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Gastrointestinal Pathology
Optimal interpretation of endoscopic gastrointestinal biopsy specimens requires adequate clinical information including medication history and illnesses that may have associated gastrointestinal findings. The clinical history can guide additional studies in addition to the standard hematoxylin and eosin staining. Precise identification of the biopsy site enables the most accurate and definitive diagnosis. The endoscopist should attempt to obtain the largest possible piece of tissue. Multiple biopsies for each site often provide the best information. If special studies such as culture for microorganisms, electron microscopy, or flow cytometry are required, communication with the laboratory before biopsy is recommended. Standard histopathologic evaluation is best performed on tissue immediately placed in fixative. The resulting “final diagnosis” may require rereview if additional clinical findings are obtained.
Esophageal Biopsy
Gastroesophageal Reflux
Gastroesophageal reflux disease (GERD) describes a symptomatic clinical condition related to reflux of gastric and/or duodenal contents into the esophagus that causes troublesome symptoms and/or complications. The term reflux esophagitis refers to a subset of patients, usually with symptoms of GERD, who show endoscopic and/or histologic manifestations of inflammation within squamous and/or gastric cardia–type mucosa. Many consider esophagogastroduodenoscopy with biopsy the prudent initial evaluation of patients with symptoms of GERD. It often excludes other conditions in the clinical differential such as eosinophilic esophagitis (EoE), infective esophagitis, and “pill esophagitis.”
The endoscopic changes described with GERD are seen more often in severe cases and include erosions, ulcers, and stricture. Erosive lesions are often sampled to rule out cytomegalovirus (CMV), Candida species, and herpes virus infection. Approximately one-third of patients with reflux have endoscopically normal or only slightly hyperemic esophageal mucosa; however, endoscopic biopsy specimens show characteristic histologic changes (see later discussion). Although debated, some investigators consider histologic evaluation of biopsy specimens the “gold standard” in the diagnosis of GERD and reflux esophagitis.
Histologic Changes—Squamous Mucosa
Well-oriented normal esophageal squamous mucosa demonstrates a basal cell layer that is usually one to three cells thick. These basal cells can be discerned by their smaller size and their more basophilic cytoplasm compared with normal surface squamous cells. Lamina propria papillae are present but make up only one-half of the total epithelial thickness.
Biopsy specimens from lesions in GERD (erosions, ulcers) show acute inflammation of the mucosa and lamina propria. Exudates containing neutrophils and eosinophils often overlie an erosion or an ulcer with an inflamed granulation tissue base. Acute inflammation is fairly specific but insensitive for reflux esophagitis. , Characteristic squamous mucosal changes of reflux consist of hyperplasia (lamina propria papilla greater than 67% of the thickness of the squamous mucosa) and an increase in the basal cell layer (more than 15% of the squamous mucosal thickness). , These abnormalities are often accompanied by increased numbers of intraepithelial eosinophils and lymphocytes ( Fig. 65.1 ). A unique “hybrid” epithelium with features of both squamous and columnar mucosa has also been mentioned as a feature of reflux esophagitis. The squamous mucosa adjacent to ulcers and erosions can show striking regenerative features, with basal cells occupying the full thickness of the squamous mucosa and papillomatosis that may mimic squamous carcinoma or dysplasia. Consensus statements regarding the histologic characteristics of GERD and their observer reliability have been published. , In general, there is no histologic lesion that is pathognomonic of GERD, but the characteristic constellation of features of GERD, including basal cell hyperplasia, papillary elongation, intraepithelial eosinophil/neutrophil/lymphocyte numbers, and erosions all have at least acceptable agreement scores and are helpful in confirming histologic GERD in the appropriate endoscopic and clinical context.
Histologic Changes—Glandular Mucosa
Several investigators have suggested that the presence of gastric cardia–type mucosa in the esophagus at or near the squamocolumnar junction may be metaplastic and that inflammation of this metaplastic gastric cardia–type mucosa (so-called carditis) correlates strongly with GERD. , In contrast, other investigators have concluded that this “carditis” is a manifestation of gastric Helicobacter pylori infection. ,
The authors believe that these apparent disparate viewpoints can be reconciled based on methodologic differences and inherent biases within these studies and that, depending on the patient population and biopsy location, both schools of thought may be correct. Biopsy specimens from the stomach, even millimeters within the termination of the gastric rugae, reflect disease processes of the stomach. Therefore inflammation and intestinal metaplasia in that area correlate with H. pylori infection. However, “carditis” at the esophagogastric junction or above is characteristic of patients with gastroesophageal reflux as demonstrated by symptoms and manometric and pH probe abnormalities, and this probably comprises the majority of the gastric carditis seen in practice.
Differential Diagnosis
Infectious Esophagitis
Herpetic esophagitis typically occurs in immunosuppressed patients (e.g., those with acquired immune deficiency syndrome, those receiving chemotherapy, and following bone marrow transplantation). Endoscopic evaluation demonstrates shallow or “punched out” ulcers with adjacent normal-appearing squamous mucosa. Biopsy specimens demonstrate an ulcer base that is often limited in acute inflammation but may have prominent aggregates of mononuclear cells. Diagnostic herpes viral inclusions are found in the squamous epithelium adjacent to the ulcer and are characterized by squamous epithelial cells with nuclear molding, margination of nuclear chromatin, and multinucleation. , Infection can be confirmed with immunohistochemical stains. Occasional multinucleated squamous epithelial giant cells without viral inclusion may occur as part of reflux esophagitis and should not be confused with herpetic infection.
Inclusions of CMV are usually found at the base of ulcers rather than in the epithelium. CMV inclusions, characterized by enlarged cells with large “owl’s eye” nuclear inclusions as well as cytoplasmic inclusions, typically affect mesenchymal cells such as fibroblasts, smooth muscle, and endothelial cells ( Fig. 65.2 ). , Immunostains for CMV are also available.
Candida esophagitis often occurs in patients with other debilitating illnesses such as immunosuppression, diabetes mellitus, and long-term antibiotic therapy. Endoscopically, Candida esophagitis presents as brownish-white plaques or as a “cheesy” exudate. The diagnosis of Candida esophagitis requires the identification of budding yeast and pseudohyphae, usually within the inflammatory exudate. Their identification is certainly enhanced by using special stains for fungi (e.g., Gomori methenamine silver or periodic acid Schiff [PAS]).
Eosinophilic Esophagitis
Symptomatic and histologic reflux esophagitis does occur in children ; however, one should be wary of diagnosing reflux esophagitis in the presence of large numbers of eosinophils because many of these cases represent EoE. According to 2011consensus guidelines, “Eosinophilic esophagitis represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.” Clinicopathologic correlation of all clinical (including response to treatment), endoscopic, laboratory, and histologic data is essential for the diagnosis of EoE. Patients frequently report an “allergic history,” and males are three times more likely to be affected by EoE than females. , Clinical manifestations vary by age—infants and toddlers often present with feeding problems; school-age children typically manifest with vomiting and abdominal pain; and teenagers most often report dysphagia. , Food impaction affects more than one-third of patients during the disease course.
Upper endoscopy with biopsy of esophageal mucosa (preferably distal and proximal esophagus submitted separately) remains critical to the diagnosis of EoE. Erosions or ulcers are seldom seen, but many patients exhibit longitudinal esophageal furrows, rings, stenosis, or small white vesicles or plaques. Approximately 10% of children will have no abnormalities visually at endoscopy. , The typical biopsy from an EoE patient will show dramatic increases in eosinophils (sometimes >100 in one high-power field) in both the distal and proximal esophagus as well as eosinophilic “microabscesses,” which are small clusters of eosinophils, often towards the epithelial surface ( Fig. 65.3 ). Eosinophils may also exhibit “superficial layering” at the luminal surface. Other findings such as subepithelial fibrosis and eosinophil degranulation have been reported in EoE in addition to nonspecific reactive changes such as basal cell hyperplasia and elongation of the lamina propria papillae. Unfortunately, no single histologic finding is specific for the diagnosis, and, practically speaking, it is the responsibility of the pathologist to identify increased eosinophils (at least 15 eosinophils in a high-power field or approximately 60 eosinophils/mm 2 ) in the epithelium and attempt at identifying a cause. According to most recent guidelines, esophageal eosinophilia alone (i.e., without consideration of clinical presentation) is not diagnostic of EoE.
When the clinician receives a biopsy report of “squamous mucosa with increased intraepithelial eosinophils,” they must be aware that many other entities may cause esophageal eosinophilia, including GERD, gastrointestinal eosinophilic diseases, infections, achalasia, drug reactions/pill esophagitis, and others. , Most frequently, the differential diagnosis is GERD, wherein response to proton pump inhibitor (PPI) therapy and/or pH monitoring can be helpful (in addition to clinical history) in resolving this differential. That said, a seemingly overlap entity, preliminarily termed PPI-responsive esophageal eosinophilia, has emerged and muddied the waters in separating GERD from EoE. , , More recent research has found that EoE and GERD are not mutually exclusive. For example, approximately 50% of patients with “symptomatic esophageal eosinophilia” and endoscopic signs of EoE respond to PPI therapy. For these reasons, a PPI trial is no longer required to diagnose EoE. ,
Pill Esophagitis
Esophageal injury can occur with prolonged direct mucosal contact with medicinal tablets or capsules, even in therapeutic doses. , Endoscopic erosions and ulcers are found in more proximal locations of the esophagus (vs. GERD), often in areas of external esophageal compression such as near the aortic arch or left atrial appendage, especially in patients with cardiomegaly. The histology of “pill esophagitis” is nonspecific, but pill-induced esophageal injury can cause an eosinophilic infiltrate similar to EoE.
Barrett Esophagus
Barrett esophagus, the eponym given to columnar epithelium-lined esophagus, is acquired through chronic gastroesophageal reflux and occurs rarely in children. According to the current American College of Gastroenterology guidelines, true Barrett esophagus should be restricted to cases with salmon-colored mucosa extending 1 cm or greater into the tubular esophagus in which the biopsy demonstrates intestinal metaplasia (with goblet cells). Endoscopy remains the mainstay in the diagnosis of Barrett esophagus. In general, the color (orange-red) and appearance (velvety) of Barrett epithelium as seen through the endoscope is similar to that of normal gastric mucosa and can appear as circumferential or as tongue-like extensions of orange-red mucosa into the tubular esophagus. Because other conditions can sometimes mimic Barrett esophagus endoscopically, the endoscopist’s impression must be confirmed histologically.
Specialized columnar epithelium is the distinctive epithelial type considered diagnostic for Barrett esophagus and consists of goblet cells and columnar cells. The goblet cells contain mucin that stains positively with both PAS and alcian blue at pH 2.5. The columnar cells between goblet cells most often resemble gastric foveolar epithelium or less commonly intestinal absorptive cells.
Barrett esophagus is encountered only rarely in children undergoing upper endoscopy, with an estimated prevalence of 0.02% to 0.5%. These patients often have comorbidities that predispose to severe reflux, such as neurologic impairment, chronic lung disease, repaired esophageal atresia, or treated intrathoracic malignancy. Dysplasia or carcinoma complicating Barrett esophagus in children is even rarer. Guidelines have been proposed for surveillance endoscopy with biopsy in children with Barrett esophagus. ,
Stomach Biopsy
Endoscopy and biopsy in children are used to establish a diagnosis of gastritis and to look for specific causes of gastritis, most commonly H. pylori infection, eosinophilic gastroenteritis, or Crohn disease; however, the majority of causes of gastritis are likely nonspecific ( Table 65.1 ). Furthermore, it is well recognized that there is an imperfect correlation between the endoscopic and histologic impression ( Table 65.2 ), with endoscopy having approximately a 69% sensitivity and 36% specificity for histologic abnormalities in children.
Table 65.1
Underlying Etiology of Gastritis in Children
| Etiology | Frequency |
|---|---|
Common
|
|
Uncommon
|
|
Table 65.2
Endoscopic-Histologic Correlation in Pediatric Gastric Mucosa
| Normal Histology | Abnormal Histology | |
|---|---|---|
| Normal endoscopy | 23 | 9 |
| Abnormal endoscopy | 41 | 20 |
| Sensitivity—20/29 (69%) | ||
| Specificity—23/64 (36%) | ||
H. pylori is responsible for up to 70% of cases of chronic gastritis and can be found in the stomachs of more than 90% of children who have a duodenal ulcer. H. pylori infection is easily diagnosed in endoscopic biopsy specimens. Typical patterns of inflammation include chronic inflammation of antral mucosa and superficial lymphoplasmacytic infiltration of the lamina propria adjacent to gastric pits in gastric body type mucosa ( Fig. 65.4 ); either pattern can be associated with acute inflammation. One series of young children (<2 years) found that H. pylori infection is seen in approximately 7.5% of cases with normal histology ( Table 65.3 ). The organisms can be seen on routine hematoxylin and eosin–stained sections, but identification is enhanced by use of special techniques such as Giemsa ( Fig. 65.5 ), Steiner, Warthin-Starry, or immunohistochemistry. The comma-shaped bacilli are typically encountered in the mucous layer overlying gastric foveolar epithelium. Although active (neutrophilic) inflammation is characteristic of untreated infection, patients taking either PPIs or anti- H. pylori antibiotic regimens may not demonstrate this characteristic finding ( Table 65.4 ). Thus it is reasonable to use adjunctive stains in the setting of chronic inactive gastritis as well as chronic active gastritis.
TABLE 65.3
Gastric Endoscopic Findings in 152 Children <2 Years Old in Relation to Helicobacter pylori Status
| H. pylori (+) | H. pylori (−) | P -Value | |
|---|---|---|---|
| Endoscopic gastritis | 55.0% | 53.6% | 0.673 |
| Antral nodularity | 17.5% | 7.1% | 0.054 |
| Normal endoscopy | 12.5% | 12.5% | 0.690 |
| Histologic gastritis | 65.0% | 4.5% | <0.001 |
| Lymphoid aggregates/follicles | 57.5% | 18.8% | 0.005 |
| Normal histology | 7.5% | 28.6% | 0.378 |
Table 65.4
Histology of Helicobacter pylori + Gastric Biopsies With and Without Prior Therapy
| Histology of H. Pylori + Biopsy | |||
|---|---|---|---|
| Prior Therapy | Normal | Chronic Inactive Gastritis | Chronic Active Gastritis |
| None | 0/31 (0%) | 1/32 (3%) | 6/6 (100%) |
| PPI or anti- H. pylori | 0/5 (0%) | 28/40 (70%) | 1/1 (100%) |
PPI , Proton pump inhibitor.
The principal differential diagnostic consideration is acute erosive gastritis/reactive gastropathy, often referred to as chemical-type gastritis because of its association with bile reflux, steroid use, and nonsteroidal antiinflammatory drugs (NSAIDs). Endoscopically, the gastric mucosa of erosive gastritis/reactive gastropathy may be erythematous with areas of erosion or ulcer. Histologically, mucosal erosions and/or fibromuscular change in the lamina propria are seen; both can be associated with loss of mucin in the foveolar epithelium and foveolar hyperplasia.
Gastric inflammatory lesions of Crohn disease usually occur in association with Crohn disease lesions elsewhere in the gastrointestinal tract. Granulomatous inflammation can be seen; however, focally enhanced gastritis seen in the absence of H. pylori is a pattern more frequently seen in patients with inflammatory bowel disease (IBD) (either Crohn disease or ulcerative colitis). ,
Ménétrier-type gastritis with foveolar hyperplasia and protein loss has been described in children in whom it is usually associated with CMV infection. Unlike Ménétrier disease of adults, the pediatric lesion is usually self-limiting. Polyps such as juvenile or hyperplastic polyps, which are often indistinguishable from each other on a polyp-by-polyp basis, are most often confused with Ménétrier disease. Pathologically, Ménétrier disease can be distinguished from these polyps by the preservation of glandular architecture with “parallelism” as well as prominent smooth muscle fibers in Ménétrier lesions. In contrast, hyperplastic/juvenile polyps characteristically contain a more disorganized foveolar compartment with more impressive edema in the lamina propria and a lower gland-to-stroma ratio. Gastric polyps are rare in children and are often seen in patients with polyposis syndromes such as juvenile polyposis or familial adenomatous polyposis (FAP) ( Table 65.5 ).
Table 65.5
Upper Gastrointestinal Tract Polyps in Children
| 45/5766 (0.8%) children had polyps: |
| 17 Hyperplastic-inflammatory polyp |
| 16 Fundic gland polyp (7 at least indefinite for dysplasia) |
| 13 Familial adenomatous polyposis |
| 4 Hamartomatous (Peutz-Jeghers) |
| 2 Adenomas |
| 1 Heterotopic |
| 1 Indeterminate |
Small Intestinal Biopsy
Normal Small Intestinal Histology
The ratio of villous to crypt length approximates 3:1 to 5:1. Inflammatory cells, including plasma cells, are normally present in the lamina propria. Intraepithelial lymphocytes are present in a ratio of up to 20 lymphocytes per 100 enterocytes. A brush border should be discernible on the enterocyte. Enterocyte nuclei should be basilar in location and evenly aligned. Identification of four normal villi in a row usually indicates that the villous architecture of the whole biopsy specimen is normal ( Fig. 65.6 ). This does not mean that biopsy specimens with fewer than four aligned normal villi should be considered inadequate for evaluation, because even one normal villous in a proximal small bowel biopsy specimen makes celiac sprue less likely. Conversely, finding four normal villi in a row does not necessarily rule out focal lesions, although this is frequently the case.
Patterns of Abnormal Small Bowel Architecture
The small bowel mucosal responses to injury are limited, and recognition of a response pattern can be useful in the differential diagnosis ( Table 65.6 ). In this chapter, the term severe villous abnormality describes a flat intestinal mucosa in which no villi are seen or the villi are markedly shortened (villous to crypt length approximately 1:1). Usually, this change is diffuse, accompanied by epithelial lymphocytosis (30 to 40 or more intraepithelial lymphocytes per 100 enterocytes) and associated with crypt hyperplasia, evidenced by numerous mitotic figures. The term variable villous abnormality describes specimens in which the villi are either only focally flat or are less than flat (mild or moderate villous shortening). Many specimens in this category also show increased intraepithelial lymphocytes. These changes may be associated with features that suggest a specific diagnosis (e.g., numerous eosinophils, granulomas, parasites) or may be nonspecific.
TABLE 65.6
Patterns of Abnormal Small Bowel Architecture
| Pattern | Conditions |
|---|---|
| Entities usually associated with a diffuse severe villous abnormality and crypt hyperplasia | Celiac sprue Refractory or unclassified sprue Other protein allergies Lymphocytic enterocolitis |
| Entities usually associated with a variable villous abnormality and crypt hypoplasia | Kwashiorkor, malnutrition |
| Megaloblastic anemia variable | |
| Radiation and chemotherapeutic effect | |
| Microvillus inclusion disease | |
| End-stage refractory or unclassified sprue | |
| Entities usually associated with a nonspecific variable villous abnormality, usually not flat | Changes associated with dermatitis herpetiformis |
| Partially treated or clinically latent celiac sprue | |
| Infection | |
| Stasis | |
| Tropical sprue | |
| Mastocytosis | |
| Nonspecific duodenitis | |
| Autoimmune enteropathy | |
| Entities associated with variable villous abnormalities illustrating specific diagnostic changes | Collagenous sprue |
| Common variable immunodeficiency | |
| Whipple disease | |
| Mycobacterium avium-intracellulare complex infection | |
| Eosinophilic gastroenteritis | |
| Parasitic infestation | |
| Lymphangiectasia | |
| Abetalipoproteinemia | |
| Tufting enteropathy |
Entities Associated With a Diffuse Severe Villous Abnormality and Crypt Hyperplasia
Celiac sprue
Celiac sprue, also known as gluten-induced enteropathy , gluten-sensitive enteropathy , and nontropical sprue , is a major cause of malabsorption. , The pathogenesis of celiac sprue involves immunologic injury to the enterocyte associated with the ingestion of the protein gluten, which is found in cereal grains such as wheat, rye, and barley. Celiac sprue is clearly a human leukocyte antigen (HLA)-associated condition, primarily associated with the major histocompatibility complex class II alleles DQA1∗0501 and DQB1∗0201. This HLA-DQ2 allelic combination is found in 98% of patients with celiac sprue. Patients with celiac sprue usually show a quick and dramatic clinical improvement following removal of gluten from the diet and quickly relapse after its reintroduction. ,
The severe villous abnormality of celiac sprue is associated with increased lymphocytes and plasma cells in the lamina propria and intraepithelial lymphocytosis ( Fig. 65.7 ). Current guidelines suggest a minimum threshold of 25 lymphocytes per 100 enterocytes for a diagnosis of intraepithelial lymphocytosis, often showing increased density at the tips of the villi. Assessment of intraepithelial lymphocytosis is best performed on the hematoxylin and eosin–stained slide, and immunohistochemical staining for CD3 is not currently advocated. The enterocyte nuclei lose their basilar alignment and become stratified. The histologic abnormality is most severe in the duodenum and gradually lessens distally along the small bowel. With gluten withdrawal, the abnormalities recede from distal to cephalad in the small intestinal mucosa. Thus proximal small bowel biopsy specimens may remain abnormal for quite some time, even in patients showing marked clinical improvement. In both the pediatric and adult population, involvement may be patchy, and studies have shown that increased numbers of biopsy fragments aid pathologists in the diagnosis of celiac disease. The most recent guidelines from the American College of Gastroenterology and the American Gastroenterological Association currently recommend two biopsies from the duodenal bulb and at least four biopsies from the distal duodenum. , In addition to the number of biopsy fragments, it has also been suggested that the biopsy technique may impact the quality of the biopsy fragments, with the single-biopsy per pass technique associated with more well-oriented specimens than the double-biopsy per pass technique. A pathologist does not make the diagnosis of celiac sprue. All that can be said is that the specimens contain a villous abnormality (villous blunting or atrophy) and increased intraepithelial lymphocytes that are consistent with celiac sprue. Definitive diagnosis depends on demonstration of a suitable clinical presentation, compatible serologic tests (e.g., immunoglobulin A [IgA] antiendomysial antibodies, anti–tissue transglutaminase antibodies, antideaminated gliadin) and small bowel histology, and clinical and, ideally, histologic response to a gluten-free diet.
The histologic differential diagnosis includes all entities that may cause at least a focal severe villous abnormality: immunodeficiency syndromes, protein allergies other than gluten, some cases of infectious gastroenteritis, tropical sprue, stasis, IBD including Crohn disease, drug effect (especially NSAIDs), and nonspecific duodenitis. Clinicopathologic correlation is essential for proper diagnosis. All biopsy specimens should be evaluated carefully for plasma cells because their absence in common variable immunodeficiency (CVID) syndrome is easy to overlook. Numerous neutrophils, cryptitis, and crypt abscess formation are usually not part of celiac sprue, and entities such as infectious gastroenteritis, Crohn disease, nonspecific duodenitis, and stasis syndromes should therefore be considered. That said, some amount of neutrophilic inflammation is often encountered in celiac sprue, particularly in children.
The most common cause of unresponsiveness after implementing a gluten-free diet is that the diet is not really gluten free. If dietary indiscretions are ruled out, patients may have refractory or unclassified sprue, , which may respond to the administration of corticosteroids. Refractory sprue can also be associated with cavitation of mesenteric lymph nodes and hyposplenism. Refractory sprue has been classified into two types, based on the predominant subset of intraepithelial T cells within the biopsy. Type 1 refractory sprue is characterized by CD3+, CD8+ T cells infiltrating the epithelium, which is the same as classic celiac sprue. Type 2 is characterized by CD3+, CD8− T cells within the epithelium. It is thought that the type 2 refractory sprue patients are less responsive to treatment and are at are risk of developing T-cell lymphoma. , Persistent symptoms despite gluten withdrawal with small-bowel histologic improvement should prompt a search for other comorbidities that may cause diarrhea, such as pancreatic insufficiency, lactase deficiency, lymphocytic colitis, bacterial overgrowth, or coexisting IBD.
Other protein allergies
Patients with allergic reactions to chicken, soy protein, milk, eggs, and tuna fish have been described and show a flat small-bowel mucosa similar to that seen in celiac sprue. Definitive diagnosis depends on identifying the offending protein, showing a response to its withdrawal from the diet, and demonstrating recrudescence of symptoms and pathology with its reintroduction.
Entities Associated With a Variable Villous Abnormality and Crypt Hypoplasia
Marasmus and kwashiorkor
Biopsy specimens from malnourished patients with marasmus (severe calorie and protein deficiency) and kwashiorkor (low-protein but adequate caloric intake) have reportedly shown variable villous abnormalities associated with increased intraepithelial lymphocytes, sometimes indistinguishable from those of celiac sprue. ,
Megaloblastic anemia–radiation and chemotherapy effect
Nutritional deficiency of folate and vitamin B 12 may result in impaired epithelial cell replacement because of decreased DNA synthesis. Consequently, a variable villous abnormality with or without megaloblastic epithelial changes can be seen. , Because radiation therapy and chemotherapeutic agents inhibit DNA synthesis, the intestinal mucosal changes are similar to those in folate and vitamin B 12 deficiency and are associated with decreased mitotic activity in the crypts. Chemotherapy and irradiation may also cause focal necrosis of epithelial cells (apoptosis) and increased numbers of chronic inflammatory cells within the mucosa and submucosa. ,
Microvillus inclusion disease
Microvillus inclusion disease, which also includes patients classified as microvillus dystrophy, is an inherited autosomal recessive condition causing intractable diarrhea with steatorrhea in infants. It was first reported under the designation familial enteropathy, and mutations of the MYO5B gene have been found in microvillus inclusion disease patients. Diarrhea persists despite total parenteral nutrition, and patients often require small bowel transplantation. The entity should be recognized so that genetic counseling can be offered. Small bowel biopsy specimens show a severe villous abnormality with crypt hypoplasia. From low magnification, the histology may resemble celiac sprue, but intraepithelial lymphocyte levels are usually not increased. PAS stain may show absence of the apical brush border. Transmission electron microscopy can establish the diagnosis by identifying abnormal microvillus structures at the luminal border of the enterocyte and apical intracytoplasmic inclusions lined by microvilli in the same cells ( Fig. 65.8 ). The intracytoplasmic vacuoles can also be detected with PAS stain or with carcinoembryonic antigen (CEA) immunostaining. Prominent cytoplasmic enterocyte CD10 immunoreactivity is also described in microvillus inclusion disease.
Entities Associated With a Nonspecific Variable Villous Abnormality
Many diseases are associated with nonspecific variable villous abnormalities in which the villi are not completely or diffusely flattened. Although most biopsy specimens showing this change are from patients with clinically latent or partially treated celiac sprue, , other conditions entering the differential diagnosis include dermatitis herpetiformis, tropical sprue, infectious gastroenteritis, stasis of small intestinal contents, Zollinger-Ellison syndrome, mastocytosis, duodenitis and peptic ulcer disease, and autoimmune enteropathy. Furthermore, approximately 10% of pediatric patients with duodenal intraepithelial lymphocytosis and normal villous architecture will have a new definitive diagnosis of celiac sprue.
The term autoimmune enteropathy has been applied to an intractable watery diarrhea syndrome that has been associated with circulating autoantibodies against intestinal epithelial cells. , The patients often have variable immunodeficiency and autoimmune phenomena such as juvenile-onset diabetes mellitus, rheumatoid arthritis, and hemolytic anemia. , The related IPEX syndrome refers to an X-linked immune dysregulation, polyendocrinopathy, and enteropathy associated with a mutation of the FOXP3 gene. The small bowel mucosa shows a variable villous abnormality that is often severe and resembles that of celiac sprue. Surface and crypt epithelial degenerative and regenerative changes occur, but many illustrated cases show few intraepithelial lymphocytes, a feature that may distinguish autoimmune enteropathy from celiac sprue. Furthermore, intraepithelial lymphocytosis, if present, tends to be found in the deep crypts rather than the tips of the villi as in sprue. Loss of goblet cells and/or Paneth cells as well as increased crypt apoptotic activity have also been described as characteristic of autoimmune enteropathy. Adjunctive testing such as anti-enterocyte and anti–goblet cell antibody testing (performed at Children’s Hospital of Philadelphia and other specialized laboratories) is also helpful in some cases. Some patients with autoimmune enteropathy also have colitis. In some patients, the associated colitis resembles lymphocytic colitis, whereas in others, the endoscopic and histologic pictures are similar to that of ulcerative colitis. Untreated autoimmune enteropathy is usually severe and intractable, often requiring total parenteral nutrition. There have been scattered reports of favorable responses to tacrolimus, cyclosporin, and infliximab.
Entities Associated With Variable Villous Abnormalities Illustrating Specific Diagnostic Changes
Collagenous sprue
The term collagenous sprue describes the excessive subepithelial deposition of collagen associated with a severe villous abnormality noted in small-bowel biopsy specimens from some patients with malabsorption. Often these patients are diagnosed presumptively with celiac sprue but are unresponsive to gluten-free diet. When initially described and for many years thereafter, collagenous sprue was generally considered to follow a fulminant course that was often fatal. However, series have described better-than-expected responses to a strict gluten-free diet, immunosuppression, or both.
Immunodeficiency syndromes (excluding acquired immune deficiency syndrome)
Normal small bowel morphology is often seen on routine light microscopy in selective IgA deficiency, although nodular lymphoid hyperplasia may also be present. Decreased numbers of IgA-containing plasma cells can be demonstrated by immunocytochemical techniques, but these stains are not recommended for routine diagnosis.
Patients with CVID may have chronic diarrhea, malabsorption, and recurrent gastrointestinal giardiasis. , The morphology of small intestinal biopsy specimens may vary from normal to a severe villous abnormality mimicking celiac sprue. The majority, but not all, cases of CVID demonstrate nodular lymphoid hyperplasia associated with absent or markedly reduced numbers of plasma cells. Nodular lymphoid hyperplasia without plasma cell changes may also be seen in asymptomatic patients without an immunodeficiency syndrome, especially in children, in whom it may be considered a normal finding. An injury pattern resembling acute graft-versus-host disease (GvHD), with numerous apoptotic bodies deep in crypts, can also be seen in selective IgA deficiency and in CVID.
Chronic granulomatous disease (CGD), an X-linked or autosomal recessive defect in various subunits of nicotinamide dinucleotide phosphate (NADPH), is a well-recognized cause of inflammatory-mediated injury to the gastrointestinal tract and should be in the differential diagnosis of any young patient with IBD-type symptomatology. A review of 87 CGD patients with 313 upper and lower endoscopic biopsies revealed abnormal histology in 95% of patients, with the colon being the most frequently affected site and the esophagus being the least. Microgranulomas were seen in 61% and pigmented macrophages in 74%. Biopsies were either chronically or acutely inflamed in 63%, with 31% revealing mucosal eosinophilia. In most patients, an infectious etiology could not be identified.
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