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© 2000 American Society for Clinical Oncology Enteropathy-Type Intestinal T-Cell Lymphoma: Clinical Features and Treatment of 31 Patients in a Single CenterFrom the Cancer Research Campaign Wessex Medical Oncology Unit, Royal South Hants Hospital, Southampton, United Kingdom. Address reprint requests to Joanna Gale, MD, CRC Wessex Medical Oncology Unit, Royal South Hants Hospital, Brinton’s Terrace, Southampton, SO14 OYG, United Kingdom; email JGale{at}soton.ac.uk
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.
PRIMARY GASTROINTESTINAL lymphomas account for 4% to 12% of all non-Hodgkin’s lymphoma and 1% to 4% of all gastrointestinal tumors. Primary T-cell gastrointestinal lymphomas are rare, and, although various histologic types have been reported, the only defined clinicopathologic entity is enteropathy-type intestinal T-cell lymphoma.1,2 Small-bowel lymphomas account for 20% to 40% of primary gastrointestinal lymphomas in Western populations; survival data indicate that T-cell lymphomas carry the worst prognosis.3 The association between malabsorption and lymphoma was first described in 1855 by Sir William Gull, who suggested lymphoma as a cause of steatorrhea,4 but it was not until 1962 that it was suggested that intestinal lymphoma was a complication of adult celiac disease5,6 and that "widespread mucosal derangement of the small bowel, found in idiopathic steatorrhea, was itself a premalignant condition."6,7 In 1968, Whitehead8 reported lymphadenopathy associated with celiac disease in seven patients and proposed that hyperplasia of lymphoid cells in the bowel led to the development of lymphoma. Ten years later, in 1978, Isaacson and Wright9 reviewed the pathology of 18 patients with lymphoma of the small intestine. All of the patients studied had villous atrophy and crypt hyperplasia, and five had a documented history of adult-onset celiac disease. On the basis of immunophenotype, the lymphomas were thought to derive from histiocytes, and the term "malignant histiocytosis of the intestine" (MHI) was coined to describe these cases. An association with ulcerative jejunitis was subsequently noted.10 MHI was described grossly as a constricting, perforating, or infiltrative intestinal lesion consisting of a pleomorphic large-cell lymphoma, sometimes associated with a heavy eosinophilic infiltrate, which also involved mesenteric lymph nodes.11 Subsequent studies have shown MHI to be of T-cell origin.12,13 These lymphomas were not listed within the Working Formulation, Kiel, Rappaport, and Lukes-Collins classifications.14,15 The International Lymphoma Study Group simply referred to "intestinal lymphoma,"16 with the term "enteropathy-associated T-cell lymphoma" being coined by O’Farrelly et al.17 The subsequent Revised European American Lymphoma classification used "intestinal T-cell lymphoma" (with or without enteropathy),2,15 which has been used until recently, when the World Health Organization International Classification Project updated the terminology to "enteropathy-type intestinal T-cell lymphoma."2,15,16,18 The International Lymphoma Study Group has shown the diagnosis to account for less than 1% of non-Hodgkin’s lymphomas.16 This article documents the clinical experience of this condition in a Regional Oncology Unit over a 17-year period.
This is a retrospective study of 31 patients with enteropathy-type intestinal T-cell lymphoma diagnosed between January 1979 and November 1996. During this time, 2,314 patients with non-Hodgkin’s lymphoma were examined at the Wessex Regional Medical Oncology Unit in Southampton. The lymphoma database was searched for cases of gastrointestinal non-Hodgkin’s lymphoma (primary stomach or bowel), and the records of these patients were examined to identify those with a diagnosis of MHI or enteropathy-associated T-cell lymphoma. Thirty-one cases were found (23 men, eight women), accounting for 17% of gastrointestinal non-Hodgkin’s lymphoma and 1.3% of all non-Hodgkin’s lymphoma treated over the specified time period. Details of presenting history, physical examination, staging investigations, treatment, and clinical outcome were taken from patient records. Routine staging procedures varied during the course of this study, but latterly included a peripheral-blood count, erythrocyte sedimentation rate, serum biochemical profile, and lactate dehydrogenase. Bone marrow samples obtained by aspiration and trephine biopsy specimens of the posterior iliac crest were examined, and small-bowel and liver biopsies were performed as clinically indicated. Radiologic investigations included chest radiograph, abdominal ultrasound, abdominopelvic computed tomography (CT), and bipedal lymphangiography. Patients’ disease was then staged according to the Ann Arbor system.19 All available antemortem and postmortem histologic material was reviewed, and the diagnosis was confirmed by immunohistochemical or gene rearrangement studies. Twenty-five patients underwent laparotomy at the time of presentation. Six patients were treated with surgery alone, when all visible disease was resected. A further patient underwent surgical resection and then defaulted from further treatment. A variety of chemotherapy regimens were used over the period of this study, either as first-line treatment or after surgery, and most contained an anthracycline. The regimens included an intensive weekly combination of vincristine, doxorubicin, prednisolone, and high-dose methotrexate (n = 5)20; cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) at 21-day intervals (n = 12)21; alternating 21-day cycles of CHOP with procarbazine, etoposide, and prednisolone orally on days 3 to 7, and doxorubicin intravenously on day 1 (n = 1)22; cyclophosphamide, vincristine, doxorubicin, and prednisolone (n = 1)23; and alternating weekly cycles of prednisolone, doxorubicin, cyclophosphamide, and etoposide with prednisolone, bleomycin, vincristine, and methotrexate (PEACE-BOM; n = 3).24 Complete remission (CR) was defined as a return to normal by all documented tumor sites. Partial remission (PR) was defined as a more than 50% reduction in disease bulk, persisting for at least 1 month. All other patients were regarded as nonresponders. Response duration was measured from the time of achievement of CR or PR and survival from the date of initial diagnosis and treatment.
The median age at presentation was 50 years (range, 20 to 80 years). Twenty-three (74%) were men, and eight (26%) were women. Twelve patients were said to have a history of celiac disease diagnosed 3 months to more than 40 years before the diagnosis of enteropathy-type intestinal T-cell lymphoma. The diagnosis of celiac disease was biopsy-proven (before and after gluten withdrawal and after gluten rechallenge) in nine patients. Eight patients were reported to have adhered to a gluten-free diet. Three became refractory—one had also been treated with corticosteroids and sulphasalazine—but the other five remained on a diet until the time of diagnosis of lymphoma. Another one of the patients was not following a diet because her celiac disease was said to have spontaneously resolved in childhood.
Clinical Presentation
Diagnosis In 25 of the 31 patients, the diagnosis of enteropathy-type intestinal T-cell lymphoma was made at laparotomy. In 13 patients, surgery was performed as an emergency: in four because of severe abdominal pain, in five because of features of bowel obstruction, and in four because of peritonism. The remaining six patients were diagnosed from barium studies together with small-bowel biopsies. Surgical procedures included small-bowel resection with or without mesenteric nodal and liver biopsies. At diagnosis, lymphoma was found in a single site within the small bowel in 21 patients and at multiple small-bowel locations in 10. Enlarged mesenteric nodes were histologically infiltrated with lymphoma in 11 patients, the omentum was affected in two, the liver was affected in two, mesentery was affected in one, and colon (contiguous with small bowel) was affected in one.
Pathology The histology of the tumor was variable. In most cases, there was a large population of inflammatory cells that diffusely infiltrated the tumor and occasionally masked the tumor cell population. The tumor cells were blastic, usually with rounded vesicular nuclei and a single nucleolus. Greater degrees of pleomorphism were present in some cases with the formation of binucleate or multinucleated cells. Paraffin immunocytochemistry was performed on all cases. The tumor cells expressed CD3 and CD45RO, and CD8 was detected in half of the cases. The tumor cells all expressed the T-cell–restricted intracellular antigen TIA-1, indicating a cytotoxic T-cell origin for the tumors. A small proportion of the cells expressed granzyme-B, also a marker for cytotoxic T cells. All of the cells were of T-cell receptor alpha/beta origin. In all specimens, the adjacent uninvolved small-bowel mucosa showed villous atrophy and crypt hyperplasia with increased numbers of intraepithelial lymphocytes of the CD3, CD8 phenotype.
Blood Indices
Staging Investigations Bone marrow was examined in 24 patients and was found to be infiltrated with lymphoma in two (8%). Twenty-three patients (74%) had chest radiographs taken at the time of presentation, of which six were reported as abnormal: one showed a pleural effusion, another showed nodular changes thought to be infective, three showed areas of calcification, and the other bilateral change at the bases believed to be inflammatory. Another three patients had CT scans of the thorax, two of which were reported as normal, the third showing right lower lobe consolidation. Liver biopsy was performed in only four cases and revealed tumor in two. Lymphangiography was performed in five cases, of which three were positive. Twenty-eight of the 31 patients underwent either ultrasound or CT of the abdomen for the purposes of staging.
Treatment and Posttreatment Complications
Less than 50% of patients completed their planned chemotherapy courses, largely because of complications of treatment. Poor nutritional status was common, requiring parenteral nutrition during chemotherapy in 10 patients and enteral feeding in another two. Gastrointestinal bleeding occurred in one patient 5 days after starting treatment. Four patients suffered small-bowel perforation. In three, this occurred after the first cycle of treatment (at 1, 2, and 4 days) and proved a fatal event. In the fourth patient, three cycles of chemotherapy had already been administered; this patient survived and remained disease-free at 99 months. One of the patients who died after perforation subsequently developed an enterocolic fistula. Episodes of neutropenic sepsis were encountered in six patients; two of these patients each suffered three episodes (patients no. 19 and 28). In addition, one patient developed vincristine neuropathy during chemotherapy, another developed anthracycline cardiomyopathy while receiving CHOP, and one suffered a postoperative wound infection subsequent to the commencement of chemotherapy.
Response and Outcome Relapses occurred 1 to 60 months from diagnosis (median, 6 months) in 15 (79%) of the 19 patients who responded to initial therapy, whether with surgery alone or surgery and chemotherapy. Twelve patients relapsed at small-bowel sites; one in large bowel and spleen; one in liver, spleen, and mesenteric nodes; and another in a pelvic node only. Three patients have undergone salvage surgery with further bowel resection, one of whom then proceeded to 12 cycles of PEACE-BOM chemotherapy. A total of 11 patients received salvage chemotherapy, with a response observed in five: the patient who underwent surgery followed by PEACE-BOM was admitted with confusion only 8 days after completion of treatment and was found to have several intracerebral lesions consistent with lymphoma (patient no. 23).This patient subsequently died, but no postmortem data were obtained. Another patient showed a transient response to four cycles of PEACE-BOM before developing a large abdominal mass (patient no. 14). Patient no. 7 showed a complete response to one cycle of CHOP followed by one cycle of prednisolone, cytarabine, lomustine, etoposide, and thioguanine,25 but died 4 months later from disseminated aspergillosis with no evidence of lymphoma at postmortem evaluation. Patient no. 15, a man aged 54 years at the time of diagnosis who had an initial remission of 20 months after six cycles of CHOP, received six cycles of PEACE-BOM before proceeding to cyclophosphamide priming, peripheral-blood stem-cell collection, and high-dose chemotherapy with carmustine, etoposide, cytarabine, and methotrexate (BEAM). He remained disease-free 64 months after original diagnosis. Patient no. 16, a woman aged 56 years at diagnosis whose initial remission after six cycles of CHOP lasted 60 months, also received BEAM high-dose treatment after four cycles of PEACE-BOM but developed overwhelming sepsis, resulting in her death. Two patients received no further treatment at the time of relapse; both died within 1 month. Twenty-six (84%) of the 31 patients have died. The median survival duration of the group who died was 7.5 months (range, 0 to 83 months). All who died did so as a result of progressive disease (n = 15) or complications of the disease and/or its treatment (n = 11). Five patients are still alive 49 to 219 months from diagnosis; all are disease-free (Table 2). 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 (Figs 1 and 2).
We describe the clinical course of 31 patients with a diagnosis of enteropathy-type intestinal T-cell lymphoma, the largest reported series in the literature. One other study documents a single-institution experience of 30 cases, but only 24 tumor specimens were reviewed. In this series, the overall 1-year survival rate was 31%, and the 5-year survival rate was 11%.26 Review of 175 British National Lymphoma Investigation cases between 1974 and 1988 revealed only 16 cases of MHI. These were associated with a survival rate of less than 25% at 18 months.27 The important clinical features of lymphoma at presentation in this cohort were weight loss, abdominal pain, and diarrhea. Thirteen patients presented with features of small-bowel obstruction or perforation, and nine described B symptoms. The disease was confined to the abdomen, with no peripheral lymphadenopathy or pulmonary infiltrates observed. These patients often tolerate surgical intervention poorly because they are frequently malnourished at the time of presentation. Lymphoma is usually detected in multiple segments of the small intestine or is disseminated to mesenteric nodes, liver, spleen, or bone marrow. Lesions are most frequently observed in the jejunum and may be seen as nodules, plaques, or strictures. Large masses are uncommon. It is sometimes possible to make the diagnosis without surgery (six patients in our series) by using techniques of endoscopic small-bowel biopsy, liver biopsy, and bone marrow aspirate and trephine. In all patients, CT scanning should be used for staging. Histologically, the malignant cells are characteristically highly pleomorphic, with numerous bizarre, multinucleated forms.28 Small-intestinal histology remote from the site of the tumor is important; usually, this shows celiac appearances, with villous atrophy, crypt hyperplasia, plasmacytosis in the lamina propria, and an increase in intrepithelial lymphocytes. Mucosal change is usually maximal proximally; the lower jejunum and ileum may appear normal. However, this is certainly not observed in all cases. Techniques of immunocytochemistry, together with gene rearrangement studies, now make the histologic diagnosis of enteropathy-type intestinal T-cell lymphoma more straightforward. Most cases are CD3+, CD7+, CD4-, and CD8-. However, a number of cases have been reported with CD8 positivity (half the patients in our series). Positive staining with the monoclonal antibody human mucosal lymphocyte-1 is characteristic of this subset.29,30 In cases in which large immunoblast-like cells predominate, CD30 expression is characteristic and can be a useful marker to distinguish tumor cells in an inflammatory background.31 Genotypic studies have confirmed monoclonal T-cell receptor beta gene rearrangement.12,32 Once diagnosed, chemotherapy should be considered for all patients and should constitute combination therapy with drugs known to be active in intermediate- and high-grade lymphoma. A variety of regimens, including CHOP,21 have been used, but other combinations need to be investigated in an attempt to improve the poor prognosis of these patients. Prognosis, in part, reflects late diagnosis and poor performance status at the time of presentation. Associated malabsorption and malnutrition make tolerance of chemotherapy difficult, and treatment-related complications such as gastrointestinal bleeding and perforation also worsen prognosis.22,33 Nutritional support with parenteral or enteral feeding should always be considered in these patients. The role of salvage treatments and high-dose chemotherapy at relapse is not clear. In our series, only one patient, who suffered a late relapse after 20 months, had a prolonged disease-free interval after salvage treatment (with BEAM high-dose chemotherapy). However, it is encouraging that there are five long-term survivors in our patient population. Efforts should therefore be made to diagnose enteropathy-type intestinal T-cell lymphoma early. The diagnosis should be considered in all patients who present in midlife with celiac disease and in those who experience a clinical deterioration after a period of stability on a gluten-free diet.13 Patients known to have celiac disease should be encouraged to follow a gluten-free diet, but in a proportion of patients there will be no preceding celiac history, making diagnosis more difficult: only nine of our patients had a biopsy-confirmed diagnosis of celiac disease (29%), the duration of which ranged from 1 month to 29 years. Celiac disease is characterized by a gluten-sensitive enteropathy, resulting in symptoms of malabsorption. It can present at any age and in infancy appears after weaning onto gluten-containing food. In adults, the peak incidence is in the third and fourth decades. If wheat protein is withdrawn from the diet, the histologic changes of enteropathy usually reverse, with clinical symptomatic improvement.17 Celiac disease is relatively common in Europe, with an incidence of approximately 1 in 2,000 in the United Kingdom and 1 in 300 in Ireland. The disease occurs worldwide, but is rare in black Africans. Celiac disease that is well controlled carries an excellent prognosis, contrasting with the high mortality associated with intestinal lymphoma. Holmes et al have shown that treatment of enteropathy with more than 5 years of gluten-free diet will reduce the risk of development of intestinal lymphoma to that of the general population,34,35 making this an important part of the treatment of the celiac patient. In 1967, Harris et al5 suggested that the mean duration of symptoms of celiac disease before a diagnosis of lymphoma was 21.2 years; none of their patients had a history of celiac disease less than 10 years. They believed that the patient with celiac disease in whom lymphoma was most likely to develop was male, older than 40 years, with a history of celiac disease in excess of 10 years and not adhering to a gluten-free diet. However, later studies have suggested a shorter mean interval between diagnosis of celiac disease and lymphoma development: Brandt et al36 suggested a mean interval of 3 years, and Cooper et al37 suggested 5 years. The newly diagnosed adult with celiac disease consequently requires careful follow-up: among one reported group, one in 20 had developed lymphoma within 4 years of diagnosis, and, with age older than 50 years, the risk was one in 10.5,35,38,39 There has been widespread debate regarding the relationship between the malabsorption syndrome and malignant intestinal lymphoma: does malabsorption predispose to the development of lymphoma? Is lymphoma present throughout the clinical course or is a "preneoplastic" lesion, equivalent to the pretumor stage of mycosis fungoides, responsible for malabsorption?7,10 It would seem that low-grade neoplastic cells may be present, but clinically silent, in the bowel for long periods. It is also possible that the apparent long-term latency of low-grade T-cell lymphoma in the gut can be potentiated by gluten withdrawal from the diet. The main feature differentiating chronic ulcerative jejunitis from malignant lymphoma complicating malabsorption has been the absence of histologic evidence of neoplasia in the intestine and mesenteric lymph nodes. The polymorphic nature of the infiltrate observed in ulcer bases of patients with ulcerative jejunitis, together with the absence of solid tumor masses, led some investigators to use the term "pseudolymphoma" to describe the lesions. However, evidence from the literature strongly suggests that ulcerative jejunitis, pseudolymphoma, and malignant lymphoma, when associated with villous atrophy and malabsorption, are all one and the same, ie, malignant lymphoma. Although there are a number of long-term survivors, the prognosis of enteropathy-type intestinal T-cell lymphoma in this historical series was poor, because many patients presented with complications of locally advanced disease and poor performance status. Earlier diagnosis and development of more effective treatments are required to improve the outcome for these patients. The concept that most cases of ulcerative jejunitis are a manifestation of malignant lymphoma is of particular importance: it is possible that chemotherapy is indicated in these patients, who, with rare exception after bowel resection, die as a result of their disease.
1. Isaacson PG: The pathology and biology of non-Hodgkin’s lymphoma, in Peckman M, Pinedo HB, Veronisi U (eds): Oxford Textbook of Oncology. Oxford, United Kindgom,Oxford University Press, 1995, pp 1768-1788 2. Pileri SA, Milani M, Fraternali-Orcioni G, et al: From the R.E.A.L. classification to the upcoming WHO scheme: A step toward universal categorisation of lymphoma entities? Oncol 9:607-612, 1998 3. Domizio P, Owen RA, Shepherd NA, et al: Primary lymphoma of the small intestine: A clinicopathological study of 119 cases. Am J Surg Pathol 17:429-442, 1993[Medline] 4. Gull W: Fatty stools from disease of the mesenteric glands. Guys Hosp Rep 1:369, 1855 (letter) 5. Harris OD, Cooke WT, Thompson H, et al: Malignancy in adult celiac disease and idiopathic steatorrhea. Am J Med 42:899-912, 1967[Medline] 6. Gough KR, Read AE, Naish JM: Intestinal reticulosis as a complication of idiopathic steatorrhoea. Gut 3:232-239, 1962 7. Wright DH, Jones DB, Clark H, et al: Is adult-onset coeliac disease due to a low-grade lymphoma of intraepithelial T lymphocytes? Lancet 337:1373-1374, 1991[Medline]
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Whitehead R: Primary lymphadenopathy complicating idiopathic steatorrhoea. Gut 9:569-575, 1968 9. Isaacson P, Wright DH: Intestinal lymphoma associated with malabsorption. Lancet 1:67-70, 1978[Medline] 10. Isaacson P, Wright DH: Malignant histiocytosis of the intestine: Its relationship to malabsorption and ulcerative jejunitis. Hum Pathol 9:661-667, 1978[Medline] 11. Hodges JR, Isaacson P, Smith CL, et al: Malignant histiocytosis of the intestine. Dig Dis Sci 24:631-638, 1979[Medline] 12. Isaacson PG, O’Connor NTJ, Spencer J, et al: Malignant histiocytosis of the intestine: A T-cell lymphoma. Lancet ii:688-691, 1985 13. Loughran TP, Kadin ME, Deeg HJ: T-cell intestinal lymphoma associated with celiac sprue. Med 104:44-47, 1986
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Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994
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Campo E, Gaulard P, Zucca E, et al: Report of the European Task Force on Lymphomas: Workshop on peripheral T-cell lymphomas. Ann Oncol 9:835-843, 1998
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The Non-Hodgkin’s Lymphoma Classification Project: A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 89:3909-3918, 1997 17. O’Farrelly C, Feighery C, O’Briain DS, et al: Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T-cell lymphoma. BMJ 293:908-910, 1986
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Lopez-Guillermo A, Cid J, Salar A, et al: Peripheral T-cell lymphomas: Initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. classification. Ann Oncol 9:849-855, 1998
19.
Carbone PP, Kaplan HS, Musshoff K, et al: Report of the committee on Hodgkin’s disease staging classification. Cancer Res 31:1860-1861, 1971 20. Mead GM, Macbeth FR, Williams CJ, et al: Poor prognosis non-Hodgkins lymphoma in the elderly: Clinical presentation and management. Q J Med New series L111 211:381-390, 1984 21. Armitage JO, Dick FR, Corder MP, et al: Predicting therapeutic outcome in diffuse histiocytic lymphoma treated with cyclophosphamide, Adriamycin, vincristine, and prednisolone (CHOP). Cancer 50:1695-1702, 1982[Medline] 22. Mead GM, Whitehouse JM, Thompson J, et al: Clinical features and management of malignant histiocytosis of the intestine. Cancer 60:2791-2796, 1987[Medline] 23. Barton C, Waxman J: Effects of cancer chemotherapy on fertility, in Peckham M, Pinedo HB, Veronesi U (eds): Oxford Textbook of Oncology. Oxford, United Kingdom,Oxford University Press, 1995, pp 2327-2341 24. Sweetenham JW, Mead GM, Whitehouse JMA: Intensive weekly combination chemotherapy for patients with intermediate-grade and high-grade non-Hodgkins lymphoma. J Clin Oncol 9:2202-2209, 1991[Abstract] 25. Sweetenham JW, McKendrick JJ, Mead GM, et al: Prednisolone, cytosine arabinoside, lomustine (CCNU), etoposide, and thioguanine (PACET) combination chemotherapy for relapsed or refractory non-Hodgkin lymphoma. Eur J Cancer 29A:190-192, 1993 26. Egan LJ, Walsh SV, Stevens FM, et al: Celiac-associated lymphoma: A single institution experience of 30 cases in the combination chemotherapy era. Gastroenterol 21:123-129, 1995 27. Morton JE, Leyland MJ, Vaughan Hudson G, et al: Primary gastrointestinal non-Hodgkin’s lymphoma: A review of 175 British National Lymphoma Investigation cases. Br J Cancer 67:776-782, 1993[Medline] 28. Isaacson PG, Norton AJ (eds): Malignant lymphoma of the gastrointestinal tract, in Extranodal Lymphomas. Edinburgh, United Kingdom, Churchill Livingstone, 1994, pp 15-65 29. Primary gut lymphomas. Lancet 337:1384-1385, 1991 (editorial) 30. Spencer J, Cerf-Bensussan N, Jarvy A, et al: Enteropathy-associated T-cell lymphoma (malignant histiocytosis of 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[Abstract] 31. Isaacson PG: Gastrointestinal lymphoma. Hum Pathol 25:1020-1029, 1994[Medline] 32. Jones DB, Foreman R: Cell origin of lymphoma complicating coeliac disease. Lancet 2:1067-1068, 1985 (letter) 33. Levine EG, Hanson CA, Jaszcz W, et al: True histiocytic lymphoma. Semin Oncol 18:39-49, 1991 34. Ilyas M, Niedobitek G, Agathanggelou A, et al: Non-Hodgkin’s lymphoma, coeliac disease, and Epstein-Barr virus: A study of 13 cases of enteropathy-associated T- and B-cell lymphoma. J Pathol 177:115-122, 1995[Medline]
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Holmes GKT, Prior P, Lane MR, et al: Malignancy in coeliac disease: Effect of a gluten free diet. Gut 30:333-338, 1989 36. Brandt L, Hagander B, Norden A, et al: Lymphoma of the small intestine in adult coeliac disease. Acta Med Scand 204:467-470, 1978[Medline] 37. Cooper BT, Holmes GKT, Ferguson R, et al: Celiac disease and malignancy. Medicine 59:249-261, 1980[Medline] 38. Cooper BT, Holmes GKT, Cooke WT: Lymphoma risk in coeliac disease of later life. Digestion 23:89-92, 1982[Medline] 39. Stokes PL, Holmes GKT: Coeliac disease and malignancy. Clin Gastroenterol 3:159, 1974 (letter) Submitted June 8, 1999; accepted October 8, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
