Diagnostic Problems in GI Pathology
Case 1 -
Significance of Intraepithelial Lymphocytes in the Small Bowel
Lisa Yerian, John Hart and Amy Noffsinger
Small bowel biopsy is an indispensable component of the diagnostic work-up of patients with
malabsorption and/or diarrhea secondary to mucosal damage. A systematic approach to the light
microscopic examination of duodenal biopsy specimens is important in order to make a specific histologic
diagnosis whenever possible. Many authors
have adopted an approach in which diagnostic
categories are constructed based on mucosal morphology, generally in the following fashion:
There are disease entities in each of these morphologic categories in which intraepithelial lymphocytosis can occur. Some of these disorders exhibit no
additional diagnostic abnormalities, and the pathologist can offer only a differential diagnosis. Other
disorders manifest additional histologic features that allow a specific diagnosis to be made.
- Complete villous flattening with crypt hyperplasia
- Villous and crypt shortening (mucosal atrophy)
- Variable villous flattening with crypt hyperplasia (focal or diffuse)
- Normal mucosal architecture
The number of intraepithelial lymphocytes that separates normal individuals from those with small
bowel disease has, surprisingly, not been studied extensively. Forty IELs per 100 enterocytes was
adopted as the cutoff for the diagnosis of celiac disease by Furguson and Murray because the highest
level in their control group of normal individuals was 40, and the mean value plus two standard
deviations was 36.1 . However, a recent larger study of a Swedish population concluded that a value
of 20 IELs per 100 enterocytes was more appropriate (their mean plus 3 SD was 18.5). The authors
calculated that using that cutoff no more that 1 in 1000 healthy persons would be falsely diagnosed with
intraepithelial lymphocytosis . They also studied the use of CD3 immunostains to highlight IELs and
calculated a cutoff of 30 per 100 enterocytes, with 25-29 IELs reported as "borderline" . The authors
stress the importance of not performing counts of IELs in the epithelium anywhere in the vicinity of even
small lamina propria lymphoid aggregates, since increased numbers of IELs are normal there. This is
particularly critical in the evaluation of biopsies of the terminal ileum, since lymphoid aggregates and
follicles often occupy large portions of such samples. Immunohistologic studies to highlight IELs
utilizing a CD3 antibody may aid in the recognition of intraepithelial lymphocytosis in biopsies without
villous blunting , but the use of this strategy is generally not required in daily practice.
Recently it has been proposed that an abnormal distribution of IELs along the length of the villi,
even if the overall number is not significantly increased, is suggestive of celiac disease . This
proposal is based on the observation that in healthy individuals there is a progressive decrease in the
density of IELs from the base of a villus to its tip. In contrast, in a subset of patients with celiac
disease this normal "decrescendo pattern" of IEL distribution is lost, and instead, the number of IELs is
similar along the entire length of the villus, or is actually higher at the tip than at the base.
However, the author emphasizes that this pattern of IEL distribution merely suggests the need for
serologic testing to rule out celiac disease, as there are other causes of this histologic finding, and
some patients may have no disease state at all .
Complete Villous Flattening Pattern
Celiac disease occurs because of the ingestion of alpha-gliadin within gluten containing foods by
sensitive individuals, and can be diagnosed in patients of any age after institution of gluten to the
diet. Gluten is present at high levels in wheat, rye and barley but is absence in corn and rice. Oats
(in moderate amounts) has been shown to be tolerated by some celiac patients without adverse effects
. Gliadin injures the enterocytes in celiac disease patients, causing them to aberrantly express HLA
antigens and secrete IL-15. This, in turn may lead to the intraepithelial infiltration of CD8+ T-cells
that is so characteristic of celiac disease. The gliadin is deaminated by tissue transglutaminase in the
interstitium, resulting in a peptide that is recognized by an expanded population of CD4+ T-cells (DQ2
and DQ8 restricted)
in the lamina propria .
Presentation with the classic symptoms of malabsorption (diarrhea, steatorrhea, abdominal bloating and
pain, weight loss, poor weight gain, failure to thrive, fatigue, metabolic bone disease) is becoming less
and less frequent. Instead, a large (and ever increasing) number of "atypical" presenting symptoms are
being reported, including low serum folate, calcium, magnesium or phosphorus levels, intra-cranial
calcifications causing seizures, and growth retardation in children . Unexplained iron deficiency
anemia is now one of the leading presenting signs of celiac disease, particularly among adolescent
There has also been a significant increase in diagnosis through screening of patients
with Down's syndrome, and juvenile onset diabetes mellitus and other autoimmune disorders (e.g. PBC).
Virtually every patient with dermatitis herpetiformis has or will develop celiac disease. About 90% of
patients with celiac disease carry a HLA-DQ2 of HLA-DQ8 allele.
In the past elevation of serum anti-gliadin and anti-endomysial antibody
titers were required to establish a diagnosis of celiac disease. In patients with a high clinical
suspicion of celiac disease (i.e. those with classic symptomatology) the sensitivity and specificity of
these assays were in the range of 90%. However, as screening tests in asymptomatic adult blood donors,
for example, the positive predictive value for a positive anti-gliadin antibody test was only 20% .
Moreover, the value of these serologic tests varied by geographic area and ethnicity, even among
high-risk patient populations . Most studies have shown that the anti-endomysial antibody test is
more sensitive and specific than the anti-gliadin antibody test . It is important to remember,
though, that the anti-endomysial antibody test only detects IgA antibodies, while both IgA and IgG
anti-gliadin antibody tests are available. This is important because the frequency of selective IgA
deficiency is more than 10 times higher in patients with celiac disease than in the general population
Recently it was demonstrated that the primary antigen detected by the anti-endomysial indirect
immunofluorescent test is a peptide portion of tissue transglutaminase (tTG)
. Automated ELISA
assays utilizing either human or guinea pig tTG have become the primary test for celiac disease, and have
supplanted the more time consuming and subjective anti-endomysial antibody test in some laboratories
However, no single test is 100% sensitive and specific in all testing situations, and currently
a panel including anti-tTG, anti-endomysial and anti-gliadin antibody tests is usually performed .
One recent screening study of unselected healthy infants reported that nine of 484 had a positive
anti-tissue transglutaminase test at age 2 ½ years. In seven of these children duodenal biopsies
confirmed the diagnosis of celiac disease .
Classic histologic features of untreated celiac disease include: 1) total villous blunting (flat
mucosa) and crypt hyperplasia, with an increased number of mitotic figures in the crypts; 2) a dense
inflammatory cell infiltration in the lamina propria, including numerous plasma cells and lymphocytes,
admixed with eosinophils and neutrophils, and 3) an increased number of intraepithelial lymphocytes
(IELs). If the duodenal mucosa is completely flat the diagnosis of celiac disease is almost assured,
although rarely autoimmune enteropathy, viral enteritis, common variable immunodeficiency syndrome and
tropical sprue can result in a flat mucosa. Disorganization, flattening, and/or vacuolization of the
surface epithelium are also evident in some cases of celiac disease. After withdrawal of gluten from the
diet there is slow resolution towards normal villous architecture. The mucosa of the most distal portion
of the small bowel recovers most quickly, while the duodenum is the last to normalize. It may take
several months or longer of a strict gluten free diet before the biopsy appearance returns to normal.
As more patients with "atypical" symptoms underwent duodenal biopsy to rule out celiac disease it
became clear that a range of pathologic abnormalities could expected. Marsh has proposed a
classification for the morphologic appearance of duodenal biopsies in celiac disease patients
which can be briefly summarized as follows:
Type 1 morphology (also known as the "infiltrative lesion"), which represents the earliest
recognizable light microscopic change, was first documented in biopsies from first-degree relatives of
celiac disease patients and in patients with dermatitis herpetiformis. These patients had no
gastrointestinal complaints and were considered to suffer from a form fruste
of celiac disease . It has been shown that the infiltrative lesion can be induced in full fledged
celiac disease patients who have been on a gluten free diet (with a documented entirely normal duodenal
mucosa) by administering a low dose of dietary gluten. Increasing the load of dietary gluten can produce
evolution to a flat mucosa.
It has recently been estimated that only 30% of "gluten sensitive"
patients exhibit a flat mucosa . The number of duodenal biopsies that are obtained has been shown to
influence the likelihood of identifying flat mucosa, indicating that the morphologic changes in celiac
disease can be patchy
Since a flat mucosa with increased IELs is much more specific for celiac
disease than an increase in IELs alone, the procurement of multiple biopsies (4 to 6) is clearly
desirable . It is currently unknown what percentage of patients with the "infiltrative lesion" will
go on to develop flat mucosa and the full blown clinical syndrome of celiac disease. It is important to
recognize this morphologic expression of gluten sensitivity because the atypical symptoms of these
patients will respond to dietary gluten withdrawal. For that reason, and because of the greater risk of
lymphoma in untreated patients, a gluten-free diet is recommended for all celiac patients, regardless of
the presence or absence of villous blunting.
- Type 0 – normal crypt & villous architecture; no increase in IELs
- Type 1 – normal crypt & villous architecture; > 40 IELs/100 enterocytes
- Type 2 – crypt hyperplasia but normal villous length; > 40 IELs/100 enterocytes
- Type 3 – crypt hyperplasia &villous blunting (mild to flat); >40 IEL/100 enterocyte
Complications of Celiac Disease
Some celiac patients who are asymptomatic on a gluten free diet sudden redevelop symptoms of
malabsorption. Most of these patients are ultimately discovered to have discontinued the gluten free
diet, inadvertently or not. Some patients, however, relapse despite strict adherence to the proper diet,
and are said to suffer from refractory sprue.
Collagenous sprue is a very rare condition, with less than 50 cases reported in the literature
As the name suggests it refers to the development of a thickened band of collagen beneath the
flat surface mucosa of the small bowel (analogous to collagenous colitis). This is a serious
complication because it is often impossible to re-establish normal villous architecture, despite the use
of high dose immunosuppression. The patients die either of malnutrition or due to the development of a
The other feared complication of celiac disease is the development of small bowel lymphoma, which is
sometimes heralded by the redevelopment of malabsorption. These lymphomas are unusual in that they are
almost always of T-cell phenotype , while almost all sporadic gastrointestinal lymphomas are of
B-cell origin. In many patients gene rearrangement studies are necessary to confirm the diagnosis of a
clonal T-cell proliferation, since significant cytological atypia may not be present. The relative risk
of small bowel lymphoma in celiac patients has been variously estimated at 40 to 100 fold greater that
the normal population , but there is some evidence that strict adherence to a gluten free diet may
prevent the development of lymphoma . The mucosa in celiac patients with lymphoma often appears
atrophic, with both crypt hypoplasia and total villous blunting (Marsh type 4 morphology).
The evolution to lymphoma was initially overlooked in some celiac patients who developed diffuse
ulceration of the small bowel mucosa (so-called ulcerative jejuno-ileitis), making it difficult to
discern the underlying clonal lymphoid infiltrate, especially in biopsies
There has been some
confusion in the literature, however, in that the term ulcerative jejuno-ileitis is also used to describe
large areas of small bowel mucosal ulceration in non-celiac patients. In this population there is no
association with lymphoma.
A small number of patients also develop lymphocytic or collagenous colitis, which may manifest
simultaneously, before or after the diagnosis of sprue . In one study of 21 patients with
"refractory sprue" collagenous colitis was responsible for the development of diarrhea in three patients
on a strict gluten free diet .
This ill-defined disorder shares many clinical and pathologic features with celiac disease, but there
is no relationship with the ingestion of gluten and a gluten free diet has no effect on the severe,
protracted watery diarrhea . Symptoms usually begin in the first year of life, but an adult onset
form is also described . Serum autoantibodies directed against enterocytes or goblet cells are
characteristic of this disorder . However, this assay is not routinely available, it is not well
standardized, and the epitopes have not been completely defined. The lack of a clear clinical,
morphologic or genetic marker for this disease indicates that there are probably a number of unrelated
disorders that share common clinical and pathologic features. These patients often have (or develop)
other autoimmune diseases. In most patients both the small and large intestine are severely affected,
with biopsies showing dense lamina propria infiltrates and intraepithelial lymphocytosis. Apoptosis of
crypt epithelium is usually also a prominent feature. The duodenal mucosa is usually flat; compensatory
crypt hyperplasia may or may not be evident.
Crypt and Villous Atrophy Pattern
This pattern is probably the most uncommonly encountered. Crypt atrophy is usually a result of the
patient's inability to increase cell proliferation because of severe malnutrition. Infants with cow's
milk protein intolerance
or microvillous inclusion disease
may develop this pattern for
this reason (given the remarkably high caloric need at this age). Some chemotherapeutic agents (e.g.,
vincristine, vinblastine, VP-16) may also produce this pattern due to interference with the process of
cell division (mitotic arrest). However, intraepithelial lymphocytosis is not a feature of any of the
foregoing conditions. There are rare reports of autoimmune enteritis with both crypt and villous
atrophy, but in most cases while the mucosa is flat, there is some degree of crypt hyperplasia (see
Variable Villous Flattening with Crypt Hyperplasia Pattern
Many malabsorptive disorders produce mild to moderate villous blunting and crypt hyperplasia but
exhibit no other diagnostic feature, which means that the pathologist is not able to make a specific
diagnosis. Therefore, correlation with the clinical history is of paramount importance. Of course
patients with celiac disease may also exhibit this pattern during the sometimes lengthy process of
mucosal healing following institution of a gluten free diet.
The recognition of mild villous blunting can itself be a difficult task, since poor biopsy orientation
is common. Some degree of villous shortening is common over Brunner's glands, and is not indicative of a
disease state. Therefore, small bowel biopsies performed to evaluate diarrhea and/or malabsorption
should always be obtained as distally as possible to avoid this possible confounding factor. Also,
shallow biopsies that don't include fibers of the muscularis mucosae can tend to stretch out during
processing, producing an artifactual appearance of mild villous blunting. In most cases villous blunting
does not occur in isolation, and the absence of an inflammatory component (either an intraepithelial
lymphocytosis or significant lamina propria infiltrate including neutrophils) should raise the
possibility that the apparent villous shortening is in fact artifactual.
In most cases an etiologic agent is never cultured from the stool and thus only a presumptive
diagnosis is possible . Norwalk agent, rotavirus, and other viruses have been implicated in various
studies. These viruses do not produce inclusions visible by light microscopy. Villous blunting and an
increase in intraepithelial lymphocytes are often evident. In some patients (primarily children, but
also adults) the mucosa may become completely flat, and an erroneous diagnosis of celiac disease may be
made. Since these infections are self-limited the patient will appear to respond to a gluten free diet,
thus "confirming" the misdiagnosis. This highlights the importance of serologic tests for anti-tTG,
anti-endomysial and anti-gliadin antibodies in making a diagnosis of celiac disease .
In the U.S. cases are primarily seen among patients who have spent prolonged periods of time in the
Caribbean islands. This disorder is presumed to be a result of overgrowth of toxic strains of
non-anaerobic bacteria and will respond to long term therapy with antibiotics, B12 and folate . The
villous flattening is said to be more severe distally in the small bowel, and occasionally completely
flat mucosa is present. An intraepithelial lymphocytosis is also evident, which can lead to confusion
with celiac disease.
Bacterial overgrowth occurs in the setting of reduced bowel motility, due to a surgical procedure (eg
Roux-en-Y limb), fistula, or organic disease (eg diverticulum, scleroderma). Malabsorption is caused by
villous blunting (? due to the toxic products of the bacteria themselves) and the bacterial deconjugation
of bile salts, interfering with luminal digestion). A mild intraepithelial lymphocytosis may also be
"Normal" Mucosal Architecture
On occasion the pathologist is faced with a patient with diarrheal of malabsorptive symptoms but a
biopsy that appears normal on cursory examination. In that situation there are several disorders that
can be diagnosed by very careful examination, including the infiltrative lesion of some celiac patients,
as discussed extensively above. In addition, an intraepithelial lymphocytosis may be noted in small
bowel biopsies obtained incidentally or to rule out a non-diarrheal condition
manifest an intraepithelial lymphocytosis but normal mucosal architecture are discussed below.
Most patients with Giardia infection exhibit completely normal villous architecture and no
intraepithelial lymphocytosis . Therefore, it is incumbent on the pathologist to carefully examine
every "normal" small bowel biopsy from patients with diarrhea for Giardia organisms. In immunocompetent
individuals the number of organisms can be quite small. In fact, light microscopic examination of small
bowel biopsies is not a sensitive test for the diagnosis of Giardiasis. Although a Giemsa stain is
classically recommended to highlight the organism, a trichrome stain actually may be preferable. The
organism is slightly larger than an enterocyte nucleus when seen in full section. Making touch preps
from the biopsy tissue may increase the diagnostic yield. Far better is the examination of a duodenal
aspirate specimen. In patients with a heavy infestation or organisms a mild intraepithelial
lymphocytosis may occur.
Common Variable Immunodeficiency Disease
Any biopsy that reveals the presence of Giardia organisms should be examined carefully for the
possibility of common variable immunodeficiency disease. In this condition (which actually includes a
spectrum of immunologic disorders) there is a failure of maturation of B-lymphocytes to fully developed
plasma cells. The underlying defect may actually be in T-cell function or signal transduction .
This results in an absence of or severe decrease in immunoglobulin production, (including IgA antibodies,
which are an important host defense against intestinal parasites). These patients may present as
children or adults with multiple episodes of infection (predominantly respiratory and gastrointestinal).
Biopsies usually reveal at least mild villous blunting, but a completely flat mucosa may be present. A
mild intraepithelial lymphocytosis is also present in many cases. The combination of flat mucosa and
intraepithelial lymphocytosis may lead to a mis-diagnosis of celiac disease.
The correct diagnosis can be made by noticing the absence of mature plasma cells, which are normally
numerous in the lamina propria of the small bowel. In addition, prominent nodular lymphoid hyperplasia
is often present, particularly in children. The presence of numerous large lymphoid aggregates in these
patients can lead to an erroneous diagnosis of lymphoma, although there may also be a true increase in
the incidence of G.I. lymphomas in these patients .
Biopsies of the duodenum in patients with an established diagnosis of Crohn's disease involving the
colon and/or ileum sometimes reveal a mild intraepithelial lymphocytosis with preserved mucosal
This feature alone should not be taken as evidence of clinically significant
involvement of the upper G.I. tract by Crohn's disease.
Helicobacter pylori Gastritis
Severe H. pylori gastritis can also cause an increase in IELs in biopsies
of the duodenal bulb, but usually not more distally . The degree of intraepithelial lymphocytosis is
usually quite mild, or even only borderline abnormal, and resolves upon antibiotic treatment of the H. pylori infection
Interestingly, the gastric biopsies from such
patients usually do not exhibit intraepithelial lymphocytosis
It is possible that NSAIDs can cause intraepithelial lymphocytosis
although a causative
link has not yet been proven by demonstration of resolution following discontinuation of the offending
agent. Likewise, intraepithelial lymphocytosis has been reported in patients with various autoimmune
conditions (rheumatoid arthritis, Hashimoto's thyroiditis, SLE, etc.), but no direct relationship has
been established. Rarely a mild intraepithelial lymphocytosis has been reported in patients with
microsporidia or cryptosporidium infection. In a significant proportion of patients with duodenal
intraepithelial lymphocytosis no associated disease state can be identified
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