—  SHORT COURSE  —

A PRACTICAL APPROACH TO GASTROINTESTINAL PATHOLOGY


SMALL BOWEL BIOPSY: INTERPRETATION AND SPECIMEN HANDLING

Robert E. Petras, M.D.




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.


Case 8 - Lymphocytic Enterocolitis
Case 8 - Lymphocytic Enterocolitis



Case 9 - Nodular Lymphoid Hyperplasia with Changes Consistent with Common Variable Immune Deficiency Syndrome - Giardiasis
Case 9 - Nodular Lymphoid Hyperplasia with Changes Consistent with Common Variable Immune Deficiency Syndrome - Giardiasis
Case 9 - Nodular Lymphoid Hyperplasia with Changes Consistent with Common Variable Immune Deficiency Syndrome - Giardiasis

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 does.5 

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
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 be considered.

Refractory Sprue
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.

Lymphocytic enterocolitis
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.


Case 8 - Lymphocytic Enterocolitis
Case 8 - Lymphocytic Enterocolitis



Case 9 - Nodular Lymphoid Hyperplasia with Changes Consistent with Common Variable Immune Deficiency Syndrome - Giardiasis
Case 9 - Nodular Lymphoid Hyperplasia with Changes Consistent with Common Variable Immune Deficiency Syndrome - Giardiasis
Case 9 - Nodular Lymphoid Hyperplasia with Changes Consistent with Common Variable Immune Deficiency Syndrome - Giardiasis

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 

TABLE 1
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


TABLE 2
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 lymphomaUlcers 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

REFERENCES

  1. Trier JS Diagnostic value of per oral biopsy of the proximal small intestine. New England Journal of Medicine 285:1470-1473, 1971.
  2. Achkar E, Carey WD, Petras RE, Sivak MV, Revta R Comparison of suction capsule and endoscopic biopsy of small bowel mucosa. Gastrointestinal Endoscopy 32:278-281, 1986.
  3. Dandalides WM, Carey WD, Petras RE, Achkar E Endoscopic small bowel mucosal biopsy: A controlled trial evaluating forceps size and biopsy location in the diagnosis of normal and abnormal architecture. Gastrointestinal Endoscopy 35:197-200, 1989.
  4. Dobbins WO III Small bowel biopsy in malabsorption states in Norris HT editor. Pathology of the Colon, Small Intestine, and Anus, New York, Churchill Livingstone 1991 pp 137-188.
  5. Petras RE Non-neoplastic intestinal diseases in Sternberg SS editor. Diagnostic Surgical Pathology 3rd edition Lippincott Williams & Wilkins, Philadelphia, 1999 pp1349-1411.
  6. Segal GH, Petras RE Small intestine in Sternberg SS editor. Histology for Pathologists 2nd edition Lippincott-Raven, Philadelphia 1997, pp 495-518.
  7. An Evolving Spectrum. Gastroenterology 120:636-651, 2001.
  8. Walker-Smith JA, Guardlini S, Schmitz J, Shmerling PH, Visakorpi JK Revised criteria for diagnosis of Coeliac Disease. Archives Diseases of Children 65:909-911, 1990.
  9. Vogelsang H, Genser O, Wyatt J, et al. Screening for celiac disease: a prospective study on the value of noninvasive tests. Amer J Gastroenterol 1995;90:394-398.
  10. Valdimarsson T, Fransen L, Grodzinsky E, Skogh T, Strom M. Is small biopsy necessary in adults with suspected celiac disease and IgA anti-endomesial antibodies? 100% positive predictive value for celiac disease in adults. Dig Dis Sc 1996;41:83-87.
  11. Barnes GL, Townley RRW. Duodenal mucosal damage in 31 infants with gastroenteritis. Arch Dis Child 1973;48:343-349.
  12. Swanson VL, Thomasson RW. Pathology of the jejunal mucosa in tropical sprue. Am J Pathol 1965;46:511-551.
  13. Ament ME, Shimoda SS, Saunders DR, Rubin CE. Pathogenesis for steatorrhea in three cases of small intestinal stasis syndrome. Gastroenterology 1972;63:728-747.
  14. Perera DR, Weinstein WM, Rubin CE Small intestinal biopsy. Human Pathology 6:157-217, 1975.
  15. Maturcharski C, Colin R, Hemet J, et al Cavitation of mesenteric lymph nodes, splenic atrophy, and a flat small intestinal mucosa. Gastroenterology 87:606-614, 1984.
  16. DuBois RN, Lazenby AJ, Yardley JH, Hendrix TR, Bayless TM, Giardiello FM Lymphocytic enterocolitis in patients with "refractory sprue". JAMA 262:935-937, 1989.
  17. Wolber R, Owen D, Freeman H Colonic lymphocytosis in patients with celiac sprue. Human Pathology 21:1092-1096, 1990.
  18. Bell SW, Kerner JA Jr., Sibley RK Microvillus inclusion disease. The importance of electron microscopy for diagnosis. American Journal of Surgical Pathology 15:1157-1164, 1991.
  19. Cutz E, Rhoades JM, Drumm B, Sherman PN, Durie PR, Forstner GG Microvillus inclusion disease; an inherited defect of brushed border assembly and differentiation. New England Journal of Medicine 320:646-651, 1989.
  20. Robert ME, Ament ME, Weinstein WM. The Histologic Spectrum and Clinical Outcome of Refractory and Unclassified Sprue. Am J Surg Pathol 24:676-687, 2000.
  21. Cunningham-Rundles C, Bodian C. Common Variable Immunodeficiency: Clinical and Immunological Features of 248 patients. Clinical Immunology 92:34-48,1999.
  22. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120:225-231, 2000.
  23. Teahon K, Webster AD, Price AB, Weston J, Bjarnason I. Studies on the enteropathy associated with primary hypogammaglobulinaemia. Gut 35:1244-1249, 1994.
  24. Sander CA, Medeiros JL, Weiss LM, Yano T, Sneller MC, Jaffe ES. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Amer J Surg Pathol 16:1170-1182, 1992.
  25. Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal Pathology in patients with common variable immunodeficiency and X-linked Agammaglobulinemia. Amer J Surg Pathol 20:1240-1252, 1996.
  26. Fasano A, Catassi C. Current Approaches to Diagnosis and Treatment of Celiac Disease:
  27. Ryan BM, Kelleher D. Refractory Celiac Disease. Gastroenterology 119:243-251, 2000.

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 clinical follow-up.

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).

REFERENCES

  1. Bayless TM. "Small intestinal ulcers and strictures: Isolated and diffuse." In: Sleisenger MH, Fordtran JS (Eds). Gastrointestinal Disease: Pathophysiology, Diagnosis, Management 4th ed. WB Saunders, Philadelphia, PA, 1989, pp. 1320-1327.
  2. Baer AN, Bayless TM, Yardley JH. Intestinal ulceration and malabsorption syndromes. GASTROENTEROLOGY 79:754-765, 1980.
  3. Bayless TM, Kapelowitz RF, Shelley WM, Ballinger WF, Hendrix TR. Intestinal ulceration - a complication of celiac disease. N ENGL J MED 276:996-1002, 1967.
  4. Klaeveman HL, Gebhard RL, Sessoms C, Strober W. In vitro studies of ulcerative ileojejunitis. GASTROENTEROLOGY 68:572-582, 1975.
  5. Jeffries GH, Steinberg H, Sleisenger MH. Chronic ulcerative (non-granulomatous) jejunitis. AM J MED 44:47-59, 1968.
  6. Armstrong BK, Ammon RK, Finlay-Jones LR, Joske RA, Vivian AB. A further case of chronic ulcerative enteritis. GUT 14:649-652, 1973.
  7. Isaacson P, Wright DH. Malignant histiocytosis of the intestine: Its relationship to malabsorption and ulcerative jejunitis. HUM PATHOL 9:661-677, 1978.
  8. 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.
  9. Foucar K, Foucar E, Mitros F, Clamon G, Goeken J, and Crossett J. Epitheliotropic lymphoma of the small bowel: Report of a fatal case with cytotoxic/suppressor T-cell immunotype. CANCER 54:54-60, 1984.
  10. Robertson DAF, Dixon MF, Scott BB, and Simpson FG, and Losowsky MS. Small intestinal ulceration: Diagnostic difficulties in relationship to coeliac disease. GUT 24:565-574, 1983.
  11. Isaacson PG, O'Conner NTJ, Spencer J et al. Malignant histiocytosis of the intestine: A T-cell lymphoma. LANCET ii:688-691, 1985.
  12. 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.
  13. 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.
  14. Isaacson PG, Wright DH. Intestinal lymphoma-associated with malabsorption. LANCET i:67-70, 1978.
  15. Isaacson P, Wright DH, Judd MA, Mepham BL. Primary gastrointestinal lymphomas: A classification of 66 cases. CANCER 43:1805-1819, 1979.
  16. 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.
  17. Loughran TP Jr, Kadin ME, Deeg HJ. T-cell intestinal lymphoma associated with celiac sprue. ANN INTERN MED 104:44-47, 1986.
  18. Salter DM, Krajewski AS, Dewar AE. Immunophenotypic analysis of malignant histiocytosis of the intestine. J CLIN PATHOL 39:8-15, 1986
  19. Salter DM, Krajewski AS. Histogenesis of malignant histiocytosis of the intestine. GASTROENTEROLOGY 92:2050, 1987.
  20. Murray A, Cuevas EC, Jones DB, Wright DH. Study of the immunohistochemistry and T-cell clonality of enteropathy-associated T-cell lymphoma. AMER J PATHOL 146:509-519, 1995.
  21. 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.
  22. 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.
  23. Wright DH, Jones DB, Clark H, Mead GM, Hodges E, Howell WM. Is adult-onset coeliac disease due to a low-grade lymphoma of intraepithelial T lymphocytes? LANCET 337:1373-1374, 1991.
  24. Schmitt-Graff A, Daum S, Hummel M, Zemlin M, Stein H, Riecken EO. Presence of clonal T-cell receptor gene rearrangements provides evidence of widespread intramucosal intestinal T-cell lymphoma. ZEITSCHRIFT FUR GASTROENTEROLOGIE 34(10):680-5, 1996 Oct.
  25. Cellier C, Patey N, Mauvieux L, et al. Abnormal intestinal intraepithelial lymphocytes in refractory sprue. GASTROENTEROLOGY 114:471-481, 1998.
  26. 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. Blood 94:260-264, 1999.
  27. Carbonnel F, Grollet-Bioul L, Brouet JC, Teilhac MF, Cosnes J, Angonin R, Deschaseaux M, Chatelet FP, Gendre JP, Sigaux F. Are complicated forms of celiac disease cryptic T-cell lymphoma? Blood 92:3879-3886, 1998.
  28. DeBruin PC, Connolly CE, Oudejans JJ, et al. Enteropathy-associated T-cell lymphomas have a cytotoxic T-cell phenotype. HISTOPATHOLOGY 31:313-317, 1997.