Background

This aggressive lymphoma almost always arises in the setting of celiac disease. Rarely the lymphoma may arise in extraintestinal sites. The most common location is the jejunum and presents as single or multiple tuors.

Outline

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Malignant histiocytosis of the intestine
Risk of Non-Hodgkin Lymphoma in Celiac Disease Carlo Catassi, MD; Elisabetta Fabiani, MD; Giovanni Corrao, PhD; Maria Barbato, MD; Amalia De Renzo, MD; Angelo M. Carella, MD; Armando Gabrielli, MD; Pietro Leoni, MD; Antonio Carroccio, MD; Mariella Baldassarre, MD; Paolo Bertolani, MD; Paola Caramaschi, MD; Michele Sozzi, MD; Graziella Guariso, MD; Umberto Volta, MD; Gino R. Corazza, MD; for the Italian Working Group on Coeliac Disease and Non–Hodgkin's-Lymphoma	JAMA. 2002;287:1413-1419 Abstract quote Context Celiac disease is one of the most common lifelong disorders. Non-Hodgkin lymphoma is a possible complication of celiac disease and may lead to a large portion of lymphoma cases. Objective To quantify the risk for developing non-Hodgkin lymphoma of any primary site associated with celiac disease. Design and Setting Multicenter, case-control study conducted between January 1996 and December 1999 throughout Italy. Patients Cases were older than 20 years (median, 57; range, 20-92 years) with non-Hodgkin lymphoma of any primary site and histological type and were recruited at the time of the diagnosis. Controls were healthy adults (2739 men and 2981 women) from the general population. Main Outcome Measure Positive test result for class A serum antiendomysial antibody. Results Celiac disease was diagnosed in 6 (0.92%) of 653 patients with lymphoma. Of the 6 cases, 3 were of B-cell and 3 were of T-cell origin. Four of 6 cases had lymphoma primarily located in the gut. In the control group, 24 (0.42%) had celiac disease. The odds ratio (adjusted for age and sex) for non-Hodgkin lymphoma of any primary site associated with celiac disease was 3.1 (95% confidence interval [CI], 1.3-7.6), 16.9 (95% CI, 7.4-38.7) for gut lymphoma, and 19.2 (95% CI, 7.9-46.6) for T-cell lymphoma, respectively. The risk for non-Hodgkin lymphoma for the overall population, which was adjusted for age and sex, was 0.63% (95% CI, - 0.12% to 1.37%). Conclusion Celiac disease is associated with an increased risk for non-Hodgkin lymphoma, especially of T-cell type and primarily localized in the gut. However, the association does not represent a great enough risk to justify early mass screening for celiac disease.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Celiac disease
Primary intestinal T-cell lymphoma and sclerosing cholangitis: a cytokine-mediated association? Schattner A, Kozak N, Lassry Y, Sokolovskaya N. Department of Medicine, Kaplan Medical Center, Rehovot; and Hadassah Medical School, Jerusalem, Israel.	J Intern Med 1998 Dec;244(6):537-41 Abstract quote A 63-year-old woman with a 1-year history of abdominal pain and intrahepatic cholestasis developed anorexia, weight loss, lassitude and diarrhoea. Studies led to a diagnosis of primary intestinal T-cell lymphoma involving especially the proximal small intestine and infiltrating the mesenteric lymph nodes, bone marrow and skin. An associated severe hypoalbuminaemia (1.3 g dL-1) was most probably the result of protein-losing enteropathy. Liver biopsy demonstrated concentric fibrosis of the bile ducts ('onion skin' lesions, with an inflammatory cell infiltrate and lymphoid aggregates) and was considered almost pathognomonic of primary sclerosing cholangitis. Sudden death due to pulmonary embolism occurred and a limited autopsy confirmed the diagnosis. Other associated diseases such as coeliac disease or inflammatory bowel disease were not found. This first report of the simultaneous occurrence of two rare diseases - primary sclerosing cholangitis and intestinal T-cell lymphoma - may indicate an intriguing association, possibly mediated by the effect of cytokines released by the infiltrating T-cells into the portal circulation.

 

PATHOGENESIS

CHARACTERIZATION

Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Daum S, Weiss D, Hummel M, Ullrich R, Heise W, Stein H, Riecken EO, Foss HD. Medical Clinic I, Gastroenterology and Infectious Diseases, Universitatsklinikum Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

Gut 2001 Dec;49(6):804-12 Abstract quote BACKGROUND: Clonal T cell receptor (TCR) gene rearrangements and loss of T cell antigens such as CD8 and TCR-beta in intraepithelial lymphocytes (IELs) may indicate the development of an enteropathy-type intestinal T cell lymphoma (EITCL) in patients with refractory sprue. AIMS: To define the diagnostic value of these markers in duodenal biopsies from patients with villous atrophy as a result of various underlying disorders. PATIENTS AND METHODS: Duodenal biopsies from eight patients with coeliac disease and five patients with villous atrophy caused by defined disorders were compared with three patients with refractory sprue evolving into overt EITCL, two patients with ulcerative jejunitis, and with eight patients with overt EITCL, for expression of CD3, CD4, CD8, and TCR-beta in IELs using immunohistochemistry and for clonal TCR-gamma gene rearrangements using polymerase chain reaction. In addition, biopsies from six consecutive patients with refractory sprue of uncertain cause were examined. RESULTS: Clonal TCR-gamma gene rearrangements were found in all resected tumours of patients with EITCL, in 3/8 duodenal biopsies of patients with EITCL, in 2/2 patients with ulcerative jejunitis, in 2/3 patients with refractory sprue evolving into overt EITCL, and in 1/6 patients with refractory sprue. No rearrangements were found in biopsies from patients with refractory sprue caused by defined disorders or those with coeliac disease. Clonality in duodenal biopsies was associated with an abnormal phenotype of IELs in all cases and in all but one case in patients with evidence of underlying coeliac disease. Specificity for detection of an EITCL using immunohistology was 77% for CD8 and for TCR-beta staining, and 100% for detection of a clonal TCR-gamma gene rearrangement. Sensitivity was 62% for staining with CD8 and clonality investigation, while sensitivity reached 100% for TCR-beta staining in all investigated patients with EITCL. CONCLUSIONS: Clonal proliferations of phenotypically abnormal IELs in refractory sprue represent an early manifestation of EITCL, for which the term "sprue-like intestinal T cell lymphoma" is proposed. This constellation is also found in duodenal biopsies from patients with an overt EITCL and is not related to other sprue syndromes, resulting in a high specificity for detection of an EITCL or refractory sprue evolving into EITCL. Overt EITCL may develop directly from coeliac disease without a precursor lesion (refractory sprue with clonal IELs) being demonstrable in duodenal biopsies or via a "sprue-like intestinal T cell lymphoma". This latter entity is a complication of coeliac disease.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy. Howell WM, Leung ST, Jones DB, Nakshabendi I, Hall MA, Lanchbury JS, Ciclitira PJ, Wright DH. Molecular Immunology Group, Tenovus Laboratory, Southampton General Hospital, United Kingdom.	Hum Immunol 1995 May;43(1):29-37 Abstract quote CD is a gluten-sensitive enteropathy, strongly associated with expression of the DQA1*0501, DQB1*0201 genotype. CD patients have an increased risk of malignancy, particularly EATCL. However, it is controversial as to whether adults with EATCL represent a subgroup of patients with CD or should be regarded as a distinct entity. To investigate the genetic relationship between CD and EATCL, HLA class II DRB1, DQA1, and DQB1 typing of peripheral blood, frozen or paraffin-embedded biopsy tissue obtained from Caucasian patients with CD (n = 91) or EATCL (n = 47) was performed by PCR-SSOP typing. Genotype frequencies were compared with those observed in 151 unrelated control individuals. A total of 83 (91%) of 91 CD patients were of DQA1*0501, DQB1*0201 genotype (pc < 10(-6), RR = 522.2), compared with 40 (93%) of 43 EATCL patients (pc < 10(-6), RR = 44.2) with amplifiable DNA versus 35 (23%) of 151 controls. DRB1*03 frequencies were also elevated in both patient groups (79 of 91 in CD [87%; pc < 10(-6), RR = 24.5] and 38 of 40 in EATCL [95%; pc < 10(-6), RR = 70.7]) compared with controls (32 of 151, 21%). These results confirm previous studies of HLA associations in CD and also suggest that EATCL arises in individuals with the DQA1*0501, DQB1*0201 CD-predisposing genotype. However, the frequency of DRB1*03,04 heterozygotes was significantly increased in the EATCL group (16 of 40, 40%) compared with both control individuals (3 of 151, 2%; pc < 10(-6), RR = 32.9) and uncomplicated CD patients (6 of 91, 7%; pc = 0.04, RR = 9.4).(

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Enteropathy associated T cell lymphoma presenting as an isolated CNS lymphoma three years after diagnosis of coeliac disease: T cell receptor polymerase chain reaction studies failed to show the original enteropathy to be a clonal disorder. Tutt AN, Brada M, Sampson SA. Royal Marsden NHS Trust Hospital, Neuro-Oncology Unit, Sutton, Surrey UK	Gut 1997 Jun;40(6):801-3 Abstract quote A case of enteropathy associated T cell lymphoma is reported in a 45 year old woman, presenting with isolated disease in the CNS, three years after diagnosis of coeliac disease. Initial staging showed no evidence of gastrointestinal tract lymphoma. A presumptive diagnosis of T cell primary cerebral lymphoma was made and the patient was treated with combination chemotherapy and craniospinal radiotherapy. The patient relapsed, seven months after treatment, with small bowel lymphoma. The immunophenotype and T cell receptor polymerase chain reaction analysis confirmed the same tumour as in the CNS. Retrospective polymerase chain reaction analysis of intraepithelial lymphocytes in the duodenal biopsy sample, taken at the time of diagnosis of coeliac disease, failed to show evidence of a clonal T cell proliferation.
Enteropathy-associated T cell lymphoma with brain involvement. Berman EL, Zauber NP, Rickert RR, Diss TC, Isaacson PG. Department of Pathology, Saint Barnabas Medical Center, Livingston, New Jersey 07039, USA.	J Clin Gastroenterol 1998 Jun;26(4):337-41 Abstract quote In a patient with enteropathy-associated T cell lymphoma. there was dissemination to the brain manifesting as an inflammatory lesion. the intestinal and brain lesions were studied using routine histology, immunohistochemistry, and polymerase chain reaction. The jejunum was involved by a multifocal large cell lymphoma associated with multiple inflammatory ulcers and villous atrophy with crypt hyperplasia of the intervening mucosa. The lesion in the brain consisted of necrotic tissue associated with an infiltrate of histiocytes and a relatively scant infiltrate of primarily small lymphocytes. The appearance was that of an inflammatory rather than a neoplastic process. The intestinal lymphoma cells were positive for T cell markers and contained cytotoxic granules detected with the TIA-1 monoclonal antibody. The small lymphocytes and occasional large cells in the cerebral lesion showed the same immunophenotype. DNA extracted from the intestinal lymphoma and the cerebral lesion showed identical monoclonal rearrangement of the TCR-gamma gene. Dissemination from enteropathy-associated T cell lymphoma may masquerade as an inflammatory lesion. Molecular analysis is useful in confirming the diagnosis.
Cytotoxic T-cell lymphoma diffusely involving the entire gastrointestinal tract associated with Epstein-Barr virus and tubercle bacilli infection. Abe Y, Muta K, Ohshima K, Hirase N, Matsushima T, Yufu Y, Nishimura J, Nawata H. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.	Int J Hematol 2000 Jun;71(4):379-84 Abstract quote We describe a rare case of cytotoxic gastrointestinal T-cell lymphoma with protein-losing enteropathy. Initial examination revealed the coexistence of T-cell lymphoma and tuberculosis in the mesenteric lymph node and liver. Despite anti-tuberculosis and anti-cancer treatment, the patient experienced chronic diarrhea and malabsorption and died approximately 3 years after onset. Autopsy specimens revealed medium-sized lymphoma cells, with a phenotype of CD3+, CD4-, CD7+, CD8+, CD30-, CD56-, CD103 (HML-1)-, TIA-1+, and granzyme B+, proliferating primarily and consistently in the mucosa of the entire bowel tract from esophagus to rectum. Interestingly, Epstein-Barr virus (EBV)-encoded small nuclear RNAs were detected in the tumors by in situ hybridization. Southern blot analysis revealed monoclonal proliferation in the EBV-infected T cells. Although the present case can possibly be categorized as an intestinal T-cell lymphoma according to the Revised European-American Lymphoma Classification, the case showed a unique clinical course and distribution of lymphoma cells. We present here an interesting case of gastrointestinal cytotoxic T-cell lymphoma and examine the possible association with infectious agents.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	Pleomorphic to anaplastic large cells Occasional cases with small or medium sized cells Epitheliotropism common May be accompanied by an intense infiltrate of eosinophils or histiocytes which may obscure the diagnosis Surrounding small bowel mucosa shows villous atrophy, crypt hyperplasia and intraepithelial lymphocytosis, indicative of celiac disease
NOTE:	If an intestinal lymphoma morphologically looks like an anaplastic large cell lymphoma and is CD30+, it should not be called an anaplastic large cell lymphoma if there are features consistent with enteropathy-type T-cell lymphoma
Expression of killer cell inhibitory receptors is restricted to true NK cell lymphomas and a subset of intestinal enteropathy-type T cell lymphomas with a cytotoxic phenotype. Dukers DF, Vermeer MH, Jaspars LH, Sander CA, Flaig MJ, Vos W, Willemze R, Meijer CJ. Department of Pathology, Vrije Universiteit, Amsterdam, The Netherlands	J Clin Pathol 2001 Mar;54(3):224-8 Abstract quote BACKGROUND/AIMS: Killer inhibitory receptors (KIR) have a modulating effect on the cytotoxic functions of natural killer (NK) cells and T cells. Because lymphoma cells often have the same receptors as their non-neoplastic counterparts, this study investigated the expression of KIR on well defined groups of NK and T cell lymphomas, with and without a cytotoxic phenotype, from different sites of origin. METHODS: Nine CD56+/CD3- NK cell lymphomas, 29 CD3+/CD56- T cell lymphomas with a cytotoxic phenotype, and 19 T cell lymphomas without a cytotoxic phenotype were stained for KIR using monoclonal antibodies specific for CD94, CD158a, and CD158b. In addition, the expression of KIR was studied on normal lymphoid tissues. RESULTS: KIR expression was seen in five of nine true NK cell lymphomas including three of four nasal, one of four cutaneous, and one of one intestinal lymphoma nasal type. Double staining for CD56 and CD94 in normal lymphoid tissues revealed that KIR was predominantly expressed by CD56+ NK cells and sporadically on CD8+ T cells. Moreover, enteropathy-type T cell lymphomas with a cytotoxic phenotype showed KIR expression (three cases expressing CD94 and one case expressing CD158a). All nodal and extranodal nonintestinal T cell lymphomas with or without a cytotoxic phenotype lacked expression of KIR. CONCLUSIONS: These results show that KIR expression is restricted to CD56+/CD3- true NK cell lymphomas originating from the nose, gut, and skin, as well as in a subset of extranodal T cell lymphomas originating from the small intestine, which possessed a cytotoxic phenotype. Thus, the presence of KIR on NK/T cell lymphomas seems to mimic the distribution of KIR found on NK and T cells in normal lymphoid tissue.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
T cell markers positive	CD3, CD7, CD103 positive CD4 and CD8 often negative
Cytotoxic molecules positive	TIA1, perforin, granzyme B
CD30	Positive in cases with large anaplastic cells
EBV	Usually negative
Enteropathy-associated T-cell lymphomas have a cytotoxic T-cell phenotype. de Bruin PC, Connolly CE, Oudejans JJ, Kummer JA, Jansen W, McCarthy CF, Meijer CJ. Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.	Histopathology 1997 Oct;31(4):313-7 Abstract quote AIMS: Enteropathy-associated T-cell lymphoma (EATCL) is a rare complication of coeliac disease. We investigated whether EATCLs are the neoplastic counterparts of activated cytotoxic T-cells (CTLs). METHODS AND RESULTS: Eight cases, clinically and histologically defined, were stained with monoclonal antibodies against components of the cytotoxic granules of CTLs, granzyme B and T-cell restricted intracellular antigen (TIA-1). It was found that all cases had a cytotoxic phenotype, i.e. expression of TIA-1 in most of the tumour cells, whereas granzyme B was found in six of eight cases, mostly in a smaller number of tumour cells compared to TIA-1. Since TIA-1 and granzyme B are expressed at different stages of activation of CTLs it is hypothesized that differences in expression between granzyme B and TIA-1 in EATCL represent different stages of activation in which the tumour cells are arrested. Clinically, seven of the eight patients died within 10 months after diagnosis of EATCL. CONCLUSIONS: EATCL is a clinicopathological entity with a grim prognosis and with tumour cells representing a unique neoplastic equivalent of CTLs arrested in varying stages of activation.
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. Spencer J, Cerf-Bensussan N, Jarry A, Brousse N, Guy-Grand D, Krajewski AS, Isaacson PG. Department of Histopathology, University College and Middlesex School of Medicine, London, England.	Am J Pathol 1988 Jul;132(1):1-5 Abstract quote Enteropathy-associated T cell lymphoma (EATCL; malignant histiocytosis of the intestine) arises in patients with enteropathy, which in some cases is known to be a result of gluten sensitivity. The lymphoma arises in the intestine, where it may remain localized, although eventual dissemination is the rule. Intraepithelial tumour cells often are seen at the mucosal tumor margin. These features suggest that EATCL may be a tumor of intraepithelial lymphocytes. A monoclonal antibody (HML-1) has been produced recently that recognizes the entire intraepithelial lymphocyte population and 50% of lamina propria T cells but very few cells outside the mucosa. Immunocytochemistry has shown that all cases of enteropathy-associated T cell lymphoma studied are HML-1 positive and all peripheral T cell lymphomas and mucosal B cell lymphomas are HML-1 negative. This suggests strongly that EATCL is a tumor of mucosal T cells, possibly the intraepithelial T cell component.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Anaplastic large cell lymphoma
MALToma

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Refractory coeliac disease: a window between coeliac disease and enteropathy associated T cell lymphoma. Mulder CJ, Wahab PJ, Moshaver B, Meijer JW. Depts. of Gastroenterology and Pathology, Rijnstate Hospital, P.O. Box 5555, 6800 TA Arnhem, The Netherlands	Scand J Gastroenterol Suppl 2000;(232):32-7 Abstract quote The treatment of coeliac disease (CD) is straightforward and simple: life-long adherence to a gluten-free diet. However, in a small subgroup of patients, the clinical and histological abnormalities persist or recur. This non-responsiveness leaves a poorly understood syndrome known as refractory coeliac disease (RCD). A specific definition of RCD is lacking in the literature. We speculate that RCD may appear in a subgroup of coeliacs with persisting histologic abnormalities. In all patients screened for RCD we look for DQ2 and DQ8. In non-DQ2/DQ8 patients we reconsider the diagnosis of CD and of auto-immune enteropathy. Most of the patients referred to us because of suspicion of RCD are affected by other diseases. Probably the commonest cause of non-responsiveness is continued gluten intake. Exocrine pancreas insufficiency, hyperthyroid disease, collagenous colitis are other common explanations. RCD and enteropathy-associated T cell lymphomas (EATL) can be distinguished by intra-epithelial lymphocyte phenotyping and TCR-gamma gene rearrangements. In RCD, an unexplained sustained stimulation of T cell cytotoxic activity is present. Immunosuppressive treatment might moderate this. Cyclosporine has been reported as a resounding success in case reports; however, our results were disappointing. We suggest azathioprine and steroids in RCD without aberrant T-lymphocytes in their mucosa. However, in RCD with aberrant T-lymphocytes we suggest chemotherapy. As the prognosis of EATLs is extremely poor the early detection of RCD with aberrant T cells is crucial.
TREATMENT
Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Cancer Research Campaign Wessex Medical Oncology Unit, Royal South Hants Hospital, Southampton, United Kingdom.	J Clin Oncol 2000 Feb;18(4):795-803 Abstract quote PURPOSE: We report the clinical features and treatment of 31 patients with a diagnosis of enteropathy-type intestinal T-cell lymphoma treated at the Wessex Regional Medical Oncology Unit in Southampton between 1979 and 1996 (23 men, eight women). PATIENTS AND METHODS: Patients were identified from our lymphoma database. Details of history, physical examination, staging investigations, treatment, and outcome were taken from patient records. RESULTS: Twelve patients (35%) had a documented clinical history of adult-onset celiac disease, and a further three had histologic features consistent with celiac disease in resected areas of the small bowel not infiltrated with lymphoma. After diagnosis, 24 (77%) of the 31 patients were treated with chemotherapy; the remaining seven had surgical treatment alone. More than half were unable to complete their planned chemotherapy courses, often because of poor nutritional status; 12 patients required enteral or parenteral feeding. A response to initial chemotherapy was observed in 14 patients (complete response, n = 10; partial response, n = 4). Observed complications of treatment were gastrointestinal bleeding, small-bowel perforation, and the development of enterocolic fistulae. Relapses occurred 1 to 60 months from diagnosis in 79% of those who responded to initial therapy. Of the total 31 patients, 26 (84%) have died, all from progressive disease or from complications of the disease and/or its treatment. The actuarial 1- and 5-year survival rates are 38.7% and 19.7%, respectively, with 1- and 5-year failure-free survival rates of 19.4% and 3.2%, respectively. CONCLUSION: The prognosis for these patients is poor. This, in part, reflects late diagnosis and poor performance status at the time of presentation. The role of salvage treatments and high-dose chemotherapy at relapse is not clear. However, it is encouraging that there are five long-term survivors in our patient population.

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Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001

Celiac Disease

Lymphoma

Last Updated 3/22/2002

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