The Clinical Significance of Duodenal Lymphocytosis
With Normal Villus Architecture
Suntrea T. G. Hammer, MD; Joel K. Greenson, MD
 Context.—The finding of increased intraepithelial lympho-
cytes with normal villous architecture (Marsh I lesion) is seen
in up to 3% of duodenal biopsies. The differential diagnosis
includes a wide range of possibilities, including celiac
disease, bacterial overgrowth, nonsteroidal antiinflammatory
drug damage, reaction to Helicobacter pylori infection,
tropical sprue, and chronic inflammatory bowel disease.
Objectives.—To highlight the histologic features of the
Marsh I lesion, review the diseases and conditions associated
with that finding, and to provide pathologists with a rationale
and a template for how to identify and report such cases.
T he full significance of intraepithelial lymphocytosis in
duodenal biopsies remains an enigma to both pathol-
ogists and clinicians. Intraepithelial lymphocytes (IELs) can
be identified in normal duodenal mucosa as part of the
normal host-defense system. However, a number of
symptomatic patients biopsied each year show more IELs,
which have been described in association with a number of
disease conditions, most notably, celiac disease. Separating
celiac disease from other diseases associated with increased
IELs is difficult.
Celiac disease affects approximately 1% of the US
population. Clinically, the disease leads to malabsorption
and nutritional deficiencies. Prolonged involvement of the
small intestine by celiac disease can lead to the development
of enteropathy-associated T-cell lymphoma and other
malignancies.1 The changes of increased IELs with normal
villous architecture may represent early celiac disease.
Recognition of this by pathologists and clinicians may lead
to earlier therapeutic intervention, which would hopefully
prevent the long-term complications of celiac disease. These
histologic findings are common and occur in 1% to 3% of
duodenal biopsies.2,3 Here, we discuss the relevance of these
histologic changes, the ability to distinguish those associ-
ated with celiac disease from other diseases, and the general
approach to signing out these cases.
Accepted for publication May 5, 2013.
From the Department of Pathology, University of Michigan Health
System, Ann Arbor.
The authors have no relevant financial interest in the products or
companies described in this article.
Presented in part at the New Frontiers in Pathology: An Update for
Practicing Pathologists meeting; Homestead Resort; August 3–5,
2012; Glen Arbor, Michigan.
Reprints: Suntrea T. G. Hammer, MD, Department of Pathology,
University of Michigan Health System, 1301 E Catherine St, 4211
MS1, Ann Arbor, MI 48109 (e-mail: sgoudeau@med.umich.edu).
1216 Arch Pathol Lab Med—Vol 137, September 2013
Data Sources.—A review of the literature regarding the
histologic features and clinical associations of Marsh I
lesions.
Conclusions.—Marsh I lesions are a nonspecific finding
associated with a number of disease conditions. Histori-
cally, between 9% and 40% of cases have been shown to
represent celiac disease. Current data do not suggest
histologic features to differentiate between diseases
associated with this histologic change.
(Arch Pathol Lab Med. 2013;137:1216–1219; doi:
10.5858/arpa.2013-0261-RA)
HISTOLOGY OF THE SMALL INTESTINE
Small intestinal mucosa has the same general architecture
throughout. The mucosa is made up of villi, which extend
above the surface mucosa, and the crypts of Lieberkuhn,
which extend below the surface. The normal small intestinal
mucosa has a villous to crypt ratio of around 3:1 in mucosal
biopsy samples.4 When assessing the villous to crypt ratio,
several histologic changes must be taken into consideration.
Blunting and distortion of villi may be observed in the
duodenal bulb, secondary to expanded Brunner glands.
Similar villous changes can be seen in the terminal ileum
from Peyer patches. Additionally, poor orientation can affect
the appearance of the ratio, so care must be taken to
evaluate properly oriented sections.
The villous epithelium is composed primarily of absorp-
tive cells with occasionally interspersed goblet cells.
Between the epithelial cells is a normal population of
CD3þ IELs, which are normally present at a level of 4 IELs
per 20 epithelial (EP) cells, or 20 IELs/100 EP cells.5,6 The
level of lymphocytosis may be increased in regions overlying
intestinal lymphoid aggregates, areas that should be avoided
when performing lymphocyte counts.
MARSH-OBERHUBER CLASSIFICATION SCHEME
The histologic changes seen in duodenal and jejunal
biopsies of celiac disease are within a spectrum of
inflammation levels and architectural distortions that often
occur over time.7,8 In the modified Marsh grading system,
there are 5 main categories of severity from 0 to 4.9 Type 0
represents normal small intestinal mucosa with less than 40
IELs/100 ep. Type 1, or the Marsh I lesion, has normal
villous architecture with increased IELs (.40 IEL/100 EP
cells) (Figure). Type 2 lesions also have a normal villous
architecture with increased IELs; however, type 2 also has
crypt hyperplasia. The type 3 lesions (destructive lesions) all
Clinical Significance of Marsh I—Hammer & Greenson
show some level of a villous blunting and are further
subdivided into types 3a, 3b, and 3c. Type 3a lesions have
mild villous blunting, type 3b lesions have marked villous
blunting, and type 3c lesions have a flat mucosal surface.
These type 3 lesions also have increased IELs as well as crypt
hyperplasia. Type 4 lesions (hypoplastic lesions) tend to
occur in children and are characterized by flattened mucosa
with normal crypt height and normal levels of IELs.
The Marsh I lesion is the earliest recognizable, histologic
abnormality in patients with celiac disease. It is also the most
difficult to recognize. The histologic changes include an
increase in lamina propria cellularity, primarily plasmacytic,
with an appreciable increase in villous IELs. Although
histologic evaluation for diagnosis tends to be subjective,
there are defined levels of lymphocytosis that are considered
normal, which varies based on the histologic preparation. The
reference range for IELs set by Marsh and Oberhuber of 40
IELs/100 EP cells was based on hematoxylin-eosin (H&E) 7-
lm-thick sections. Veress et al6 studied H&E-stained, 3-lm-
thick sections and found the mean number of IELs plus 3 SD
to be 20 IELs/100 ep. Other authors have found similar
numbers. Hayat et al10 reported an upper level of the reference
range to be 25 IELs/100 EP cells (mean [2 SD]) in 4-lm-thick,
H&E sections. Jarvinen et al5 found a level of 4.2 IELs/20 EP
cells at the villus tips to distinguish between patients with
probable celiac disease and controls, which included patients
with dyspepsia and nonceliac intestinal disease. In our own
data, we found that patients without celiac disease had lower
levels of IELs (range, 0–4.3 IELs/20 EP cells at the villus tips;
mean [SD] ¼ 1.9 [1.1]) than did patients with confirmed celiac
disease (range, 5–17.5 IELs/20 EP cells at the villus tips; mean
[SD] ¼ 9.6 [2.3]).11 Kakar et al2 found that patients with
gluten-sensitive enteropathy had increased levels of IELs;
however, they were not able to demonstrate significant
elevations compared with patients with immune disorders
or nonsteroidal antiinflammatory drug use.
Different methods for counting IELs have been pro-
posed.6,9,12,13 Oberhuber et al14 supports the use of
traditional H&E staining for quantification. Other authors
have explored the use of immunohistochemistry for CD3 to
quantify the number of intraepithelial T cells. In general,
CD3 staining identifies a slightly greater number of IELs,
and correspondingly, the upper limit of the IEL reference
range is slightly greater when immunohistochemistry is
used. For example, Veress et al6 reported an upper reference
range of 25 IELs/100 EP cells when using CD3 staining,
compared with 20 IELs/100 EP cells by H&E analysis.
Nasseri-Moghaddam et al13 found a higher level of
lymphocytosis with 35 IELs/100 EP cells using immunohis-
tochemistry compared with an H&E level of 34 IELs/100 EP
cells in 4-lm-thick sections. We caution against using CD3
stains in ambiguous cases unless the pathologist is used to
reviewing such stains in normal small bowel because the
apparent increase in T cells from easy identification with
chromagen may increase the IELs reported.
Specificity of the Marsh I Lesion
Although the Marsh I lesion has been recognized as an
early manifestation of celiac disease, it lacks specificity.
Previous studies15 have found that patients with Marsh I
lesions have a prevalence of celiac disease ranging from 9%
to 40%. Several diseases have been associated with
duodenal biopsies showing normal villous architecture and
increased IELs. These findings are summarized in the Table.
Arch Pathol Lab Med—Vol 137, September 2013
High-power view of a normal duodenal villus (left), compared with
Marsh I villus (right). Note the increase in intraepithelial lymphocytes in
an architecturally normal villus (hematoxylin-eosin, original magnifica-
tions 320 [left and right].
Helicobacter pylori infection is one of the more common
associations seen with Marsh I lesions. Memeo et al16
evaluated 50 consecutive, paired gastric antral and duodenal
biopsies to evaluate the level of duodenal lymphocytosis in
patients with gastric infections of H pylori. The levels of
duodenal lymphocytosis were significantly greater than it
was in noninfected controls and overlapped with the
reported levels seen in celiac disease (range, 3–45 IELs/100
EP cells). Monzon et al17 reported similar findings. The
association has been further solidified by the response of the
lymphocytosis to treatment in these patients. Nahon et al18
reported a significant decrease in the level of intraepithelial
lymphocytosis 2 months after the eradication of H pylori
infection. These data strongly support H pylori as a cause of
Marsh I lesions.
Other infectious conditions have also been described as
associated with increased IELs. A number of studies have
identified associations with giardiasis, small-intestine bac-
terial overgrowth, and other infective enteritities.19–22
Tropical sprue has also been associated with Marsh I
lesions. Marsh et al23 describe increased levels of IELs in
patients with tropical sprue. They noted that the lympho-
cytosis tended to predominate within the crypt epithelium
in contradistinction to celiac disease. Usually, there is also
some degree of villous blunting.
The most commonly reported drug association seen with
Marsh I lesions is with nonsteroidal antiinflammatory drugs.
Kakar et al2 reported that association in approximately 14%
of his study patients with increased IELs. In our experience,
8 of our 100 patients (8%) with Marsh I lesions had
nonsteroidal antiinflammatory drug use as the only known
clinical association.11 Brown et al15 reported similar findings
in 15% of patients and in 20% of patients using a proton-
pump inhibitor.
Inflammatory bowel disease has also been associated with
Marsh I lesions. Kakar et al2 reported a statistically
significant rate of association of about 12%, which were
all cases of Crohn disease. Memeo et al16 also reported a
case of Crohn disease in a patient with increased IELs,
Clinical Significance of Marsh I—Hammer & Greenson 1217
 Table 1. Disease Associations
Kakar et al,2 2003,
Disease Associations No. (%), n ¼ 43
Celiac disease 4 (9)
Tropical sprue 1 (2)
Helicobacter pylori 0 (0)
Bacterial overgrowth 2 (5)
NSAID use 6 (14)
Inflammatory bowel disease 5 (12)
Autoimmune conditions 6 (14)
Infection 0 (0)
Unexplained 3 (7)
Irritable bowel syndrome 4 (9)
Other 12 (28)
Abbreviation: NSAID, nonsteroidal antiinflammatory drugs.
although that was not statistically significant. Similarly, we
found 8 cases of associated inflammatory bowel disease
(including both Crohn disease and ulcerative colitis cases).11
Several immunologic disorders are associated with Marsh
I lesions, including Hashimoto thyroiditis, Grave disease,
rheumatoid arthritis, psoriasis, multiple sclerosis, diabetes
mellitus, systemic lupus erythematosus, graft versus host
disease, chronic variable immunodeficiency syndrome, and
immunoglobulin (Ig) A deficiency.2,24–26
THE MARSH I LESION: DISTINGUISHING CELIAC
DISEASE FROM OTHER ASSOCIATED DISEASES
Few studies have evaluated specific histologic changes that
can reliably separate the early changes of celiac disease from
other associated conditions. Patients with celiac disease have
classically been described as having a tip lymphocytosis.
Many studies examining this feature have not been able to
establish this pattern as a distinguishing factor between celiac
and nonceliac-associated Marsh I lesions.2,27 Goldstein et al28
found a diffuse villous pattern of lymphocytosis to be
supportive of a celiac association in Marsh I lesions. This
was statistically significant, although there was overlap
between patients with celiac disease and other disease-
associated groups. Interestingly, Memeo et al16 noted an
equal tendency toward basal and diffuse villous lymphocy-
tosis in patients with H pylori infection, further complicating
the picture. Most studies do not recognize a statistically
significant difference in the level of lymphocytosis between
patients with celiac disease and patients with nonceliac-
associated Marsh I lesions either.2,27 However, Mino et al27
was able to find a statistically significant difference in the tip
to crypt IEL ratio between gluten-associated and nongluten-
associated increases in IELs with higher ratios being present
in patients with celiac disease.
Location of Intestinal Biopsy
There is some question as to whether the site of a small-
intestine biopsy helps in making a diagnosis of celiac
disease. Some small differences between duodenal and
jejunal mucosa have been noted on stereomicroscopy. Scott
et al29 found a tendency for the villi to be broader in the
duodenum and a tendency for the crypts to be shorter in the
jejunum. Some studies have reported on the patchiness of
celiac disease, which seems to be true regardless of the site
of biopsy. The Scott et al29 study focused on the distribution
and severity of disease in patients suffering from celiac
disease or dermatitis herpetiformis, and they found that
differences in the severity of mucosal changes could be
patchy and limited to either the duodenum or the jejunum.
1218 Arch Pathol Lab Med—Vol 137, September 2013
Mahadeva et al,4 2002, Hammer et al,11 2010,
No. (%), n ¼ 14 No. (%), n ¼ 100
3 (21) 18 (18)
0 (0) 1 (1)
0 (0) 6 (6)
0 (0) 3 (3)
0 (0) 8 (8)
0 (0) 8 (8)
0 (0) 6 (6)
0 (0) 0 (0)
3 (21) 26 (26)
2 (14) 20 (20)
6 (43) 4 (4)
Another study, performed by Meijer et al,30 also found the
disease to be patchy but found a good concordance rate
between duodenal and jejunal biopsies (94% agreement),
which is concordant with other research.31,32 Furthermore,
he found that the remaining 6% of biopsies, although they
showed different grades, would not have significantly
affected clinical management. Lesions of higher severity
could be found limited to either the duodenum or the
jejunum. Severity of lesions also varies within different parts
of the duodenum. Evans et al33 found a difference in severity
between bulb biopsies and biopsies taken from the second
part of the duodenum in cases of both confirmed celiac
disease and newly diagnosed celiac disease. That study
advocated sampling the duodenal bulb in addition to other
areas of the small intestine. Discrepancies in histologic
severity can exist between different intestinal sites within
the same patient.
The Diagnostic Line
Patients undergo duodenal biopsies to identify a number
of treatable conditions, ranging from microbial disease to
autoimmune diseases. These disease categories, although
very different in etiology, often have overlapping clinical
symptoms. One percent to 3% of patients undergoing
duodenal biopsy are found to have a Marsh I lesion, leaving
both pathologists and clinicians alike to ponder the
significance.3,34 The association between Marsh I lesions
and celiac disease is well established. Wahab et al35 reported
on a clinical study in which symptomatic patients with
biopsy-demonstrated Marsh I lesions underwent trials of
gluten challenge and withdrawal, followed by subsequent
biopsies. The study was able to demonstrate histologic
changes in 37% of patients undergoing gluten diet
modification. Despite that knowledge, multiple studies have
attempted without success to identify histologic features to
differentiate celiac disease from other associated disease
states. The specificity of the Marsh I lesion remains low.
Most authors agree that the association between celiac
disease and Marsh I lesions is strong enough that it needs to
be mentioned in the pathology report. At our institution,
these histologic changes are reported as ‘‘increased intra-
epithelial lymphocytes with normal villous architecture’’ and
includes an accompanying comment mentioning the most
commonly associated diseases. In our experience, these
include celiac disease, H pylori gastritis, nonsteroidal
antiinflammatory drug use, bacterial overgrowth, tropical
sprue, and certain autoimmune diseases. In most cases, a
clinical association is never identified. However, this
diagnostic approach provides enough information to allow
Clinical Significance of Marsh I—Hammer & Greenson
the gastroenterologist to provide further work for the
patient and to avoid missing potential cases of celiac disease.
There are other important factors. A diagnosis of celiac
disease involves not only histologic evaluation but also
clinical signs and symptoms, serologic testing, and the
clinical response to diet modification. Immunoglobulin A
deficiency can often accompany a diagnosis of celiac
disease.36 In patients with IgA deficiency, results from
several of the serologic tests used to diagnose celiac disease
may be negative, putting a higher emphasis on histologic
findings.37,38 Notably, the current American Gastroentero-
logical Association guidelines39 currently support tissue
transglutaminase IgA antibodies as first-line serologic
testing in patients with suspected celiac disease. Antibody
results can also be lower or negative in patients with less-
destructive histologic lesions.40–47 When dealing with a
Marsh I lesion, negative or low-level antibody titer findings
do not exclude a diagnosis of celiac disease.
In summary, duodenal lymphocytosis with normal villous
architecture can be seen in a variety of conditions. It is
important for the pathologist to recognize this relatively
subtle diagnosis because it can have important implications
for the patient.
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