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T-Cell/Histiocyte-Rich Large B-Cell Lymphomas and Classical Diffuse Large B-Cell Lymphomas Have Similar Outcome After Chemotherapy: A Matched-Control Analysis

R. Bouabdallah, N. Mounier, C. Guettier, T. Molina, V. Ribrag, C. Thieblemont, A. Sonet, A. Delmer, K. Belhadj, P. Gaulard, C. Gisselbrecht, L. Xerri

From the Cancer Center Institut Paoli-Calmettes-Université de la Méditerranée, Marseille; Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis; Hôpital Paul Brousse; and Hôpital Hôtel Dieu, Paris; Institut Gustave Roussy, Villejuif; Hospices civils de Lyon, Lyon; Hôpital Henri Mondor, Créteil, France; and Université catholique de Louvain, Ivoir, Belgium.

Address reprint requests to Réda Bouabdallah, MD, Department of Hematology, Institut J. Paoli-I. Calmettes, 232 Boulevard Sainte-Marguerite, 13 273 Marseille Cédex 09; email: hemato1{at}marseille.fnclcc.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: Because it is unclear whether T-cell/histiocyte-rich large B-cell lymphomas (H/TCRBCL) should be considered as a true clinicopathologic entity, we conducted a matched-control analysis comparing patients with H/TCRBCL and patients with diffuse large-B cell lymphoma (B-DLCL).

Patients and Methods: More than 4,500 patients were enrolled onto non-Hodgkin’s lymphoma trials conducted by the Groupe d’Etude des Lymphomes de l’Adulte. After histologic review, 50 patients were subclassified as H/TCRBCL. They were matched to 150 patients with B-DLCL for each of the factors of the International Prognostic Index (IPI).

Results: Clinical characteristics of H/TCRBCL patients showed a male predominance and a median age of 47 years. Performance status was normal in 89% of patients, whereas lactate dehydrogenase level was increased in 60% of patients. The disease was disseminated in 81% of patients, and 48% had two or more involved extranodal sites. The IPI score was 2 in 53% of patients. The complete response rate to chemotherapy was 63%, and 5-year overall survival (OS) and event-free survival (EFS) rates (mean ± SD) were 58% ± 18% and 53% ± 16%, respectively. The matched-control analysis showed a trend toward a better response to chemotherapy for patients with B-DLCL (P = .06), whereas no difference was observed in OS (P = .9) and EFS (P = .8).

Conclusion: H/TCRBCL is an aggressive disease that often presents with adverse prognostic factors. However, when treatment is adapted to the disease risk, outcome is equivalent to that observed in patients with B-DLCL. Thus H/TCRBCL should be considered a pathologic variant that belongs to the B-DLCL category.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THE SO-CALLED T-cell/histiocyte-rich large B-cell lymphoma (H/TCRBCL) entity was first reported in 1988.¹ This term was initially used to describe a heterogeneous category of B lymphoproliferative disorder, characterized by a predominant infiltrate of reactive T lymphocytes representing 65% to 90% of the total cell population.^2–6 More recently, a number of series have attempted to provide criteria to allow more reproducible diagnosis and better delineation of H/TCRBCL. Although the precise definition of these tumors remains controversial, most authors now agree that H/TCRBCL correspond to a consistent pathologic subtype of high-grade B-cell non-Hodgkin’s lymphoma (NHL), in which a sparse component of large neoplastic B cells is obscured by a prominent stromal component comprising both T cells and histiocytes but only rare or absent small B cells.^7,8 Large tumoral B cells exhibit a broad morphologic spectrum that includes Reed-Sternberg–like patterns and express the CD20 antigen, whereas CD30 expression is usually absent.^2,3,7,8 Clonality of these tumoral B cells has been demonstrated by light-chain restriction and/or immunoglobulin gene rearrangements.^5,6

After the initial description of H/TCRBCL in the 1980s, some preliminary studies reported variable therapeutic results.^4,9,10 At present, it is still unclear whether H/TCRBCL should be considered as a true clinicopathologic entity with distinct outcome and therapeutic implications because only a few series have been reported in the literature and results are contradictory. Chittal et al⁹ and Delabie et al¹⁰ described 15 H/TCRBCL patients, including six patients who died from disease progression less than 12 months after diagnosis. Two larger series of patients with H/TCRBCL have been reported that focus on clinical characteristics and evaluate responsiveness to therapy. Twenty-three cases of H/TCRBCL were registered at the M.D. Anderson Cancer Center between 1988 and 1991,¹¹ whereas Greer et al¹² described a series of 44 patients. Both reports showed no significant difference in survival between H/TCRBCL and classical diffuse large B-cell lymphoma (B-DLCL) patients. The authors concluded that the poor results observed in some patients with H/TCRBCL could be explained by an inappropriate initial therapy rather than a more aggressive clinical pattern. More recently, a clinicopathologic study of 40 patients has been reported by Achten et al.¹³ Authors concluded that H/TCRBCL constitutes a distinct clinicopathologic entity that is characterized by an aggressive behavior. They also recommended experimental therapeutic strategies to improve outcome of this disease.

In this report, the Groupe d’Etude des Lymphomes de l’Adulte analyzed characteristics and clinical outcome of patients with H/TCRBCL enrolled onto multicenter consecutive trials. NHL patients included in the LNH (lymphomes Non Hodgkiniens) 93 and LNH 98 protocols were reviewed by a panel of pathologists to confirm the diagnosis of B-DLCL. As a result, 50 B-NHL patients could be precisely subtyped as H/TCRBCL according to the most recent admitted criteria.^7,8 To evaluate whether H/TCRBCL should be considered as a distinct clinicopathologic entity, we conducted a matched-control analysis using a population of 150 patients with unspecified B-DLCL sharing the same repartition according to prognostic factors and receiving the same chemotherapeutic regimen as H/TCRBCL patients.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Selection
This series includes patients registered in the LNH 93 and LNH 98 protocols. These two multicenter collaborative clinical trials were conducted by the Groupe d’Etude des Lymphomes de l’Adulte throughout 80 participating medical centers in France and Belgium. Patients had to be older than 15 years, with a diagnosis of intermediate or high-grade NHL in the LNH 93 study and a diagnosis of diffuse large-cell NHL in the LNH 98 study.^14,15 The initial histologic diagnosis was performed by the local pathologist, and slides were subsequently reviewed by a panel of pathologists to confirm the histologic subtype according to the World Health Organization (WHO) scheme. Patients with previous cancer and comorbid disease that could interfere with the chemotherapy regimen were excluded. All of the patients underwent physical examination, chest x-ray, computed tomography scans of the whole body, and bone marrow biopsy. Other examinations (endoscopies, liver biopsies) were performed according to the site of disease. Stratification of patients in the LNH 93 and LNH 98 protocols was dependent on the number of adverse factors according to the age-adjusted International Prognostic Index (Aa-IPI).¹⁶ The LNH 98 protocol also stratified patients on the basis of immunohistochemical characteristics (B- and T-cell lineage).

From 1993 to 1998, 3,500 patients were included in the LNH 93 study; the LNH 98 is still ongoing. To date, slides from approximately 75% of the patient cases have been reviewed by a panel of expert pathologists, leading to the identification of 50 H/TCRBCL patients. The control group was also selected in both LNH 93 and LNH 98 studies and comprised patients with B-DLCL of classic histologic pattern.

Treatment
Both LNH 93 and LNH 98 protocols were randomized and comparative trials. For patients 60 years of age, the reference arm of treatment was three to four courses of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) followed by consolidation of the LNH 87 protocol.¹⁷ The experimental arm of treatment was dependent on the Aa-IPI score and consisted of the following: three cycles of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) with additional involved-field radiotherapy for patients with no factors (LNH 93–1); four cycles of ACVBP-like chemotherapy followed by a modified consolidation for patients with one factor (LNH 93–2 and 98–2); and four cycles of ACVBP-like chemotherapy followed by high-dose chemotherapy with peripheral-blood stem-cell rescue for patients with two or more factors (LNH 93–3 and 98–3).¹⁸ For patients older than 60 years, the reference arm of treatment was six to eight courses of CHOP or a CHOP-like regimen. The experimental arms were as follows: four cycles of CHOP with additional involved-field radiotherapy for patients with no factors (LNH 93–4); eight cycles of CHOP for patients younger than 70 years with one to three factors (LNH 93–5); six cycles of reduced CHOP for patients 70 years and performance status (PS) 2 (LNH 93–6); an oral chemotherapy regimen of etoposide, chlorambucil, and prednisone repeated each 21 days for patients 70 years and PS 2 (LNH 93–7); eight cycles of CHOP with rituximab at each cycle (LNH 98–5).¹⁹

Pathologic Analysis
Four-micrometer sections were cut and stained with hematoxylin and eosin and Giemsa. Immunohistochemistry was performed in a subset of cases on paraffin sections using a standard avidin-biotin-peroxidase method. The minimal antibody panel included antibodies directed against CD20, CD3, CD30, and, in most instances, epithelial membrane antigen (EMA), CD15, and CD 57 (Dakopatts, Copenhagen, Denmark). Among the LNH 93 and LNH 98 patients, 71 patient cases had been considered as possible H/TCRBCL by the initial pathologist. Each patient case was then carefully reviewed by at least two expert hematopathologists. The criteria required for the unequivocal diagnosis of H/TCRBCL were established in accordance with recent studies as follows^7,8:

• Lymphoma containing a minority of large neoplastic cells staining positively for CD20, scattered among a major reactive cell component including lymphocytes, but also a variable proportion of histiocytes.
  
• Diffuse growth pattern occupying more than 90% of the infiltrated tissue.
  
• Paucity of small reactive B cells (virtually absent or < 10%) in the inflammatory background infiltrate.
  

Using these criteria, 50 of 71 patient cases were finally subclassified as true H/TCRBCL. The remaining 21 excluded patient cases were either classified as unspecified B-DLCL (owing to the arrangement of neoplastic cells in small sheets and the lack of significant proportion of histiocytes) or considered gray-zone lymphomas when it was not possible to rule out the diagnosis of nodular lymphocyte predominant Hodgkin’s disease (LPHD) or classic Hodgkin’s lymphoma (owing to the presence of an extensive meshwork of follicular dendritic cells and/or significant amounts of small B cells).

Criteria of Response
Complete response (CR) was defined as the disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms, and normalization of biochemical abnormalities assigned to NHL. CR unconfirmed (CRu) includes patients in CR with residual lymph node mass greater than 1.5 cm in greater transverse diameter that has regressed by more than 75% in the sum of the products of the greatest diameters or with indeterminate bone marrow. No CR/CRu defined all other situations (partial response, stable disease, or progressive disease).²⁰

Statistical Methods
Analysis of data from H/TCRBCL patients. The stopping date was set at September 1, 2001. The study end points were response rate, event-free survival (EFS), and overall survival (OS). EFS was calculated from the date of random treatment assignment to the date of progression, relapse, or death. OS rates were measured from the date of random treatment assignment to the date of death (regardless of cause) or the stopping date. All analyses were performed on an intention-to-treat basis. Survival rates were estimated using the Kaplan and Meier method. Curves were compared by the log-rank test. Survival rates are presented with their 95% confidence intervals (CIs). Tests statistics for comparison of major end points were regarded as significant when the two-sided P value was < .05. Statistical analyses were conducted with SAS software (version 8; SAS Institute, Cary, NC).

Case-controlled studies. Case-controlled studies were performed by matching the H/TCRBCL population with B-DLCL patients (control group) selected from the prospective LNH 93 and LNH 98 protocols. The IPI was used to fully match 50 patients with H/TCRBCL to 150 patients with B-DLCL (one-to-three ratio) for each of the following clinical characteristics: age, Eastern Cooperative Oncology Group PS, lactate dehydrogenase (LDH) level, Ann Arbor stage, and number of extranodal sites.

The Cox proportional hazards model was used in a multivariate analysis to assess the relationship between the pathology variables and the IPI score and their effects on OS and EFS.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
H/TCRBCL Patient Cases
Pathologic and phenotypical characteristics. The 50 patient cases selected as true H/TCRBCL contained a minority of neoplastic B cells (Fig 1A) that exhibited polylobulated nuclei and resembled either popcorn cells or centroblasts (Fig 1B). A proportion of cells exhibiting a prominent central eosinophilic nucleolus were observed in many cases, with a pattern reminiscent of immunoblasts (Figs 1B and 1C) and rare cells resembling Hodgkin’s Reed-Sternberg cells. In some cases, tumor cells tended to form small clusters.

View larger version (141K): [in this window] [in a new window]   Fig 1. (A) Typical immunohistochemical pattern of CD20 expression in T-cell/histiocyte-rich large B-cell lymphoma cases, with a minority of scattered and a diffuse growth pattern. (B) and (C) CD20+ atypical B-cells exhibiting various cytologic features, such as irregular nucleus with peripheral nucleolus (B), or round nucleus with prominent central nucleolus (C). (D) Low-power view of bone marrow showing a diffuse neoplastic infiltrate. Neoplastic cells were similar to those shown in (B) and (C).

A faint CD30 positivity was discernible in a minority of neoplastic cells in two of 46 analyzed patient cases, with a heterogeneous intensity of staining from cell to cell within the same case. Because of the limited amount of tumoral tissue, additional immunohistochemical markers (EMA, CD15) could be fully analyzed in only 38 of 50 patient cases. A variable proportion of large CD20⁺ atypical cells were EMA-positive in 34 of 38 cases. CD15 was never positive (zero of 38). Reactive lymphocytes in diffuse areas were predominantly CD3⁺ in all cases and included rare CD57⁺ cells without any rosette pattern. Variable numbers of epithelioid cells were present in most cases, being more prominent in a few cases, in which they formed large aggregates. Neutrophils and eosinophils were virtually absent.

Clinical characteristics. The clinical characteristics of the 50 patients with H/TCRBCL are listed in Tables 1 and 2. The majority of patients were male (88%). Eighty percent of patients were younger than 60 years, with a median age of 47 years (range, 20 to 79 years). PS was less than 2 in 89% of patients. The disease was disseminated in 81% of patients. In such cases, there was nodal involvement in variable sites, ranging from 30% (mediastinal nodes) to 54% (lumboaortic nodes). Spleen was enlarged in 60% of the patients. The LDH value was above the normal range in 60% of patients.

The IPI showed 47% of patients with low-risk and low-intermediate–risk score; 53% of patients had high-intermediate–risk and high-risk score.

Response to treatment and survival. Among the 50 patients with H/TCRBCL, 41 (82%) were included in the LNH 93 protocol and nine (18%) were included in the LNH 98 protocol. Forty-nine patients (98%) completed the treatment and were assessable for response (Table 3). A complete response (CR + CRu) was achieved in 31 patients (63%), whereas 18 patients failed to respond (37%). With a median follow-up of 39 months (range, 5 to 93 months), the 5-year OS and EFS rates are at 58% (95% CI, 40% to 76%; Fig 2) and 53% (95% CI, 37% to 69%; Fig 3), respectively.

View larger version (10K): [in this window] [in a new window]   Fig 2. Overall survival of patients with T-cell/histiocyte-rich large B-cell lymphoma (black line) and patients with diffuse large B-cell lymphoma (grey line).

View larger version (11K): [in this window] [in a new window]   Fig 3. Event-free survival of patients with T-cell/histiocyte-rich large B-cell lymphoma (black line) and patients with diffuse large B-cell lymphoma (grey line).

Response and survival. The control group included 150 patients, of whom 79% received the LNH 93 protocol and 21% received the LNH 98 protocol. There was no difference in the repartition of the therapeutic arms between H/TCRBCL and B-DLCL patients (Table 1). The response could be assessed in 148 (98%) of 150 patients, and 114 patients (77%) achieved a CR (Table 3). The statistical analysis showed a trend toward a better response for patients with B-DLCL compared with those with H/TCRBCL (P = .06).

With a median follow-up of 40 months (range, 2 to 96 months), the 5-year OS and EFS rates of the control group are 58% (95% CI, 48% to 68%; Fig 2) and 51% (95% CI, 41% to 61%; Fig 3), respectively. The statistical analysis showed no significant difference in survival between the two groups of patients (Table 3).

In a Cox proportional hazards model and after stratification on the IPI score, the pathology variables had no substantial effects on OS (P = .87) or EFS (P = .66).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The definition of H/TCRBCL is controversial because it is still considered a mere variant of diffuse large-cell lymphoma in the WHO classification.¹⁵ Most authors agree with some obvious characteristics of H/TCRBCL, such as the paucity of large neoplastic cells and small reactive B cells, but do not use precise diagnostic criteria.^21,22 The same authors admit the existence of some gray-zone cases displaying features common to both H/TCRBCL and LPHD because lymphoma cells in H/TCRBCL morphologically and phenotypically resemble Hodgkin’s cells, and some nodular growth patterns recently have been described in H/TCRBCL.^7,21,22 This biologic overlap between both diseases as well as the observation of their sequential or simultaneous occurrence in the same patient has led to the hypothesis that H/TCRBCL can result from the transformation of LPHD.⁸

To evaluate whether the recognition of H/TCRBCL as an entity may have any prognostic implication, we decided to choose stringent, commonly admitted criteria for its diagnosis and to exclude any borderline patient case in which suspicion of classic diffuse large-cell lymphoma or Hodgkin’s lymphoma could not be totally excluded. Even when these criteria were used, a minority of tumors harbored vaguely nodular areas, whereas more than 90% of the section disclosed a diffuse growth pattern. This feature, which has been also described in other recent H/TCRBCL series, was somewhat reminiscent of LPHD remnants.^7,8 An important finding supporting the classification of these patient cases as true H/TCRBCL was that they exhibited a diffuse pattern typical of H/TCRBCL in involved bone marrow biopsies. Furthermore, they did not show any significant differences in clinical presentation and follow-up when compared with other H/TCRBCL patients. These histologic features suggestive of LPHD-derived remnants in otherwise typical H/TCRBCL could support the view that LPHD can transform into H/TCRBCL, as previously suggested by others.⁸

Clinical data regarding T-cell rich B-cell lymphomas remain confusing because previous reported series studied few patients. In the report of Greer et al,¹² the frequency of H/TCRBCL was estimated at 1% to 2% of all cases of NHL. In the present study, which is based on more than 4,500 patients enrolled in two consecutive multicentric trials, 50 patients (1.2%) were identified as true H/TCRBCL cases. Table 4 summarizes the main features of H/TCRBCL patients previously reported in the largest series of the literature. With the exception of the report of Rodriguez et al,¹¹ there is a male predominance, and this was particularly true in our study (88%). The median age of disease ranged from 47 to 62.5 years, and at least half of the patients are younger than 60 years. The disease is often disseminated at the time of diagnosis because 57% to 82% of patients present with Ann Arbor stages III and IV disease. The LDH value was increased in approximately half of the patients. The IPI score was assessable only in the report of Achten et al¹³ and was 2 in 77% of the patients.

The concept of T-cell rich B-cell lymphoma raises two major questions. On one hand, is there any clinical and/or biologic feature that could separate H/TCRBCL patients from unspecified B-DLCL patients? In this report, although both groups of H/TCRBCL and B-DLCL patients were well matched according to the IPI, the matched-control analysis revealed some variable clinical features. For instance, mediastinal involvement was less frequent in H/TCRBCL (P = .02), whereas subdiaphragmatic nodal localization was more frequent (P = .02). Splenomegaly was a key symptom in H/TCRBCL; 60% of our patients were affected (P < .0001). These data were correlated with the reports of Rodriguez et al¹¹ and Achten et al,¹³ in which splenomegaly occurred in 35% and 60% of patients, respectively (Table 4). Liver involvement seemed also to be more specific of H/TCRBCL (P = .001). No patients with H/TCRBCL presented with gastrointestinal tract disease.

On the other hand, does the T-cell component confer to patients a prognostic value different from that observed in other B-DLCL? In both studies of Chittal et al⁹ and Delabie et al,¹⁰ the poor outcome of patients could be the result of inappropriate therapy because most of them received treatment for Hodgkin’s disease. In the series reported by Greer et al,¹² the outcome of patients with H/TCRBCL who received NHL regimen chemotherapy did not differ from that observed in B-DLCL. The most recent published studies showed a worse outcome of H/TCRBCL than for classic B-DLCL.^7,13 However, the conclusions of these studies are hampered by the absence of a relevant B-DLCL control group; B-DLCL and H/TCRBCL patients were not matched for all adverse prognostic factors. To our knowledge, our study is the first comparative study of matched-histologic categories of B-DLCL and H/TCRBCL. Both H/TCRBCL and control B-DLCL groups have been selected from common protocols and they all received NHL chemotherapy regimens. Because the matched-control analysis has been performed on the basis of the IPI, the treatment arms were equally distributed among the two groups of patients. Our data showed a trend toward a better response to therapy for classical B-DLCL patients (P = .06), but there was no statistically significant difference in terms of survival.

Finally, several conclusions can be drawn from the results of this study. Although the diagnosis of H/TCRBCL sometimes can be difficult in cases of gray-zone lesions, most cases can be distinguished from others entities such as LPHD or other large-cell lymphomas using accurate histologic and phenotypic criteria. Our matched-control study fully confirms that H/TCRBCL often presents as an aggressive disease with poor-risk factors, but it also indicates that there is no argument to separate H/TCRBCL and B-DLCL categories in clinical trials. The observed lack of difference in both response and survival indeed suggests that the diagnosis of H/TCRBCL does not imply a worse prognosis when compared with that of classic B-DLCL exhibiting the same adverse IPI risk factors. Therefore, we believe that after scoring patients according to their IPI, therapy should be similar in H/TCRBCL and classic B-DLCL patients. Our study thus confirms that H/TCRBCL should be regarded as a variant that fully belongs to the B-DLCL category of the WHO criteria.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following investigators participated in the study: N. Albin, C. Allard, M. Aoudjane, D. Assouline, M. Attal, B. Audhuy, M. Azagury, J.C. Barats, C. Beaumont, E Baumelou, P. Biron, M. Blanc, D. Bordessoule, A. Bosly, K. Bouabdallah, C. Bouleuc, P. Bourquard, P. Bourquelot, F. Boué, O. Boulat, P. Brice, J. Brière, G. Brun, D. Caillot, O. Casasnovas, P. Carde, S. Castaigne, S. Chèze, B. Christian, B. Coiffier, P. Colin, C. Collet, T. Conroy, T. Cosnard, B. Corront, H. Curé, V. Delwail, L. Detourmignies, A. Devidas, H. Dombret, J.F. Dor, C. Doyen, F. Dreyfus, S. Dront, G. Dupont, B. Dupriez, J.C. Eisenmann, M. Fabbro, C. Fermé, G. Fillet, M. Flesch, C. Fruchart, J. Gabarre, C. Haioun, R. Herbrecht, O. Hermine, A. Huyn, F. Huguet, M. Janvier, E. Jourdan, J.M. Karsenti, Y. Kerneis, F. Kohser, V. Leblond, P. Lederlin, S. Lefort, P. Lenain, G. Lepeu, S. Lepretre, X. Levaltier, A. Le Rol, G. Marit, C. Martin, F. Mayer, C. Nouvel, P. Morel, M. Moriceau, J.N. Munck, G. Nedellec, F. Offner, J.M. Pavlovitch, I. Plantier, P.Y. Péaud, A.M. Peny, J. Pico, C. Platini, J.P. Pollet, B. Quesnel, O. Reman, B. Richard, R. Riou, P. Rodon, B. Salles, G. Salles, C. Sarazin, D. Schlaifer, C. Sebban, M. Simon, P. Solal-Céligny, J.J. Sotto, A. Stamatoullas, C. Soussain, G. Tertian, A. Thyss, H. Tilly, J.D. Tigaud, G. Tobelem, P. Travade, A. Van Hoof, B. Varet, A. Zaniboni, and J.M. Zini.

The following members of the Groupe d’Etude des Lymphomes de l’Adulte performed the histologic review: J. Bosq, J. Brière, J.F. Emile, B. Fabiani, P. Gaulard, C. Guettier, T. Petrella, T. Molina, and L. Xerri.

	ACKNOWLEDGMENTS

 
We thank Nicolas Nio, who performed the statistical analysis. Special thanks to Odile Flohic for her technical assistance.

	NOTES

 
Supported by grants from the Ministère de la Santé (Programme Hospitalier pour la Recherche Clinique [PHRC] Appel d’Offre Ministériel [AOM] grant no. 95061, PHRC LNH98 AOM grant no. 98.117), Assistance Publique Hôpitaux de Paris, France, and grants from Amgen-Roche, Neuilly sur Seine, France.

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Submitted June 7, 2002; accepted December 23, 2002.

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