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© 2003 American Society for Clinical Oncology Intestinal Non-Hodgkin’s Lymphoma: A Multicenter Prospective Clinical Study From the German Study Group on Intestinal Non-Hodgkin’s Lymphoma
From the Department of Medicine I (Gastroenterology, Infectious Diseases and Rheumatology), the Institute of Pathology, the Department of Medicine II (Hematology, Oncology and Transfusion Medicine), Universitätsklinikum Benjamin Franklin, Free University of Berlin; and the Medical Department, Auguste Viktoria-Krankenhaus, Berlin, Germany. Address reprint requests to Severin Daum, MD, Department of Medicine I, Universitätsklinikum Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany; email: severin.daum{at}medizin.fu-berlin.de.
Purpose: Intestinal non-Hodgkin’s lymphomas are not well characterized. We therefore studied prospectively their clinical features and response to standardized therapy. Patients and Methods: Fifty-six patients with primary intestinal lymphoma were included in a prospective, nonrandomized multicenter study. Lymphoma resection was recommended and staging was performed according to the Ann Arbor classification. Patients were scheduled to receive six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy, and at stages EIII to EIV, they received additional involved-field radiotherapy. Corticosteroids were used in patients who could not receive chemotherapy. Results: Thirty-five patients had intestinal T-cell lymphoma (ITCL), 21 patients had intestinal B-cell lymphoma (IBCL; 18 diffuse large-cell lymphomas, two marginal-cell lymphomas, and one follicle-center lymphoma). Thirty-four patients at stages EI to EII (14 ITCL and 20 IBCL) and nine patients at stages EIII to EIV (all ITCL) received chemotherapy. No patient in stages EIII to EIV received radiotherapy, because death occurred in 12 of 14 patients. Two-year cumulative survival in patients with IBCL was 94% (95% CI, 82% to 100%) and higher than in patients with ITCL (28% [95% CI, 13% to 43%]; P < .0001), even when only stages EI to EII were considered (ITCL, 37.5% [95% CI, 16.5% to 58.5%]; P < .0001). IBCL patients compared with ITCL patients were at lower lymphoma stages (P < .01), had higher Karnofsky status (P < .005), had intestinal perforation less often (P < .05), required emergency operation less often (P < .05), received CHOP (P < .05) more often, and reached complete remission (P < .0005) more frequently. Conclusion: IBCL patients at stages EI and EII respond well to chemotherapy, but the prognosis and treatment of ITCL patients is unsatisfactory.
PRIMARY GASTROINTESTINAL lymphomas constitute 5% to 10% of all gastrointestinal tumors.1,2 Twenty percent to 30% of gastrointestinal lymphomas, or approximately 5% of peripheral non-Hodgkin’s lymphomas (NHL), in general, are primarily located in the intestine and differ from gastric lymphomas in clinical features, pathology, treatment, and prognosis.1,2 Although substantial progress has been achieved in the diagnosis and treatment of gastric lymphomas in recent years,3–6 primary intestinal lymphomas are not well characterized, and standardized concepts for their clinical diagnosis and management are absent. Apart from one smaller case series,7 only retrospective studies1,2,8–12 of intestinal lymphomas have been published to date, and these are difficult to compare, because important data, such as stages for B-cell and T-cell lymphomas, are often missing. Two larger retrospective analyses1,2 indicate that in Western populations, 60% to 80% of intestinal lymphomas are B-cell lymphomas, mostly diffuse large B-cell lymphoma (DLBCL) of the distal small intestine and especially in the ileocecal region. Intestinal follicle center, mantle, and marginal cell lymphomas, as well as colonic localization, seem to be rare.2,13 Associations of intestinal B-cell lymphomas (IBCLs) with various autoimmune and immunodeficiency syndromes, inflammatory bowel disease, and post-organ transplantation have been reported.14–17 Intestinal T-cell lymphomas (ITCLs) have been described as often multifocal and most frequently localized in the jejunum or proximal ileum.1,4,8,10 According to the Revised European-American Lymphoma classification from 1994, ITCLs are divided into enteropathy-associated (EATCLs) and non–enteropathy-associated T-cell lymphomas (non-EATCLs) depending on the presence of enteropathy in the tumor-distant mucosa.11,18–20 The new World Health Organization classification of lymphomas does not specify non-EATCLs, which are considered peripheral T-cell–derived NHL.21 In fact, the clear association of EATCL with celiac disease,22–24 as well as specific immunologic and molecular features indicating a specific disease entity, has not been established for non-EATCL.24 However, non-EATCL and EATCL share the peculiar symptoms and clinical problems that result when the intestine is the primary lymphoma site.1 Empirical standards in the treatment of intestinal lymphoma, consisting of surgical resection of the main tumor mass followed by multimodal chemotherapy or radiotherapy (or both), have not been evaluated prospectively. Given the difficulty of establishing the diagnosis and the high frequency of initial complications, the main tumor is surgically resected in most patients with intestinal lymphoma.1,2,4,10,25–28 However, the efficacy of this procedure is not known, and results from studies of gastric lymphoma are controversial regarding the benefit of surgical resection.3,4,29,30 Postsurgical chemotherapy in intestinal lymphoma, which usually involves cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP); cyclophosphamide, vincristine, and prednisolone; or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) (or similar) regimens, is generally recommended for high-grade intestinal lymphomas in retrospective studies.8–10,12,21,27,28 The rate of patients receiving chemotherapy, however, varied enormously in earlier studies.1,2,11,29 High rates of relapses and poor responses to chemotherapy have been reported in patients with intestinal lymphoma, leading to shorter survival times in comparison with survival times in patients with gastric lymphoma.2,29,31 Radiotherapy for early stages of intestinal lymphoma has been recommended in two earlier studies,32,33 but its efficacy is controversial. The prognosis of ITCL compared with that of IBCL patients was worse1,26 or similar2 in retrospective analyses. Other prognostic factors proposed were intestinal perforation,1 high-grade histology,1,2 multiple tumors,1 and advanced tumor stage.1,2,8,27 In this German-Austrian multicenter study, primary intestinal lymphomas were investigated prospectively. Clinical presentation, initial complications, morbidity, mortality, and standardized therapeutic regimens were evaluated, and prognostic factors were identified.
Patients From April 1995 to December 1999, a prospective, nonrandomized, multicenter study was performed. Patients were considered to have primary intestinal lymphoma when they met the criteria proposed by Isaacson:19 all patients had an obviously predominant tumor mass in the intestine with secondary involvement of or spread to extraintestinal sites. Histologic diagnosis by the primary pathologist was confirmed by one of the reference institutes of pathology (H.K. Müller-Hermelink, Universität Würzburg, and H. Stein, Berlin, Germany). To be included in the study, patients had to be at least 18 years old; provide informed written consent; and have normal bone marrow, liver, and renal function, as well as sufficient cardiac function. Patients with Burkitt’s lymphoma, lymphoblastic lymphoma, mantle-cell lymphoma, or infection with human immunodeficiency virus were excluded because of divergent disease courses or divergent therapy but were enrolled into other ongoing studies whenever possible. Sixty-four patients were enrolled, but eight patients were lost to follow-up or had insufficient data; a total of 56 patients were included and observed for at least 1 year or until death. The study was approved by the Ethics Committee of the Free University of Berlin. Patients were diagnosed with celiac disease when they had villus atrophy in their first duodenal biopsy and a prompt clinical response to gluten-free diet or were positive for celiac disease–associated antibodies (ie, antiendomysium immunoglobulin A [IgA] or antitransglutaminase IgA).34–37 Patients’ histories and symptoms were documented using a standardized protocol, and the Karnofsky performance status was calculated. Blood tests including hematologic, liver, and kidney function were performed. If possible, antibodies for gliadin, endomysium, and transglutaminase were checked. We defined three significant categories of initial clinical complications: intestinal perforation, bleeding, and obstruction. Criteria for intestinal perforation were the clinical picture of an acute abdomen and the confirmation of the perforated bowel by the surgeon or pathologist. Intestinal bleeding was defined as peranal blood loss with two or more packed RBC transfusions necessary within 24 hours. Abdominal obstruction was documented when the patient complained about abdominal cramps in coincidence with meals and the abdominal x-ray showed signs of subileus or ileus.
Treatment
Staging and Treatment Response
Histology, Immunohistology, and Molecular Pathology
Statistical Analysis
Clinical Characteristics and Presentation Of the 56 patients evaluated, 35 (62.5%) had ITCL, and 21 (37.5%) had IBCL. Sex distribution and age were not significantly different between IBCL and ITCL patients (Table 1  ). Median follow-up of living patients with B-cell and T-cell lymphoma was 25.5 months (range, 12 to 56 months) and 25 months (range, 18 to 56 months), respectively. (Results were not significant.) There was no patient with IBCL at the advanced tumor stages EIII or EIV, whereas 14 patients with ITCL were at stages EIII or EIV (P < .01; Table 1).
The Karnofsky performance status was lower in patients with ITCL than in patients with IBCL (Table 1  ) but did not differ between ITCL patients at early (75% [range, 40% to 100%]) and advanced stages (80% [range, 40% to 90%]). Fever and diarrhea were found in about one third of patients with ITCL but were rare in patients with IBCL (P < .05; Table 2). Thirty-nine patients (70%) had life-threatening complications as initial presentation of lymphoma, with similar rates for IBCL and ITCL patients (Table 2). Intestinal obstruction was more common in patients with IBCL (P < .01), but intestinal perforation occurred more frequently in patients with ITCL (P < .01) and was associated with early death within 3 months in six of 14 patients, with perforation versus four of 42 patients without perforation (P < .05).
Apart from a known prior diagnosis of celiac disease in 19 patients with EATCL and in one patient with IBCL, elevated titers of celiac disease–associated antibodies were found in none of five patients with non-EATCL, none of eight patients with IBCL, but in four of six patients with EATCL. Seventeen of 19 EATCL patients with known celiac disease had been on a gluten-free diet since diagnosis (ie, for 36 months [range, 4 to 250 months]), including eight patients with more than 4 years of gluten-free diet. Recurrence of symptoms such as weight loss or diarrhea while on a gluten-free diet were seen in 12 and 10 patients, respectively, but were absent in three patients, who had only abdominal pain.
Primary tumor localization differed between ITCLs, which were predominantly found in the duodenum and jejunum, and IBCLs, which were mainly found in the ileum (P < .01; Table 2
Histology, Immunohistology, and Molecular Pathology Duodenal biopsies from 12 EATCL patients who had an earlier diagnosis of celiac disease and became refractory to gluten-free diet showed abnormalities (loss of CD8, TCR-ß expression, or clonal T-cell expansion), although primary histopathologic evaluation had been negative in seven patients. Some of these patients have already been described in an earlier report.45
Treatment and Outcome
Twelve patients (11 ITCL, one IBCL) were treated with corticosteroids or received no further therapy with or without operation. Thirty-four patients at stages EI or EII (14 ITCL, 20 IBCL) and nine patients at stages EIII or EIV (all ITCL) received chemotherapy (Table 1 None of the 21 IBCL patients but 10 (29%) of 35 ITCL patients died within 3 months of lymphoma diagnosis (P < .02), including eight of 17 ITCL patients who had emergency operation because of intestinal perforation or bleeding, compared with only two of 18 ITCL patients who did not have these complications and did not receive surgical treatment (P < .05). No ITCL patient undergoing elective surgery died within 3 months of lymphoma diagnosis. Early mortality was not associated with age, Karnofsky performance status, or lymphoma stage (data not shown). All three IBCL patients (one follicle center lymphoma, two DLBCL) who received chemotherapy and in whom the lymphoma was not resected were in complete remission after 29, 39, and 12 months, respectively. IBCL patients, with and without lymph node dissection, had similar rates of complete remission. Both ITCL patients who had lymph node dissection relapsed after a period of complete remission. Twenty-seven of 43 patients who received potential curative therapy (CHOP with or without resection) reached complete remission (eight of 23 ITCL, 19 of 20 IBCL; P < .0005). Complete remission was only observed in eight of 14 ITCL patients at early stages but in none of nine ITCL patients at stages EIII or EIV who received CHOP (P < .02). Seven patients with ITCL had tumor progression with CHOP, and eight patients with ITCL died within the first 3 months of chemotherapy; no patient with IBCL had tumor progression or died within this time (P < .0005). Mean progression-free survival was significantly longer in patients with IBCL (53 [range, 49 to 58 months]) than in patients with ITCL (28 [range,17 to 39 months]; P < .0002) who reached complete remission after chemotherapy. Six of nine ITCL patients but only one of 20 IBCL patients had lymphoma relapse after a period of complete remission (P < .01). Response to relapse therapy including surgery, radiotherapy, or chemotherapy was limited; only one ITCL patient reached complete remission for another 12 months after local radiotherapy and ifosfamide, mesna uroprotection, methotrexate, and etoposide therapy.
Two-year cumulative survival in patients with IBCL was 94% (95% CI, 82% to 100%) and higher than in patients with ITCL (28% [95% CI, 13% to 43%]; P < .0001), even when only stages EI and EII were considered (ITCL, 37.5% [95% CI, 16.5% to 58.5%]; P < .0001; Fig 1
Lower survival in patients with ITCL was significantly associated with the presence versus absence of intestinal perforation or bleeding (18% [95% CI, 0% to 36%] v 38% [15% to 61%]; P < .02), and with emergency versus elective operation (18% [95% CI, 0% to 36%] v 34% [5% to 63%]; P < .05). Karnofsky performance status below 80%, patient age above 60 years, or presence of clinical symptoms such as fever, diarrhea, or abdominal pain was not associated with survival in ITCL patients (data not shown). Main toxicities in 43 patients who received chemotherapy were leukopenia (n = 17), peripheral neuropathy (n = 9), and nausea (n = 8), and were similar in T- and B- cell lymphomas. However, four patients (two with IBCL and two with ITCL) had infectious complications in the leukopenic period, including two patients who died from Aspergillus fumigatus pneumonia (both with ITCL).
Interrelation of Predictive Factors
The proportion of 62% T-cell lymphomas and 38% B-cell lymphomas in our study differs from earlier analyses of intestinal lymphoma, which, in larger series, found a majority of 66% to 90% B-cell lymphomas.1,2,29 Study inclusion could well have been biased in favor of ITCL because of much better treatment results in patients with IBCL and because of the well known focus of interest of our institution in celiac disease and EATCL. Symptoms at presentation are inconclusive, and only abdominal pain and weight loss were found in the majority of patients with intestinal lymphoma. Diarrhea and fever were present in approximately one third of patients with ITCL but were rare in patients with IBCL. Our prospective study revealed a higher rate of 70% initial complications in intestinal lymphoma patients than found in earlier retrospective analyses.1,2,8,12,28,46 The predominant complications in patients with IBCL and ITCL were intestinal obstruction and perforation, respectively. Intestinal perforation or bleeding, but not obstruction, were associated with early mortality and their high frequency contributes to the poor prognosis of patients with ITCL. Although the tumor involved accessible sites in 37 patients (duodenum, terminal ileum, or colon), the lymphoma diagnosis could be established by endoscopy with biopsy in only 12 patients. These diagnostic difficulties, as well as the high rate of initial complications, led to primary resection of intestinal lymphomas in most patients. However, the efficacy of this procedure has not been evaluated so far. It is clear that there was no benefit from lymph node dissection in our lymphoma patients, which makes a case against extended surgical procedures. Furthermore, we, like others,10 observed complete remissions of intestinal lymphoma in patients receiving only chemotherapy. Surgery is still controversial as first-line therapy in patients with early stages of gastric lymphoma3–5 and is not part of therapeutic regimens in extraintestinal NHL.47 Our findings indicate that at least patients with IBCL could profit from a similar conservative approach. Emergency operation, however, was frequently required in ITCL patients. All but one IBCL patient reached complete remission after chemotherapy, followed by a mean progression-free survival of more than 4 years at study end. Overall, a 2-year survival rate of 94% was achieved in patients with IBCL, indicating that chemotherapy with CHOP represents an adequate and satisfactory therapeutic strategy in these patients. This is supported by the fact that considerably lower 2-year survival rates of about 50% have been reported in earlier retrospective studies of high-grade IBCL, with only 27% and 46% of patients receiving chemotherapy in the two studies, respectively.1,26 Our findings, as well as long-term data of the Southwest Oncology Group,48 do not support the need for radiotherapy in IBCL patients, as recently suggested.33 It should be noted, however, that IBCL patients at advanced lymphoma stages were absent in our study and should probably receive combined therapy with CHOP and rituximab in correspondence to patients with nodal DLBCL.49 Overall, site-related symptoms and diagnostic difficulties were the only specific features identified in our IBCL patients. These had no significant influence on the clinical course of the patients, supporting the concept that IBCLs are just peripheral lymphomas that happen to localize in the gut. Treatment response in ITCL patients was much less favorable, with an overall 2-year survival rate of only 28%, confirming the poor prognosis of ITCL patients indicated from some retrospective analyses.1,10,26,50 Complete remissions could be reached only in about 50% of ITCL patients with earlier lymphoma stages, and most of these had lymphoma relapse after a mean period of 28 months. The limited response to CHOP chemotherapy even in early-stage ITCL patients indicates that selected patients could possibly profit from high-dose chemotherapy with stem-cell transplantation.51 However, tumor progression and death during chemotherapy were common in ITCL patients; a considerable proportion of patients, especially at late stages, could not complete chemotherapy, and no patient could receive radiotherapy as scheduled. Furthermore, in about one third of ITCL patients, chemotherapy was never initiated, mostly because of the poor clinical condition of the patients. Therefore, it seems doubtful that more aggressive regimens could be employed in a major proportion of ITCL patients to overcome the unsatisfactory response to CHOP. It should be noted that outcome parameters were not different between EATCL and non-EATCL and were considerably worse than those reported for peripheral T-cell lymphomas.52,53 Our study confirms the strong association of EATCL with celiac disease24,54 and supports the possibility that EATCL, and even an early form of EATCL (termed sprue-like intestinal T-cell lymphoma), may be detected in duodenal biopsies distant from the tumor site by the demonstration of clonal T-cell expansion and reduced expression of T-cell antigens.45,55,56 Prospective studies are clearly needed to evaluate this possibility of an earlier diagnosis of EATCL and its influence on the currently poor prognosis of these patients. Gluten-free diet has been reported to reduce the increased risk of ITCL in patients with celiac disease,22,23 but eight of our EATCL patients developed lymphoma despite 4 to 20 years of gluten-free diet. Intestinal perforation occurred in five patients with celiac disease after a successful period of a gluten-free diet. Thus it seems doubtful that future screening strategies should be restricted to symptomatic celiacs. Celiac disease was not found in non-EATCL patients, so risk factors for lymphoma development in non-EATCL remain unclear. Nonetheless, the clinical features and course of non-EATCL closely resembled those of EATCL, indicating that probably both require specific management different from that for peripheral T-cell lymphoma. Thus, despite its abandonment in the World Health Organization classification,21 non-EATCL may remain useful as a clinical category. In summary, the major differences in clinical course and treatment response between ITCL and IBCL emphasize the importance of adequate histologic classification for the management of intestinal NHL. IBCL patients responded well to chemotherapy even in the absence of surgical tumor resection, so the efficacy of surgery in these patients should be critically evaluated. In contrast, the ITCL patients are characterized by high rates of initial life-threatening complications, advanced tumor stages at presentation, and poor clinical state that frequently prevents chemotherapy. Their response to chemotherapy is often incomplete, and relapses are common. In the absence of therapeutic alternatives, strategies to achieve earlier diagnosis in these patients are urgently needed. At least for EATCL, its strong association with celiac disease and recent findings of premalignant lesions in celiacs who later develop an EATCL may offer such an opportunity for earlier diagnosis and, it is hoped, effective intervention.
The following are members of the Intestinal Non-Hodgkin’s Lymphoma Study Group: E. Dühmke, Strahlentherapeutische und Radioonkologische Abteilung, Universitätsklinikum Grosshadern, München; W. Fischbach II, Medizinische Klinik, Aschaffenburg; H.-K. Müller-Hermelink, Institut für Pathologie der Universität Würzburg; A. Thiede, Chirurgische Klinik der Universität Würzburg; K. Wilms, Medizinische Poliklinik der Universität Würzburg, Würzburg; and C. Ohmann and Q. Yang, Koordinierungszentrum für Klinische Studien der Heinrich-Heine-Universität, Düsseldorf, Germany. The following investigators participated in the study: W. Augener, T. Bächle, M. Boltmann, C.-H. Bothe, D. Brunswig, H.-M. Büntzel, N. v. Bubnoff, H. Burkhart, D. Busch, M. Classen, D. Dahmen, Y. Dörffel, B. Dragosics, F. Dreier, V. Eckardt, J. Edelmann-Fischbach, A. Florschütz, H. Frotz, H. Füller, M. Grah, M. Gregor, U. Grommisch, R. Hackenthal, H. Hass, A. Heer, K.-P. Hellriegel, W. Hennicke, F.X. Hierlmeyer, E. Hiller, S. Hollerbach, W. Hopfenmüller, D. Huhn, U. Jahn, J. Karl, I. Kaskas, H. Kesseler, W. Knauf, A. Knuth, G. Koechling, Köhler, H. Kojouharoff, M.-L. Kolve, I. Koop, P. Kuhn, H. Lersch, H. Matthes, F. Möller-Faßbender, M. Mayr, U. Müllerleile, U. Pape, R. Pasold, J. Peters, M. Peters, P. Poch, S. Pucher, M. Raderer, B. Riecken, R. Rothmann, W. Ruzeck, S. Sahm, K. Schelp, H. Schlottmann, S. Schmidt, M. Schneider, J. Schölmerich, J. Schönemann, E. Schreiber, M. Schröder, J.-D. Schulzke, S. Schwender, A. Spehn, T. Steffen, H. Szelenyi, S. Übelhack, E. Ulsperger, H. Unhold-Jung, F. Vietor, S. Walker, T. Weinke, F. Wewalka, B. Wiedenmann, and B. Witzko.
We thank the many clinicians and pathologists who took part in this study and made clinical data or histologic material available to us. We also thank H. Mueller for expert technical assistance and M.R. Januszewski for data documentation.
Severin Daum and Reiner Ullrich contributed equally to this work.
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ABSTRACT
INTRODUCTION
2 test with continuity correction. Survival rates were calculated according to disease-related deaths with the method of Kaplan and Meier.
gene, and immunohistochemistry revealed that increased numbers of intraepithelial lymphocytes were CD4-, CD8-, and TCR-ß–negative. One tumor (EATCL) expressed both CD20 and CD3 antigens. CD20 expression was classified as aberrant because tumor cells were positive for CD8 and rearrangement of the TCR-
