degenerative epithelial changes are usually present, particularly at the surface, including epithelial cell disarray and loss of nuclear polarity.^31,32 Increased apoptosis may be seen in surface and glandular epithelium. In the limited number of human studies available, the severity of the histologic lesion does not appear to correlate with clinical severity of illness. Most human studies of the histopathology associated with enteric viral infection are limited to the duodenum. The rare reports that have evaluated the large bowel have documented histologic findings ranging from normal to focal cryptitis with increased apoptosis. With the exception of adenovirus infection, inclusions are not seen on light microscopy.

Other viruses that affect the GI tract include measles (rubeola),^33,34 human herpesvirus 8 (HHV-8; also known as Kaposi sarcoma–associated herpesvirus),³⁵ HHV-6,^36,37 and Epstein-Barr virus (EBV), which is associated with a wide variety of lymphoproliferative disorders.

Human Papillomaviruses

Human papillomavirus (HPV) has been implicated in the pathogenesis of esophageal papillomas, esophageal squamous cell carcinomas, anal condylomas, and anal squamous cell carcinomas. These entities are discussed in detail in Chapters 19, 24, and 32.

Human Immunodeficiency Virus

GI disease is an important cause of morbidity and mortality in patients affected by HIV and in those with AIDS. Although opportunistic pathogens are often found in these patients, there is a subgroup in whom no pathogens are found despite extensive clinical and pathologic evaluation. The two major disease entities associated with HIV in the absence of other demonstrable pathogens are chronic idiopathic esophageal ulcers and AIDS enterocolopathy.

Chronic idiopathic esophageal ulcers reportedly cause 40% to 50% of ulcers found in HIV-infected patients.^38,39 The ability of HIV to directly cause these ulcers remains controversial, although evidence of HIV within the ulcerative lesions has been demonstrated by molecular analysis, immunohistochemical studies, and enzyme-linked immunosorbent assays (ELISA).⁴⁰ Patients are seen with severe odynophagia, independent of food intake; chest pain; and weight loss. The middle esophagus is the most common location, followed by the distal esophagus. Endoscopically, the ulcers consist of one or more well-circumscribed lesions of variable depth that can mimic ulcers caused by other infectious agents, particularly viral pathogens. They can be quite large (>3.0 cm in greatest dimension) and deep, with irregular margins and overhanging, edematous edges. Mucosal bridges and sinus tract formation may occur. Histologically, the ulcers contain granulation tissue with a mixed acute and chronic inflammatory infiltrate that often contains eosinophils. By definition, special histochemical stains and immunohistochemical stains for identifiable pathogens must be negative. This finding is especially important because these ulcers are sometimes treated with steroids.⁴¹ This entity is also discussed in Chapter 5.

HIV/AIDS enteropathy/colopathy is a somewhat controversial entity that has been loosely defined as the morphologic changes seen in the gut of patients with HIV/AIDS and chronic diarrhea for which no other infectious cause has been identified. The controversy arises because asymptomatic patients may have similar morphologic findings on biopsy and, conversely, severely symptomatic patients may have normal biopsies.⁴² In addition, there is always the added concern that a causative pathogen simply has been missed. Because patients with HIV/AIDS do have severe impairments of GI function including diarrhea, malabsoprtion, and weight loss, even in the absence of any demonstrable pathogens, many authors support use of the term AIDS enteropathy (or colopathy) to describe the morphologic findings, provided that the bowel has been adequately sampled and all other infectious causes have been excluded.^43–45 However, other authorities believe that this is a poorly understood term that does not clearly represent a specific disease entity and therefore should be avoided.

Endoscopy and colonoscopy findings are usually normal. In the small bowel, the histologic features include villous blunting and atrophy, crypt hypertrophy, increased intraepithelial lymphocytes, variably increased mononuclear cells in the lamina propria, increased mitoses within glandular epithelial cells, and increased numbers of apoptotic enterocytes at the surface and in the glands. In the colon, inflammatory changes are similar, but the apoptotic epithelial cells in the glandular epithelium are often very prominent (Fig. 4.5). The changes resemble those seen in mild graft-versus-host disease and chemotherapy-related mucosal injury.^43–45 Other pathogens, particularly other viruses such as CMV and adenovirus that can produce similar histologic features, must be rigorously excluded.

Acute Self-Limited Colitis

The ASLC pattern is the most common pattern in enteric infections. Typical histologic features include neutrophils in the lamina propria, with or without crypt abscesses and cryptitis; preservation of crypt architecture; and lack of basal plasmacytosis.^1,46–51 The acute inflammatory component is often most prominent in the middle to upper levels of the crypts. Lack of crypt distortion, Paneth cell metaplasia, and basal lymphoplasmacytosis help to distinguish ASLC from IBD.^1,51 The changes may be focal, as in focal active colitis, or diffuse.

Surgical pathologists should be aware of the infections that are most likely to mimic other IBD, particularly Crohn’s disease, ulcerative colitis, and ischemic colitis (see Table 4.2). Because most patients do not present for endoscopy until several weeks after the onset of symptoms, pathologists usually are not exposed to the classic histologic features of acute infectious colitis. This is important because the resolving phase of infectious colitis is more challenging to diagnose. At this stage, only occasional foci of neutrophilic cryptitis and only patchy increases in lamina propria inflammation may be found, and these may, in fact, contain abundant plasma cells and increased intraepithelial lymphocytes, features that are also seen in Crohn’s disease or even lymphocytic colitis. It is important to be aware of the patient’s symptoms (particularly acute versus chronic onset) and, ideally, the culture results, because the exact diagnosis may be difficult to resolve on histologic grounds alone. The pathologic details of specific bacterial infections are discussed in the following sections.

V. cholerae (specifically the toxigenic O1 strain) is the causative agent of cholera, an important worldwide cause of watery diarrhea and dysentery that may lead to significant dehydration, electrolyte imbalance, and death within hours.^52,53 Most infections result from consumption of raw or undercooked seafood, especially shellfish. Other vibrios, including non-O1 strains of V. cholerae, Vibrio hollisae, and Vibrio parahaemolyticus, also can cause severe gastroenteritis.⁵⁴ Symptoms of cholera include the abrupt onset of diarrhea, usually profusely watery and rarely bloody, accompanied by abdominal pain, vomiting, muscle cramps, and fever. Disseminated infection is a particularly important risk with immunocompromised patients; patients with underlying liver disease, partial or total gastrectomy, and diseases of iron metabolism are also at risk for more serious Vibrio infections.

Despite the severity of the illness, V. cholerae O1 is a noninvasive toxin-producing organism that cause minimal or no histologic change to the intestinal mucosa. Nonspecific findings such as small bowel mucin depletion, degenerative surface epithelial changes, and a mild increase in lamina propria mononuclear cells have been rarely reported.^55,56 Non-toxigenic O1 and other non-cholerae Vibrio species may show an erosive enterocolitis with active neutrophilic inflammation and associated hemorrhage. Useful ancillary diagnostic tests include culture, PCR, and serologic studies.⁵⁷ A history of travel to or emigration from an endemic or epidemic area also can be invaluable.