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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e3181b5073a
Review Articles

Lymphocytic Disorders of the Gastrointestinal Tract: A Review for the Practicing Pathologist

Carmack, Susanne W. MD* †; Lash, Richard H. MD* †; Gulizia, James M. MD* †; Genta, Robert M. MD, FACG* †

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Author Information

*Caris Diagnostics, Irving

Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center at Dallas, Dallas, TX

Reprints: Robert M. Genta, Caris Diagnostics, 8400 Esters Boulevard, Suite 190, Irving, TX 75063 (e-mail:

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Increased numbers of intraepithelial lymphocytes (lymphocytosis) can be found in the esophagus, stomach, small intestine, and colon in a variety of clinical circumstances. This review, directed at practicing pathologists, portrays the normal resident lymphocyte population in the mucosa of each segment of the digestive tract and discusses the different situations that may result in quantitative or qualitative alterations of intraepithelial lymphocytes. Esophageal lymphocytosis has not been fully characterized and its clinical significance, if any, awaits definition. Thus, this diagnosis is presently discouraged. In the stomach, it is particularly important to exclude Helicobacter pylori infection and celiac sprue before diagnosing lymphocytic gastritis. Duodenal lymphocytic infiltrates, inextricably tied with alterations of the villous architecture of the mucosa, are often caused by gluten sensitivity. However, similar morphologic changes may be caused by a vast array of other conditions that must be carefully considered and excluded. Lymphocytic and collagenous colitis are most often unexplained, but their frequent association with autoimmune conditions or certain medications deserve a thorough investigation in each case. Using a combination of histologic and clinical clues, a cause for the intraepithelial lymphocytic infiltration can be identified in many instances. As some of the associated conditions are amenable to effective treatment, the importance of diligently seeking such associations before resorting to a diagnosis of primary lymphocytosis is emphasized.

Agastrointestinal (GI) pathologist with a sense of history will think of 1988 and 1989 as the years of the great awakening to intraepithelial lymphocytes (IELs). Although timid attempts to describe a variety of conditions in which increased density of mucosal, and particularly intraepithelial, lymphocytes had been made for more than a decade, these 2 years saw the emergence of lymphocytic gastritis in Belgium1 and the UK,2 the first detailed clinicopathologic descriptions of lymphocytic colitis in Baltimore,3,4 and the first suggestion of a more widespread disorder tentatively named lymphocytic enterocolitis.5 The following year lymphocytic gastritis was observed in association with celiac sprue,6,7 and whereas our 41st President was promising a “kinder, gentler nation,” Jack Yardley was offering a “gentler and more subtle” form of colitis.8

In this unofficial 20th anniversary of GI lymphocytosis, we have reviewed more than 300 publications on lymphocytic disorders from the esophagus (as we shall see a relatively unsuccessful newcomer) to the colon and have attempted to distil the information through the alembic of our joint experience. Our aim has been to provide practical, evidence-based information that diagnostic pathologists can employ in their everyday practice.

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Normal Esophageal Lymphocyte Population

The esophageal mucosa in healthy adults has a sparse, easily identifiable population of lymphocytes, often distorted (“squiggle cells”) with irregular nuclear contours. These cells have been identified as CD8+, TIA-1+ T lymphocyte9 and tend to be more prominent in the peripapillary epithelium. The numbers of these lymphocytes in the normal esophageal mucosa have been reported to range from 10 to 12 per high-power field9,10; Langerhans cells have been found to be frequently admixed with lymphocytes.11

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Esophageal Lymphocytosis

Although not studied as extensively as in other parts of the GI tract, esophageal lymphocytosis has been noted by several authors to be a feature of a number of local and systemic inflammatory disorders (Table 1, Fig. 1). Resnick et al found increased IELs in subjects with gastroesophageal reflux disorder (21 IELs/high-power field); this, however, has not been confirmed by other investigators, who found the absolute number of lymphocytes in reflux esophagitis to be indistinguishable from that of normal controls.10 Certain medications have been associated with lymphocytic infiltrates in the esophageal squamous epithelium, in particular gold, thiazides, and antimalarials.12 Increased numbers of IELs can often be found in the vicinity of lesions caused by a variety of etiologies, such as ingestion of caustic substances, impacted medications (“pill esophagitis”), reflux-induced ulcers and erosions, and infections.9 As the primary condition is usually evident in these circumstances, these locally increased lymphocytes rarely merit attention.

Table 1
Table 1
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Figure 1
Figure 1
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Other conditions in which esophageal lymphocytosis has been reported include achalasia13 and Behçet disease.14Lichen planus, a papular eruption most commonly found on the flexor surfaces of the upper extremities, the genitalia, and on the mucous membranes, may affect the oral cavity and the esophagus. The features of the squamous epithelium resemble more those of the oral than the cutaneous variant of lichen planus, and consist of a bandlike lymphocytic infiltrate, basal layer degeneration, and Civatte bodies (small rounded hyaline eosinophilic bodies that represent apoptotic keratinocytes), in addition to parakeratosis without hypergranulosis.15

Recently, Rubio has proposed the term “lymphocytic esophagitis” to indicate a histologic condition in which esophageal squamous mucosa harbors “high numbers of intraepithelial, mostly peripapillary lymphocytes, in the absence of intraepithelial granulocytes.”16 In this author's experience, 55% of patients with lymphocytic esophagitis were younger than 18 years, and 40% had Crohn disease; other patients had carcinoma elsewhere, gastroduodenitis, and reflux symptoms.

Other investigators, however, have not detected any significance to the presence of lymphocytosis in the esophagus. A more recent study by Purdy et al17 examined “lymphocytic esophagitis,” defined as above, and found no association between increased IELs and Crohn disease, reflux esophagitis, allergies, or particular medications.

We prefer not to use the term “lymphocytic esophagitis” to avoid conveying the impression of an established entity when in fact it only indicates a large, if unspecified, number of IELs not associated with specific signs or symptoms. If lymphocytic infiltrates are present and an etiology is not evident from either the histopathologic context or the patient's history, we mention it in a brief description.

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Normal Gastric Lymphocyte Population

The lamina propria of the normal stomach contain rare lymphocytes, mostly IgA-secreting B cells18; the normal number of intraepithelial T lymphocytes is 1 or less per 100 epithelial cells (Fig. 2).19 The normal gastric mucosa does not typically contain mucosa-associated lymphoid tissue,20 but small numbers of lymphoid aggregates can be found in antral biopsies from healthy subjects.

Figure 2
Figure 2
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Gastric Intraepithelial Lymphocytosis and Lymphocytic Gastritis

An increase in the number of gastric IELs can occur in association with a variety of conditions including Helicobacter pylori infection, syphilis, celiac sprue, Ménétrier disease, and Crohn disease (Table 2). We shall refer to this group, where the etiology is known, as “secondary gastric epithelial lymphocytosis” and reserve the term “lymphocytic gastritis” to the idiopathic condition described by Haot et al1 in 1988 and further characterized by Dixon et al.2

Table 2
Table 2
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Lymphocytic gastritis is diagnosed when the gastric surface and foveolar epithelium is infiltrated by at least 25 IELs per 100 epithelial cells, regardless of the inflammation in the lamina propria (Fig. 3, left). These lymphocytes have been characterized as CD8+ T cells (Fig. 3, right). In the initial description of this entity, most patients were symptomatic with severe dyspepsia, nausea, vomiting, and weight loss; a characteristic endoscopic appearance which included large folds, varioliform (“octopus-sucker”) gastritis, nodules, and erosions was often present.1,21,22 However, it is now clear that a large percentage of patients with lymphocytic gastritis have only mild nonspecific dyspeptic symptoms and a normal endoscopic appearance of the stomach. The diagnosis of primary idiopathic lymphocytic gastritis should be made only after conditions known to be associated with gastric intraepithelial lymphocytosis have been excluded. If the information is not available, a list of the conditions that need be excluded should be provided in a comment.

Figure 3
Figure 3
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A variant of lymphocytic gastritis is hypertrophic lymphocytic gastritis. Affected patients usually present with dyspepsia and evidence of protein loss (lower extremity edema, hypoalbuminemia) and endoscopy shows giant gastric folds.23,24 The histologic findings resemble the hypertrophic gastropathy of Ménétrier disease with the additional finding of prominent IELs.25,26 Case reports have described resolution of symptoms and a histologic normalization of the gastric mucosa with proton pump inhibitors27; H. pylori infection was detected in some patients but not others.28

H. pylori infection was one of the first putative etiologic agents for lymphocytic gastritis.2 However, fewer than 4% of patients with H. pylori infection have been found to have lymphocytic gastritis, and the rate of H. pylori infection in patients with lymphocytic gastritis is not different from that of the general population (36% in a study29). Thus, although some patients with H. pylori infection have more than 20 to 25 intraepithelial T cells per 100 gastric epithelial cells, H. pylori cannot be attributed an etiologic role in the pathogenesis of lymphocytic gastritis. In these patients lymphocytosis is more severe in the body than in the antrum, in contrast to patients who have concurrent celiac disease.29,30

In H. pylori gastritis, the lamina propria contains predominantly B lymphocytes and plasma cells with macrophages and mast cells (Fig. 4). Lymphoid follicles are common, which may help in identifying the etiology of the epithelial lymphocytic infiltration when other entities, such as celiac disease, are in the differential. Eradication of H. pylori results in a marked decrease in the mucosal inflammation, including the disappearance of intraepithelial T cells.31–33 The role of the CD8+ T lymphocytes in the epithelium in H. pylori gastritis has not been elucidated, and to our knowledge no hypotheses have been offered as to why a small subset of infected patients mounts this type of response in addition to the conventional B-cell responses found in virtually all H. pylori-infected subjects.19

Figure 4
Figure 4
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The association of gastric intraepithelial lymphocytosis with celiac disease is well established. Some degree of gastric lymphocytosis, often as low as 10 IELs/100 epithelial cells is found in 10% to 33% of adults and in up to 50% of children with celiac disease.19,34,35 In these patients, the distribution of IELs is predominantly antral.29 Rarely, concomitant lymphocytic or collagenous colitis may also be present,36 a finding that has led to the concept of “diffuse lymphocytic gastroenteropathy.”37 In patients with gastric lymphocytosis associated with celiac sprue, a gluten-free diet results in simultaneous resolution of both small intestinal and gastric disease, providing further support for a common etiology for these 2 conditions.38

Collagenous gastritis is a rare condition characterized by a patchy, thick bandlike subepithelial collagen deposition in the gastric mucosa, accompanied by focal superficial epithelial degeneration, numerous IELs, and a dense lymphoplasmacytic infiltrate in the lamina propria (Fig. 5).39–41 A relationship with lymphocytic gastritis has been hypothesized but not proven, based more on the analogy with the lymphocytic collagenous colitis sequence than on a documented evolution. Adults may present with watery diarrhea, but case reports of children note anemia from gastric bleeding.42 However, as several of the reported patients had concurrent celiac sprue, lymphocytic colitis, or collagenous colitis, the specificity of these presenting signs is uncertain.

Figure 5
Figure 5
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Medications, which are capable of inducing a wide variety of lesions in the stomach, including ulcers, parietal cell changes, apoptosis, and reactive gastropathy,43,44 are often cited as causes of gastric intraepithelial lymphocytosis. However, unlike lymphocytic colitis, no drug has been shown to increase the numbers of IELs in the gastric mucosa.

Increased numbers of IELs have been reported in the mucosa adjacent to both gastric adenocarcinomas and lymphomas.45,46 Although these findings may have interesting pathogenetic implications in tumor biology, their practical significance seems to be rather limited.

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Diagnosing Lymphocytic Gastritis

IELs should always be evaluated in areas distant from lymphoid follicles, because lymphocytes from the marginal zone may spill into the neighboring epithelium. However, these are B cells, and when in doubt immunostaining for CD3 and CD20 will provide the needed answer.

When a gastric biopsy specimen shows more than 20 or 30 intraepithelial T cells per 100 enterocytes, irrespective of the inflammatory background in the lamina propria, there exist the conditions for a diagnosis of gastric intraepithelial lymphocytosis or lymphocytic gastritis. At this point, a search for an etiology or an association should be made. If H. pylori infection is present, it is best to withhold the diagnosis of lymphocytic gastritis, and rather to describe the lymphocytosis and suggest rebiopsy 3 to 6 months after the eradication of the infection. At that point, if the lymphocytosis persists, a diagnosis of lymphocytic gastritis will be warranted. If celiac disease is present (clinically, or in duodenal biopsies) the association should be mentioned.

When there is no H. pylori infection, biopsies from other parts of the GI tract are either normal or not available, or no relevant history is provided, a diagnosis of lymphocytic gastritis can be made. If the presence of celiac disease is unknown, a comment suggesting the need to exclude it should be included.

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Normal Lymphocyte Population in the Duodenum

As the largest lymphoid organ in the body, the small intestine houses the body's defense to ingested antigens.47 In the duodenum, IELs comprise primarily CD8+ T cells (Fig. 6)48 and vary in number depending on their location: the lowest density is seen at the tips of villi, greater numbers are present in the crypts, and the largest concentrations are in the vicinity of lymphoid aggregates.49,50 Accurate evaluation of duodenal IELs requires well-oriented, 3 to 4-μm thick sections. Lymphocytes lying above the basement membrane should be counted in a stretch of 300 continuous enterocytes, excluding areas overlying lymphoid aggregates. Results are determined by the number of IELs per 100 enterocytes.49–53 In sections stained with hematoxylin and eosin, counts up to 20 IELs/100 enterocytes are considered normal; counts between 20 and 30 fall into the category of “borderline intraepithelial lymphocytosis”; more than 30 IELs/100 enterocytes is the threshold for pathologic intraepithelial lymphocytosis.47 When anti-CD8 or CD3 immunostaining is used, the numbers of identifiable IELs will rise; therefore, some authors suggest to increase the upper limit for normal to 25 IELs/100 enterocytes.50 One should note that these cut-off numbers are arbitrary, not uniformly applied, and subject to change. The upper limit for normal, for example, was considered to be 40 IELs/100 enterocytes until recently; however, this figure was based on counts performed on jejunal capsule biopsies, in which IELs are reported to be more numerous than in the duodenum, the segment of small intestine usually biopsied during a flexible upper endoscopy.50,54,55 The practicing pathologist, to whom this review is addressed, will undoubtedly ask how we could seriously suggest counting IELs in 300 enterocytes. These numbers are derived from studies specifically designed to evaluate the density of IELs in subjects with different conditions. In practice, lymphocyte counting is rarely necessary because when IELs are increased, they are readily identified without effort; when in doubt, the observer's attention should focus on the tips of villi, where a total of 12 IELs per villous tip has been suggested as the diagnostic threshold.56

Figure 6
Figure 6
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The Marsh Classification

Before discussing the specific conditions of the small intestine, it may be useful to introduce the Marsh classification system.57 Modified and adapted by several authors58–60 and most commonly used in Europe in the Oberhuber version,61 it categorizes the spectrum of histopathology associated with lymphocytosis and villous atrophy in the duodenum. A simplified version together with illustrations of the 3 basic pathologic findings is depicted in Table 3.

Table 3
Table 3
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Duodenal Intraepithelial Lymphocytosis

Table 4 lists the most common conditions associated with duodenal lymphocytosis. An increase in IELs in architecturally normal duodenal mucosa is commonly referred to as duodenal intraepithelial lymphocytosis (DIL) or, less commonly, as lymphocytic duodenosis.62 The characteristic appearance of DIL (Marsh grade 1) is depicted in Table 3.

Table 4
Table 4
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Although in most patients with DIL a specific etiology is never discovered, there are sufficient common associations to warrant a clinical evaluation. A subgroup of DIL patients has features supportive of gluten sensitivity. Approximately 11% of DIL patients test positive for IgA endomysial antibodies or antitissue transglutaminase (serologic tests highly specific for celiac disease), and one-third have the DQ2 allele (associated with celiac disease).62 In another 10% to 15%, duodenal lymphocytosis is associated with H. pylori gastritis, and a subset of these resolves when the infection is eradicated.63–65 Other etiologies have been recognized, but the causal relationship is less clear; these include food protein intolerance, common variable immunodeficiency, eosinophilic gastroenteritis, graft versus host disease, enteric viral infections, systemic autoimmune disorders, and nonsteroidal anti-inflammatory drug (NSAID) use.54,60,66–69 Some authors have noted a more pronounced eosinophil population in the lamina propria in some patients, suggesting an allergic nature for the mucosal lymphocytic infiltration.67,70 Crohn disease is often cited as a cause of DIL, but no statistically significant difference in IEL counts was found between patients with Crohn disease and normal controls.68 DIL has a seasonal incidence, with diagnostic peaks in the United States between January and April, suggesting environmental exposure as a contributing factor.71

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Celiac Disease

Also known as gluten-sensitive enteropathy, celiac sprue, and nontropical sprue, celiac disease is a condition affecting genetically susceptible individuals, who develop small intestinal injury and malabsorption after dietary exposure to gluten.72 The histology of celiac disease includes intraepithelial lymphocytosis, varying amounts of villous injury ranging from blunting to complete flattening of the villi, and increased inflammatory cells (particularly plasma cells, but also lymphocytes, neutrophils, and eosinophils) in the lamina propria. Crypt hyperplasia (an indication of higher enterocyte turnover) is a constant feature of celiac disease and is characterized by deeper crypts with large numbers of mitotic figures.

The histopathologic diagnosis of celiac disease requires examination of well-oriented duodenal biopsies. As the characteristic mucosal abnormalities are more severe in the distal duodenum and jejunum, biopsies are best obtained from the second part of the duodenum or more distally. Although the duodenal bulb may be affected and the histologic features may be diagnostic, the presence of Brunner glands and the possibility of peptic duodenopathy may preclude optimal evaluation of villous architecture.72

Several conditions may cause the duodenal mucosal changes described above, including tropical sprue and autoimmune enteropathy. Thus, the pathologist can only make a presumptive diagnosis (eg, “changes consistent with gluten-sensitivity enteropathy”); the definitive diagnosis requires characteristic duodenal histology in a patient on a gluten-containing diet with marked clinical response to a gluten-free diet, and followed by recurring symptoms on a gluten challenge.72 Confirmation with specific and sensitive serologic tests (antitissue transglutaminase and IgA endomysial antibodies) is now routine clinical practice.

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Refractory Sprue

Although most treatment failures in celiac disease can be traced to a lack of complete adherence to a gluten-free diet, either intentional or due to consumption of ubiquitous sources of gluten,73–75 a small proportion of patients with characteristic histologic and serologic features of celiac sprue fail to respond to documented gluten-free diet. These patients are categorized as having refractory sprue, a rare variant of celiac disease associated with a higher risk of progression to enteropathy-associated T-cell lymphoma.76 Immunohistochemical and molecular studies have demonstrated that the small intestinal epithelium of patients with refractory sprue contains a population of IELs consisting predominantly of CD3+ CD8 CD4 T lymphocytes, in contrast to CD3+ CD8+ CD4 T cells characteristic of untreated celiac sprue.77

In patients with refractory sprue, monoclonal T-cell receptor-γ gene rearrangements have been identified throughout the GI tract, and the diagnosis is considered by some to be akin to low grade or a forme fruste of intestinal T-cell lymphoma.78,79 However, as such rearrangements were also detected in 8% of celiac disease patients, great caution is required in the interpretation of polymerase chain reaction results, which must be carefully correlated with histology and clinical findings.80

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Collagenous Sprue

Another rare variant of celiac disease is collagenous sprue, a condition characterized by histologic findings of celiac disease accompanied by a thickened subepithelial collagen plate (Fig. 7).75,81 There are very few cases in the literature, and some therapeutic success has been reported with the use of corticosteroids added to a gluten-free diet.82,83

Figure 7
Figure 7
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Tropical Sprue

Tropical sprue is a postinfectious malabsorption syndrome found in residents of tropical areas. Initially described in British expatriates living in India and Jamaica, it is suspected to be caused by bacterial overgrowth. This hypothesis is indirectly confirmed by the temporal relationship to a bout of acute diarrhea and a good response to a variety of antibiotics (particularly tetracycline), vitamin B12, and folate therapy. The histologic features of the small intestine are indistinguishable from those found in patients with celiac disease and are reported to be similar in the duodenum and the ileum, a characteristic that may help in differentiating these 2 conditions.84–86

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Autoimmune Enteropathy

Autoimmune enteropathy is a rare condition characterized by severe and protracted diarrhea with weight loss from malabsorption and immune-mediated damage to the intestinal mucosa. This disorder generally occurs among infants and young children, although some cases involving adults have been reported.87

Patients present with protracted diarrhea, weight loss, and malnutrition.60,88 Small intestinal histopathology includes subtotal villous atrophy and lymphoplasmacytic infiltration of the lamina propria; IELs are more numerous in crypts than in surface and remaining villous tips. There is also crypt destruction, extensive apoptosis, and notably, a loss of Paneth and goblet cells.89 These features help in differentiating this condition from celiac disease.90 In most patients, celiac disease is excluded by lack of response to a gluten-free diet, absence of the celiac disease susceptibility for human leukocyte antigen (HLA) genotypes, and the presence of antienterocyte or antigoblet cell antibodies. Concomitant colitis and other autoimmune diseases are common.91

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Viral Enteritis

Duodenal biopsies are neither recommended nor commonly obtained in children with acute diarrhea. However, biopsies from children with protracted viral enteritis have been shown to feature an exuberant local immune response characterized histologically by inflammation and villous flattening similar to celiac disease.51 The temporal relationship to an acute viral enteritis and resolution over time support the diagnosis.51,92

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Lymphocytes in the Normal Terminal Ileum

The IEL population in the terminal ileum of normal subjects is markedly lower than in the duodenum, with studies reporting between 3 and 8 IELs/100 enterocytes on hematoxylin and eosin stains and up to 11 using anti-CD3 immunohistochemical stains, compared with 20 to 25 in the duodenum (Fig. 8). The same authors found an inverse relationship between the number of IELs and the patient's age.93 Peyer patches are prominent in the ileal lamina propria, and, as in the duodenum and the colon, IEL should not be counted in mucosa adjacent to lymphoid aggregates.

Figure 8
Figure 8
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Lymphocytosis in the Terminal Ileum

In patients with celiac disease, villous atrophy and crypt hyperplasia in this location are distinctly uncommon. In contrast, these patients have greater IEL counts than normal subjects, and an IEL count greater than 25 (Fig. 9) per 100 enterocytes is highly predictive of villous atrophy in the duodenum (Table 4).94,95

Figure 9
Figure 9
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Increased ileal IELs were identified in 80% of 18 patients with lymphocytic colitis (22.3±10.2 IELs/100 enterocytes) and 50% of 14 collagenous colitis patients (16.7±6.1). Villous atrophy was found in 1 patient with lymphocytic colitis (5%) and in 3 of those with collagenous colitis (21%); subepithelial collagenous thickening was detected in 2 patients with collagenous colitis.96

Ileal IELs found in association with lymphocytic and collagenous colitis are primarily CD3+ CD8+ T cells with α-β receptors, the same phenotype as the intraepithelial colonic lymphocytes.97

Although one can reasonably assume that ileal lymphocytosis could be found in some of the conditions associated with colonic or duodenal lymphocytosis, there is a dearth of studies regarding the relationship of terminal ileal lymphocytosis with medications, autoimmune diseases, and infections, likely because the terminal ileum is not consistently sampled when no endoscopic lesion is present, unless idiopathic inflammatory bowel disease (IBD) is suspected. Lymphocytosis counts are generally normal (<3 IELs/100 enterocytes) in both Crohn disease and ulcerative colitis, though.98,99 In contrast, counts higher than 5 are virtually always found in patients with lymphocytic or collagenous colitis.96,97

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Lymphocytes in the Normal Colon

The lamina propria of the normal colonic mucosa harbors a mixed population of inflammatory cells that include plasma cells, macrophages, mast cells, and both T and B lymphocytes. The density of this normal infiltrate is maximal in the cecum, where it can be misinterpreted as chronic colitis,100 and decreases distally, with the rectum containing the smallest numbers of inflammatory cells. A similar topographic gradient is found in the numbers of intraepithelial T cells, which have been found to be 50% more numerous in the ascending colon than the rectum (Fig. 9).101 The numbers of IELs in the transverse colon of normal subjects have been reported to vary between 5 and 12/100 enterocytes.102,103 Due to normal lymphocyte trafficking, large numbers of IELs are commonly seen in the surface epithelium overlying lymphoid aggregates. These areas should never be included when counting IELs for evaluation of colonic lymphocytosis.

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Colonic Lymphocytosis

The term colonic lymphocytosis is used to describe an otherwise normal colonic mucosa in which the number of IELs exceeds 10 to 20/100 enterocytes.104–108 Crucial to this definition is the premise that the colonic mucosa be otherwise normal, with no increase in the chronic inflammatory component of the lamina propria, no neutrophilic infiltrate, and no epithelial damage.

Colonic lymphocytosis as defined above can occur in a wide variety of circumstances and is not a distinct nosologic entity (Table 5). To avoid conveying the impression that a specific diagnosis is being made, we prefer using the descriptive expression “benign colonic mucosa with increased intraepithelial lymphocytes.” This diagnosis is followed by a comment describing the most common conditions with which this histologic finding can be associated.109

Table 5
Table 5
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Increased IELs in an otherwise normal colonic mucosa is a common end point to many inflammatory triggers and may be found in patients with gluten-sensitive enteropathy, autoimmune diseases,102,110–112 and drug reactions.113–120 These same associations can be found in lymphocytic and collagenous colitis, suggesting that there may be a disease spectrum from a limited and mild increase in IELs at one end and collagenous colitis at the other.

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Lymphocytic and Collagenous Colitis

Lymphocytic colitis is characterized by increased IELs (>20/100 enterocytes) in an architecturally normal colonic mucosa, accompanied by surface epithelial disarray and a mixed inflammatory infiltrate in the lamina propria (Fig. 10). Collagenous colitis is distinguished by an increase in the thickness of the subepithelial collagen band (sometimes referred to as the “collagen table”) in a setting otherwise typical of lymphocytic colitis (Fig. 11). These 2 entities are part of the spectrum of microscopic colitis, an umbrella term still used by clinicians but obsolete amongst pathologists.

Figure 10
Figure 10
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Figure 11
Figure 11
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The typical patient with lymphocytic or collagenous colitis is a middle-aged or elderly woman with a history of watery diarrhea. The endoscopic appearance of the colon is almost universally normal, and the requisition accompanying the biopsies frequently includes the request to rule out microscopic colitis. Rarely, endoscopy has shown erythema, edema, and even ulcerations.121–123 Although all age groups can be affected, including children, most patients are over 50 years of age. Lymphocytic colitis is approximately 3 times as common as collagenous colitis, and both entities are more prevalent in women than in men.124,125 Both conditions are chronic, but they have a tendency for spontaneous remission,126,127 and therapy is similar, typically comprising oral budesonide.128,129

In a considerable portion of patients with lymphocytic or collagenous colitis, a thorough investigation of the medical history may reveal a pertinent drug history, as 10% to 35% of patients have used medications shown to be associated with these conditions.110,115,130 Drugs most commonly implicated in lymphocytic and collagenous colitis include clozapine,113 lansoprazole,114 NSAIDs,115,116 ranitidine,117 ticlopidine,118 cyclo-3-fort,131 acarbose,119 and flutamide.120

Up to 45% of patients with lymphocytic and collagenous colitis110,111 have an associated autoimmune disorder, including celiac sprue,82,132 diabetes mellitus, Hashimoto thyroiditis,102,112 linear IgA disease,133 autoimmune hepatitis,134 and psoriasis.135 A familial and genetic tendency has been documented in some series,136,137 with HLA-DQ2 and HLA-DQ8 being associated with microscopic colitis and celiac disease.138 Less clear is the association with enteric infections, hypothesized in a study that detected Escherichia coli in 14 of 18 tissue biopsy cultures from Egyptian patients with lymphocytic colitis.139 A seasonal fluctuation has been identified, with increasing prevalence in the summer and fall, possibly related to infection or allergens.108

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Microscopic colitis may be patchy, and is seen more commonly in the right side of the colon.106 Lymphocytic colitis is diagnosed when increased IELs are identified in a background of superficial lymphoplasmacytosis, typically with eosinophilia in the lamina propria, and the subepithelial collagen layer is less than 10 μm. Variable epithelial disarray and damage is usually seen at least focally. A simple reference to assist in estimating the thickness of the collagen layer is the size of nearby lymphocyte nuclei (usually 5-7 μm). The diagnosis of collagenous colitis requires that the subepithelial collagen layer measures greater than 10  μm, although its relationship with the underlying lamina propria is often more useful. The collagen can have a “dripping” appearance, with an uneven, noncontiguous thickening that may be highlighted by special stains, including a Masson trichrome stain or alternatively, smooth muscle actin, collagen VI, or tenascine stains; however, such stains are usually unnecessary. The surface epithelium may peel off in strips ex vivo, leaving the collagen layer bare and without a vital fibrinopurulent reaction. There is typically a variable, but usually increased number of IELs, with capillaries, fibroblasts, and inflammatory cells (especially eosinophils) trapped in the collagen.140 If the background inflammatory changes are not present, consider artifactual pseudo-thickening, as when there is a hyalinized basement membrane when there is uniform elevation of epithelial nuclei causing the basal cytoplasm to appear as a uniform pink band. Careful examination easily reveals that such a band is above the basement membrane.

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Special Forms of Lymphocytic and Collagenous Colitis

As awareness of lymphocytic and collagenous colitis increases, numerous variations of the straightforward histology described above have been identified, and the lines between microscopic colitis and IBD have been blurred. IBD-like architectural distortion of crypts, active cryptitis, Paneth cell metaplasia, and surface erosions can make a unifying diagnosis difficult. However, such features are almost always limited to isolated foci in a background of otherwise typical lymphocytic or collagenous colitis. In a study of 150 patients, cryptitis was present in 30% and 38% of collagenous and lymphocytic colitis, respectively,141 (Fig. 12) and 44% of patients with collagenous colitis patients had Paneth cell metaplasia, compared with 14% of those with lymphocytic colitis. Both diagnoses were associated with infrequent (4%-8%) crypt architecture irregularities. These authors noted that Paneth cell metaplasia correlated with disease severity in collagenous colitis.141

Figure 12
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The relationship between IBD and microscopic colitis has not been elucidated, as several patients have been reported to progress from lymphocytic or collagenous colitis to both Crohn disease and ulcerative colitis.142–147 Interestingly, the development of collagenous colitis after longstanding ulcerative colitis has also been reported,148 and we have observed, not without initial skepticism, a similar case.

A variant of collagenous colitis showing a thickened subepithelial collagen layer with overlying necroinflammatory debris mimicking endoscopically (and histologically) pseudomembranous colitis (with negative Clostridium difficile cultures) has also been described.149–151

“Paucicellular” lymphocytic colitis (similar to traditional lymphocytic colitis, but with only 10-12 IELs/100 enterocytes) has been described in patients with endoscopically normal colonic mucosa and classic presenting symptoms (Fig. 13),152 initially considered a “minor form” of lymphocytic colitis. Although not very different from what many of us would diagnose as “colonic intraepithelial lymphocytosis” or “benign colonic mucosa with increased intraepithelial lymphocytes,”126 a recent study highlighted the immunologic differences between paucicellular and classic form of lymphocytic colitis (CD25+ FOXP3+ expression was seen only in classic forms of microscopic colitis) and supports the notion of 2 separate conditions.153

Figure 13
Figure 13
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Although only IELs on the surface epithelium are usually counted, a variant of lymphocytic colitis that preferentially affects the crypt epithelium (“cryptal lymphocytic colitis”) has been described.154,155 Individual reports of microscopic colitis with prominent pericryptal granulomatous inflammation (“granulomatous microscopic colitis”) and isolated giant cells without granulomas (“lymphocytic colitis with giant cells”), also claim to represent variants of the traditional forms and underscore that the histologic spectrum of these conditions may be more varied than initially thought.156,157

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The diagnosis of lymphocytosis in the mucosa of the digestive tract remains, like many others in histopathologic practice, a subjective one. Even as criteria based on precise lymphocyte counts are issued, the guiding principle for the practicing pathologist will be, to paraphrase an aphorism attributed to a Rolls Royce dealer, “if you have to count, you can't diagnose it.”

Our somewhat unorthodox separation of primary and secondary lymphocytosis (Tables 1, 2, 4 and 5) is not intended to propose a new classification; rather, we want to emphasize that in many instances a treatable cause for the intraepithelial lymphocytic infiltration can be identified. A detailed clinical history, although of crucial importance, is rarely available to pathologists; although fortunately useful clues are often identifiable in the biopsies we examine. For example, unusual numbers of neutrophils in a gastric biopsy with lymphocytic gastritis should prompt the use of a sensitive method, such as an immunohistochemical stain, to search for H. pylori. If organisms are found, antibacterial treatment will likely resolve the lymphocytosis. The significance of duodenal lymphocytosis will remain unclear in most patients. However, 10% of patients have positive serologic tests for celiac sprue and will benefit from a gluten-free diet; another 10% to 15% have H. pylori gastritis and their lymphocytosis will be reduced by antibacterial treatment. If large numbers of IELs are reported in the terminal ileum biopsied during the investigation of diarrhea, serologic tests or duodenal biopsies could discover celiac disease and give the patient a chance of cure. A diagnosis of lymphocytic colitis may induce a conscientious clinician to review a patient's medications, possibly allowing for curtailing of those deemed less than necessary, such as NSAIDs or proton pump inhibitors.

Thus, a diagnosis of lymphocytosis can represent an opportunity to detect an underlying condition. When neither histologic clues nor a clinical history are available, a succinct but complete comment listing known associations and suggesting further investigations should accompany the diagnosis of lymphocytosis. Only after a complete workup will the scrupulous clinician resign to the diagnosis of primary lymphocytosis.

Although treatments are available to relieve diarrhea associated with lymphocytic and collagenous colitis, the underlying causes of primary lymphocytoses remain elusive. Whereas the first 20 years of our exposure to these mysterious IEL reactions has essentially only resulted in descriptions of classic and variant forms, we hope that reviewers celebrating the 30th unofficial anniversary of GI lymphocytoses will be able to discuss not only advances in the understanding of these conditions, but also novel and effective therapies to treat them.

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The authors thank Dr Shawn Kinsey for his contributions to photography.

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Diarrhoea is not the only symptom that needs to be treated in patients with microscopic colitis
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Back to Top | Article Outline

intraepithelial lymphocytes; lymphocytic gastritis; lymphocytic colitis; duodenal intraepithelial lymphocytosis; lymphocytic disorders

© 2009 Lippincott Williams & Wilkins, Inc.


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