Specimen Procurement and Processing
Small-bowel mucosal biopsy examination remains one of the most important tests in the evaluation of patients
with clinical malabsorption.1 We now employ a standard gastroscope to obtain duodenal biopsy specimens
as distally in the small bowel as possible.2,3 The specimens, although smaller than those obtained by a
suction device, are adequate to evaluate mucosal disease, and because the biopsy is performed under direct
vision, many more specimens can safely be obtained.
The most critical part of small bowel biopsy and interpretation is the proper orientation of the specimen.
Ideally, specimens are immediately mounted, mucosa side up, on a solid substance such as filter paper, and
then placed into Hollande's (or other) fixative. After processing, the histotechnologist embeds the tissue
perpendicular to the mounting material. Proper specimen evaluation requires examination of optimally
oriented intestinal villi obtained from the central region of the biopsy specimen. Although serial
sectioning is advocated by some,4 step sectioning (obtaining ribbons of sections from at least three
levels) is a reasonable alternative.5
Our standard small-bowel biopsy procedure consists of obtaining 4-6 endoscopic biopsy specimens. The
samples are fixed in Hollande's solution and routinely processed. Five step-sectioned slides are obtained;
three are stained with hematoxylin and eosin, one with periodic acid-Schiff (PAS), and one with trichrome
stain. The PAS stain, which I now believe can be optional, is a useful screen for Whipple's disease,
foveolar metaplasia in chronic duodenitis, and Mycobacterium avium-intracellulare infection. The trichrome
stain will confirm collagen deposits in ischemia or collagenous sprue. In addition, the iron hematoxylin
counterstain used in the trichrome technique facilitates identification of Giardia lamblia.5
Normal Small-Intestinal Histology
The normal villus to crypt length ratio approximates 3:1 to 5:1.6 Inflammatory cells, including plasma
cells, are normally present in the lamina propria. Intraepithelial lymphocytes occur in a ratio of
approximately 1 lymphocyte per 5 enterocytes.4,6 A brush border is often discernable on the enterocyte.
The enterocyte nuclei should be basilar in location and evenly aligned.
Brunner's glands in proximal duodenal specimens have an inconsistent effect on villus architecture.6 In
some circumstances, normal-length villi may be encountered overlying Brunner's glands, but usually the villi
are shorter and somewhat distorted. Similarly, villi are often short and distorted next to or overlying
lymphoid aggregates. Such shortened villi should not be misinterpreted as evidence of celiac sprue.
In general, we subscribe to the philosophy that identification of four normal villi in a row indicates that
the villus architecture of the whole biopsy specimen is probably normal.4 This does not mean that biopsy
specimens with less than four aligned normal villi should be considered inadequate for evaluation, because
even one normal villus in a proximal small-bowel biopsy specimen rules out celiac sprue. Conversely,
finding four normal villi in a row does not necessarily rule out focal lesions, although it almost always
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 differential diagnosis (Table 1). I use the term "severe villus abnormality" to describe a flat
intestinal mucosa lacking villi. Usually this change is diffuse, accompanied by intraepithelial
lymphocytosis, and associated with crypt hyperplasia, evidenced by numerous mitoses. The terms "severe
villus abnormality" or "flat intestinal mucosa" are preferred to "villus atrophy" because the mucosa in the
forms associated with crypt hyperplasia is actually of normal thickness. I use the term "variable villus
abnormality" to describe specimens in which the villi are either only focally flat or are less than flat
(mild or moderate villus shortening).4 Many specimens in this category will also show increased numbers
of intraepithelial lymphocytes. These changes may be associated with features that suggest a specific
diagnosis (eg. numerous eosinophils, granulomas, parasites) or may be non-specific.
Entities Associated with a Diffuse Severe Villus Abnormality
and Crypt Hyperplasia
Celiac sprue (gluten induced enteropathy, gluten sensitive enteropathy, non-tropical sprue) is a major cause
of malabsorption. Almost all adult patients in North America with a severe villus abnormality and crypt
hyperplasia have celiac sprue.4 The pathogenesis of celiac sprue involves immunologic injury to the
enterocyte associated with gluten ingestion, which is a protein found in cereal grains such as wheat, rye,
and barley. The gliadin fraction of wheat gluten and the alcohol - soluble prolamins of the other grains
are the environmental factor responsible for the intestinal damage.25 Patients with celiac sprue usually
show a quick and dramatic clinical and histologic improvement following removal of gluten from the diet and
quickly relapse following its reintroduction.7
The flat mucosa of CS is associated with increased lymphocytes and plasma cells in the lamina propria and
increased intraepithelial lymphocytes. The enterocyte nuclei lose their basilar alignment and become
stratified. Neutrophils may be present but are usually not prominent. The histologic abnormality is most
severe in the proximal intestinal mucosa and gradually lessens distally. 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. Remember, a pathologist does not make the diagnosis of CS. All that can be said is that the
specimen contained a severe villus abnormality that is consistent with CS. Definitive diagnosis depends
upon demonstration of a suitable clinical presentation, compatible serologic tests25,8 (e.g.,
anti-tissue transglutaminase antibodies, IgA endomesial antibodies, IgG and IgA - antigliadin antibodies)
and small bowel histology,9 clinical and, ideally, histologic response to a gluten-free diet, and relapse
following gluten challenge.
The histologic differential diagnosis includes all entities that may cause at least a focal severe villus
abnormality: common variable immune deficiency, protein allergies other than gluten, some cases of
infectious gastroenteritis,10 rare cases of tropical sprue,12 stasis,12 the Zollinger-Ellison
syndrome,4,13 Crohn's disease, and nonspecific duodenitis. Clinicopathologic correlation is essential
for proper diagnosis. All biopsy specimens should be carefully evaluated for plasma cells, since their
absence in common variable immunodeficiency syndrome is easy to overlook. Numerous neutrophils, cryptitis,
and crypt abscess formation are usually not part of CS, and entities such as infectious gastroenteritis,
Zollinger-Ellison syndrome, Crohn's disease, nonspecific duodenitis, and stasis syndromes, therefore, should
If there is no clinical response to a gluten-free diet, before changing your diagnosis, remember the most
common cause of unresponsiveness is that the diet is not really gluten free.13 Furthermore, wheat is
commonly used as an extender in processed foods and can occasionally be present in seemingly
non-cereal-grain products, such as ice-cream, cocoa mixes, instant coffee, and salad dressings. Medications
and vitamin and mineral supplements may also contain gluten as an inactive ingredient.25 If dietary
indiscretions are ruled out, patients may have refractory or unclassified sprue4 which may respond to the
administration of corticosteroids. Refractory sprue can also be associated with cavitation of mesenteric
lymph nodes and hyposplenism.14 Persistent symptoms despite gluten withdrawal and small bowel
histological improvement should be a clue to search for comorbidities that may cause persistent diarrhea
such as pancreatic insufficiency, secondary lactase deficiency, bacterial overgrowth, or co-existing
inflammatory bowel disease, collagenous or lymphocytic colitis (see lymphocytic enterocolitis below).26
Lymphoma must also be considered in non-responsive patients and should prompt re-review of biopsy specimens
or re-biopsy. Furthermore, abnormal intraepithelial T-cell immunophenotypes and TCRg gene rearrangments in
some patients with refractory sprue suggest that many refractory patients could in fact be low grade T-cell
lymphomas26 (See discussion of "ulcerative jejunoileitis" below).
Other Protein Allergies
Allergic reactions to chicken, soy protein, milk, eggs, and tuna fish have been reported to show a flat
mucosa similar to celiac sprue.5,26 Definitive diagnosis depends upon identifying the offending
protein, showing a response to withdrawal from the diet and demonstration of recrudescence of symptoms and
pathology with its reintroduction.
Celiac sprue and other "sprue-like" lesions may be associated with a colonic epithelial lymphocytosis
similar to what has been described in "microscopic colitis".15,16 It is possible that in some patients
with true celiac sprue (responsive to gluten withdrawal), occult dietary gluten actually reaches the colon
and induces the histologic changes of "lymphocytic colitis". However, approximately 1/2 of the patients
with "sprue-like" small bowel lesions and "lymphocytic colitis" have not responded to gluten withdrawal.
The term "lymphocytic enterocolitis" has been coined to describe this refractory sprue-like condition
associated with colonic epithelial lymphocytosis.
Entities Associated with a Variable Villus Abnormality and Crypt Hypoplasia
This type of biopsy specimen has been described in malnourished patients with marasmus and kwashiorkor, in
patients with megaloblastic anemia and as a sequelae of radiation and chemotherapy. Microvillus inclusion
disease also typically causes a variable villus abnormality with crypt hypoplasia. This is an inherited
autosomal recessive condition that causes intractable diarrhea in infants. Diarrhea persists despite total
parental nutrition and patients rarely survive beyond the age of 2 years. The disease should be recognized
so that genetic counselling can be offered. Small bowel biopsy specimens usually show a severe villus
abnormality with shortened and hypoplastic crypts. Intraepithelial lymphocytes are usually not increased.
Transmission electron microscopy establishes the diagnosis by identifying abnormal microvillus structures at
the luminal border of the enterocyte and intracytoplasmic inclusions lined by microvilli in the same cells
.17,18 Microvillus inclusion disease can sometimes be suspected based on light microscopic findings
because the abnormal microvillus inclusions will be highlighted as PAS positive inclusions. The inclusions
can also be recognized with carcinoembryonic antigen immunostaining.
Entities Associated with a Non-Specific Variable Villus Abnormality
Many diseases are associated with non-specific variable villus abnormalities that are usually not flat (see
table 1). Although most mucosal biopsy specimens showing this change will be from patients with partially
treated celiac sprue, other conditions enter into the differential diagnosis including dermatitis
herpetiformis, tropical sprue, infectious gastroenteritis, stasis syndromes, Zollinger-Ellison syndrome,
systemic mastocytosis, duodenitis with peptic ulcer disease, autoimmune enteropathy and Torkelson syndrome.
Clinical correlation is required.5
Entities Associated with Variable Villus Abnormalities Illustrating Specific Diagnostic Changes
The specific diagnostic features seen in this group of conditions are outlined in Table 2.5
PATTERNS OF ABNORMAL SMALL BOWEL ARCHITECTURE
|I. ||Diffuse severe villus abnormality and crypt hyperplasia:|
| ||A.||Celiac sprue |
| ||B.||Refractory or unclassified sprue |
| ||C.||Other protein allergies |
| ||D.||Lymphocytic enterocolitis |
|II. ||Variable villus abnormality and crypt hypoplasia:|
| ||A.||Kwashiorkor, malnutrition |
| ||B.||Megaloblastic anemia |
| ||C.||Radiation and chemotherapeutic effect |
| ||D.||Microvillus Inclusion Disease |
|III. ||Nonspecific variable villus abnormality, usually not flat:|
| ||A.||Changes associated with dermatitis herpetiformis |
| ||B.||Partially treated or clinically latent celiac sprue |
| ||C.||Infection |
| ||D.||Stasis |
| ||E.||Tropical sprue |
| ||F.||Zollinger Ellison Syndrome |
| ||G.||Mastocytosis |
| ||H.||Nonspecific duodenitis |
| ||I.||Autoimmune enteropathy |
| ||J.||Torkelson Syndrome |
|IV. ||Variable villus abnormality with specific diagnostic changes:|
| ||A.||Collagenous sprue |
| ||B.||Immunodeficiency syndromes (excluding AIDS) |
| ||C.||Whipple's disease |
| ||D.||Mycobacterium avium-intracellulare complex infection|
| ||E.||Eosinophilic gastroenteritis |
| ||F.||Intestinal lymphoma |
| ||G.||Parasitic infestation |
| ||H.||Waldenströms macroglobulinemia |
| ||I.||Lymphangiectasia |
| ||J.||Enteropathy-associated T-cell lymphoma |
| ||K.||Abetalipoproteinemia |
| ||L.||Acrodermatitis enteropathica |
| ||M.||Tufting enteropathy |
ENTITIES ASSOCIATED WITH VARIABLE VILLUS ABNORMALITIES ILLUSTRATING SPECIFIC DIAGNOSTIC CHANGES
|Entity ||Diagnostic Feature|
|Collagenous Sprue ||Thickened subepithelium collagen plate*|
|Immunodeficiency Syndromes ||Nodular lymphoid hyperplasia Variable villus abnormality associated with absent or reduced numbers of plasma cells **|
|Whipple's Disease ||Foamy macrophages within lamina propria coarse granular intracytoplasmic PAS positive inclusions.|
|Eosinophilic Gastroenteritis ||Infiltration of mucosa, muscularis mucosae Or submucosa by large numbers of eosinophils.|
|Enteropathy associated T-cell lymphoma||Ulcers associated with sprue-like mucosa, transformation into large cell lymphoma, clonal gene rearrangement.|
|Parasitic Infestation ||Identification of organism|
|Waldenstrom's Macroglobulinemia ||Ectatic mucosal lymphatics filled with eosinophilic material, foamy macrophages in lamina propria|
|Intestinal lymphangiectasia ||Diffuse dilated lymphatics within mucosa|
|Abetalipoproteinemia ||Fat accumulation with vacuolization of enterocytes|
|Acrodermatitis Enteropathica ||Rod-like fibrillar inclusions within Paneth cells by electron microscopy|
|Tufting Enteropathy ||Focal surface epithelial crowding, disorganization and tufting|
* Reference 19
** Reference 20-24
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Enteropathy-Associated T-cell Lymphoma and "Ulcerative Jejunoileitis"
"Ulcerative jejunoileitis" is a rare and poorly understood condition characterized by mucosal ulcers
associated with a severe small intestinal villus abnormality (severe villus atrophy). Patients present with
abdominal pain, fever, intestinal obstruction, perforation, or hemorrhage usually in association with
malabsorption.1-3 Examples of ulcerative jejunoileitis4 have been reported under a number of synonyms
including diffuse ulceration of the jejunum and ileum,1 chronic ulcerative nongranulomatous jejunoileitis
,5 idiopathic chronic ulcerative enteritis,6 malignant histiocytosis,7 enteropathy-associated T-cell
lymphoma,8 and epitheliotropic lymphoma of the small bowel.9 Although some researchers exclude
patients who have had clinical celiac sprue (i.e., malabsorption initially responsive to dietary gluten
withdrawal),1-3 in my opinion, patients with ulcers and a severe intestinal villus abnormality share a
common clinical course and histologic appearance regardless of an initial response to gluten withdrawal.
Both patient groups demonstrate clinical malabsorption, a similar histologic appearance (ulcer associated
with a "flat" small bowel mucosa and atypical lymphoid cells), poor prognosis (75% dead within two years),
and a close association with concomitant or subsequent malignant lymphoma.1,2,7-12 The striking
association with lymphoma has prompted some investigators to conclude that all cases of "ulcerative
jejunoileitis" probably represent intestinal non-Hodgkin's lymphoma (Synonyms: malignant histiocytosis,
enteropathy-associated T-cell lymphoma).7,11,13
In 1978, Isaacson and Wright coined the term "malignant histiocytosis" to replace "ulcerative
jejunitis.".7 The authors reported seven patients with a severe villus abnormality, malabsorption, and
varying numbers of atypical cells that they classified as lymphoma. They cited several other examples of
"ulcerative jejunoileitis" that were either associated with or preceded overt malignant lymphoma and
concluded that the evidence strongly suggested that ulcerative jejunoileitis and lymphoma associated with
villus atrophy and malabsorption were all one condition, namely, malignant lymphoma.7 Isaacson and
Wright chose the term "malignant histiocytosis" to describe this lymphoma because the morphology,
erythrophagocytosis, the ultrastructural appearance, and the immunocytochemical reaction for
alpha-1-antitrypsin in the "atypical cells" favored origin from tissue macrophages.7,14-16 These same
investigators later demonstrated a T-cell immunophenotype and T-cell receptor beta chain gene rearrangements
.11,13 Subsequently, T-cell lineage was confirmed17-20 thus accounting for the popularity of an
alternative term, "enteropathy-associated T-cell lymphoma." There may well be "benign" ulcer complications
of malabsorption1-3 but I have been impressed with the focality of lymphoma and with the difficulty in
making that diagnosis with certainty in the cases I have examined. I, therefore, consider any ulcer in a
patient with celiac sprue or an unclassified malabsorption syndrome associated with a flat mucosa as a
potential harbinger of intestinal lymphoma and recommend extensive sampling of the lesion and careful
Another controversial point concerns whether the villus abnormality in "ulcerative jejunoileitis" is, in
fact, celiac sprue, a low grade intramucosal T-cell lymphoma, mucosal injury resulting from cytokines
released by abnormal T-cells or some other yet unrecognized small intestinal disorder.1,20-23 Spencer et
al, concluded that the lymphoma was a complication of celiac sprue, citing the histologic similarity of the
uninvolved mucosa in enteropathy-associated lymphoma to celiac sprue and the fact that the intraepithelial
T-cell subsets were identical in both conditions.21 Others demonstrating T-cell receptor gene
rearrangements in the mucosa not involved by lymphoma, provide a compelling argument that the "enteropathy"
may not be celiac sprue but could represent de novo low grade epitheliotropic/ mucosatropic T-cell lymphoma
9,20,22-27 with a cytotoxic T-cell phenotype.28 This concept may revolutionize our perception and
treatment of adult-onset unclassified sprue and celiac sprue that has become nonresponsive to dietary gluten
withdrawal. If T-cell receptor gene rearrangements are confirmed in these patients, then they could
potentially benefit from lymphoma-directed chemotherapeutic regimens rather than the standard malabsorption
treatments (e.g. total parenteral nutrition, hospitalized gluten withdrawal, and corticosteroids).
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enteritis. GUT 14:649-652, 1973.
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- Spencer J, Cerf-Bensussan N, Jarry A et al. Enteropathy-associated T cell lymphoma (malignant
histiocytosis of the intestine) is recognized by a monoclonal antibody (HML-1) that defines a membrane
molecule on human mucosal lymphocytes. AM J PATHOL 132:1-5, 1988.
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Diagnostic difficulties in relationship to coeliac disease. GUT 24:565-574, 1983.
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lymphoma. LANCET ii:688-691, 1985.
- Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteroopathy-type intestinal T-cell lymphoma:
Clinical features and treatment of 31 patients in a single center. J Clin Oncol 18:795-803, 2000.
- Ashton-Key M, Diss TC, Pan L, Du MQ, Isaacson G. Molecular analysis of T-cell clonality in ulcerative
jejunitis and enteropathy-associated T-cell lymphoma. AMER J PATHOL 151:493-498, 1997.
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- Isaacson P, Wright DH, Judd MA, Mepham BL. Primary gastrointestinal lymphomas: A classification of 66
cases. CANCER 43:1805-1819, 1979.
- Isaacson PG, Jones DB, Sworn MJ, Wright DH. Malignant histiocytosis of the intestine: Report of three
cases with immunologic and cytochemical analysis. J CLIN PATHOL 35:510-516, 1982.
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MED 104:44-47, 1986.
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intestine. J CLIN PATHOL 39:8-15, 1986
- Salter DM, Krajewski AS. Histogenesis of malignant histiocytosis of the intestine. GASTROENTEROLOGY
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enteropathy-associated T-cell lymphoma. AMER J PATHOL 146:509-519, 1995.
- Spencer J, MacDonald TT, Diss TC, Walker-Smith JA, Ciclitira PJ, Isaacson PG. Changes in
intraepithelial lymphocyte subpopulation in celiac disease and enteropathy-associated T-cell lymphoma
(malignant histiocytosis) of the intestine. GUT 30:339-346, 1989.
- Alfsen GC, Beiske K, Bell H, Marton PF. Low grade intestinal lymphoma of intraepithelial T-lymphocytes
with concomitant enteropathy-associated T-cell lymphoma: Case report suggesting a possible histogenic
relationship. HUMAN PATHOL 20:909-913, 1989.
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low-grade lymphoma of intraepithelial T lymphocytes? LANCET 337:1373-1374, 1991.
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- Bagdi E, Diss TC, Munson P, Isaacson PG. Mucosal intra-epithelial lymphocytes in enteropathy associated
T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population.
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