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ORIGINAL REPORTS
January 04, 2010

Transformation to Aggressive Lymphoma in Nodular Lymphocyte-Predominant Hodgkin's Lymphoma

Publication: Journal of Clinical Oncology

Abstract

Purpose

Prior observations suggest a higher risk of transformation of nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), than in classical Hodgkin's lymphoma. We evaluated the frequency of transformation in all patients diagnosed with NLPHL at the British Columbia Cancer Agency with long-term follow-up.

Patients and Methods

The Lymphoid Cancer Database of the British Columbia Cancer Agency was searched to identify all patients diagnosed with NLPHL between 1965 and 2006. After pathologic review, 95 patients with NLPHL were confirmed.

Results

Patients with NLPHL had the following characteristics at diagnosis: median age of 37 years, 73% male, and 68% stage I or II disease. With a median follow-up time for living patients of 6.5 years (range, 2.5 to 33 years), 13 patients (14%) experienced transformation to aggressive lymphoma (median time to transformation, 8.1 years; range, 0.35 to 20.3 years). The actuarial risk of transformation to aggressive lymphoma was 7% and 30% at 10 and 20 years, respectively. Transformation was more likely in patients with initial splenic involvement (P = .006) at the time of diagnosis of NLPHL. The 10-year progression-free and overall survival rates in patients with transformed lymphoma were 52% and 62%, respectively.

Conclusion

The risk of transformation in patients with NLPHL to DLBCL is substantial and underappreciated. Because transformation can occur years after the primary diagnosis of NLPHL, long-term follow-up of these individuals is necessary to accurately estimate the risk of development of secondary DLBCL.

Introduction

Nodular lymphocyte-predominant Hodgkin's Lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin's lymphoma (HL). NLPHL was identified as a distinct subtype of HL in the Revised European-American Lymphoma (REAL) classification and in the WHO classification of lymphomas1 based on unique histopathologic and clinical characteristics that distinguish it from classical HL. Patients with NLPHL are usually male, with a median age of 30 to 40 years, and usually present with slowly progressive, localized peripheral lymphadenopathy.2 Bulky disease, “B” symptoms, mediastinal or abdominal involvement, and extranodal disease are uncommon.3 NLPHL is characterized by a nodular or a nodular and diffuse proliferation of large neoplastic lymphocyte-predominant (LP) cells (so-called popcorn cells), which were previously referred to as lymphocytic and histiocytic or Reed-Sternberg cell variants.4 In contrast to classical Hodgkin's Reed-Sternberg cells, LP cells express the B-cell markers CD19, CD20, and CD79, as well as immunoglobulins, J chain, and epithelial membrane antigen, but they do not express CD15 and CD30.3 This B-cell phenotype and demonstration of clonally arranged immunoglobulin genes with ongoing mutations suggest a close relationship with B-cell non-Hodgkin's lymphoma (NHL).5
Despite a favorable outcome, previous observations suggest that there is an inherent tendency of NLPHL to develop secondary NHL, typically diffuse large B-cell lymphoma (DLBCL), either concurrently or subsequently.2,613 The incidence has been reported to be higher than in classical HL, but a wide range is observed from prior series (0.6% to 9.8%).6,7,10,12 This variability may reflect the accuracy of the original diagnosis of NLPHL, particularly in older studies before diagnoses were based on the REAL/WHO classification, as well as limited follow-up because this event can occur years later. Molecular studies have demonstrated a clonal relationship between the LP cells of NLPHL and the cells of the associated DLBCL in at least some patients,1418 suggesting that the large-cell lymphoma may evolve from the same germinal center precursor that has developed into a more aggressive disease manifestation.
The purpose of this study was to evaluate the frequency of transformation to aggressive lymphoma in patients with NLPHL, diagnosed by the REAL/WHO classification, and to evaluate the outcome of patients with transformed lymphoma.

Patients and Methods

The British Columbia Cancer Agency Lymphoid Cancer Hodgkin's Lymphoma Database was searched to identify all patients more than 15 years of age and less than 80 years of age who were diagnosed with NLPHL between 1965 and 2006. In the initial screen, 150 patients with NLPHL were identified. Pathologic rereview was undertaken by an expert British Columbia Cancer Agency hematopathologist (B.S.) in patients who were diagnosed before routine immunophenotyping. On pathologic reassessment, 55 patients were excluded for the following reasons: classical Hodgkin's lymphoma (total, n = 20; mixed cellularity, n = 7, lymphocyte rich, n = 9; lymphocyte depleted, n = 1; nodular sclerosis, n = 1; not classifiable, n = 2); composite or gray-zone lymphoma (n = 4) or discordant lymphoma (n = 1); NHL (DLBCL, n = 4; not classifiable, n = 1); and paraffin blocks and/or slides not available for review (n = 25).
Of the remaining 95 patients with NLPHL available for further analysis, the diagnosis was confirmed in all patients based on the established WHO criteria with both morphology and immunophenotyping analysis, with the exception of six patients in whom the diagnosis was based only on morphology alone on pathologic rereview because the original material was not available for immunohistochemistry.
Clinical information at the time of diagnosis of both NLPHL and secondary NHL was recorded, including age, sex, Eastern Cooperative Oncology Group performance status, B symptoms, stage, extranodal and/or splenic involvement, and lactate dehydrogenase (LDH). Limited stage was defined as stage IA or IIA and the absence B symptoms or bulky disease ≥ 10 cm. As of November 2001, rare patients with nonbulky, stage IB Hodgkin's lymphoma have also been considered to have limited-stage disease.

Definition of Transformation

Patients were diagnosed with transformed disease based on biopsy confirmation with the finding of DLBCL or other aggressive lymphoma. If a biopsy was not feasible, a clinical diagnosis was made based on one or more of the following: a sudden increase in LDH ≥ 2× the upper limit of normal (ULN), rapid clinical deterioration, new B symptoms, or involvement of unusual extranodal sites.

Statistical Analysis

The primary end point was the time to development of a secondary DLBCL or transformation to aggressive lymphoma and was measured from the initial pathologic diagnosis of NLPHL. Overall survival (OS) was calculated from the date of diagnosis of NLPHL (or transformation to DLBCL) to the date of last follow-up or death from any cause. Progression-free survival (PFS) was determined in patients with transformed lymphoma from the date of diagnosis of transformation to the date of relapse or progression of lymphoma (including NLPHL) or death as a result of acute treatment toxicity. The Kaplan-Meier method was used for calculation of survival and time to development of transformation.19 Survival comparisons were performed using the log-rank test. Baseline characteristics between patient groups were compared using the χ2 test. Risk factors for development of transformation were analyzed using univariate analysis. Multivariate analysis was performed using a Cox proportional hazards model and forward selection including factors with a P < .1 from the univariate analysis. All statistical analyses were performed using SPSS, version 11.5 (SPSS, Chicago, IL).

Results

Clinical Features, Primary Therapy, and Outcome of NLPHL

At diagnosis of NLPHL, the median age was 37 years (range, 15 to 77 years), and the majority of patients were male (73%) with stage I or II disease (67%) and a good performance status (0 or 1; 91%; Table 1). Of the patients with advanced-stage disease, only one had stage IV disease. A small proportion of patients had B symptoms (8%) or an elevated LDH (7%), and 12 patients (12%) had splenic involvement diagnosed by either staging splenectomy (n = 6) or imaging (n = 6). Two patients (2%) had extranodal disease at the time of diagnosis. None of the patients had bulky disease (mass ≥ 10 cm).
Table 1. Baseline Demographics and Clinical Characteristics of Patients With Nodular Lymphocyte-Predominant Hodgkin's Lymphoma at Diagnosis (N = 95)
CharacteristicNo. of Patients%
Follow-up, years  
    Median6.5
    Range2.5-33
Age, years  
    Median37
    Range15-77
Sex  
    Male6973
    Female2627
ECOG performance status  
    06669
    12122
    289
Splenic involvement1213
    Pathologic (splenectomy)6 
    Imaging6 
B symptoms  
    A9092
    B88
Stage  
    I or II6467
    III or IV3133
Elevated LDH*77
Initial therapy  
    Limited state (n = 64)  
        RT alone2438
        ABVD or MOPP/ABV ± RT3859
        Surgery alone23
    Advanced stage (n = 31)  
        RT26
        ABVD or MOPP/ABV2374
        MOPP + RT310
        Other310
Abbreviations: ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; RT, radiotherapy; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; MOPP/ABV, mechlorethamine, vincristine, procarbazine, prednisone doxorubicin, bleomycin, and vinblastine.
*
LDH level is missing in 19 patients.
Eight patients received chemotherapy alone.
Patients with limited-stage NLPHL (n = 64) received radiotherapy alone (1965 to 1993; n = 24) or chemotherapy ± radiotherapy (1993 to 2006; n = 38). Two patients underwent surgery alone for stage IA disease because the diagnosis of NLPHL was established retrospectively on pathologic rereview (Table 1). In the chemotherapy treatment era, the exceptional patient with stage IA disease and high neck node involvement received involved-field radiotherapy. Chemotherapy for limited-stage disease typically consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but four patients received mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) or cyclophosphamide, vincristine, procarbazine, and prednisone/ABV.20
The majority of patients with advanced-stage disease (n = 31) received chemotherapy (n = 29, 94%). Two patients received extended-field radiotherapy alone. Most patients received an ABVD-like regimen (ABVD, n = 19; or MOPP/ABV, n = 4), and three patients received MOPP followed by radiotherapy. Two elderly patients (≥ 65 years old) received vincristine, doxorubicin, bleomycin, etoposide, and prednisone,21 and one patient received vinblastine, etoposide, cyclophosphamide, doxorubicin, bleomycin, vincristine, and prednisone.22
The 5- and 10-year PFS rates for the whole cohort of patients with NLPHL were 85% and 73%, respectively, and the 5- and 10-year OS rates were 94% and 91%, respectively. In total, 16 patients have died, and the most common cause of death was secondary NHL (n = 5, 31%). There was one toxic death as a result of febrile neutropenia during therapy for NLPHL and no deaths as a result of refractory NLPHL. The remaining causes of death were cardiac (n = 4), secondary malignancies other than NHL (n = 4), and other (n = 2).

Transformation in NLPHL

With a median follow-up time of living patients of 6.5 years (range, 2.5 to 32 years), 13 patients (14%) experienced transformation to aggressive lymphoma have (Table 2). The median time to transformation was 8.1 years (range, 0.35 to 20.3 years; Table 2). Ten patients had a pathologic diagnosis of DLBCL (DLBCL, n = 8; T-cell–rich B-cell lymphoma [TCRBCL], n = 2), and in one patient, a fine-needle aspiration was performed that demonstrated an aggressive B-cell lymphoma, but further subclassification was not possible as a result of limited pathologic material. Clinically, the latter patient had an LDH ≥ 4× ULN and rapid clinical deterioration. In two patients, the clinical picture suggested an aggressive transformation (LDH ≥ 4× ULN, declining performance status, and splenic disease). In one of these patients, a repeat biopsy demonstrated NLPHL with an area of atypical sclerosis suggestive, but not definitive, of an evolving TCRBCL. In the other patient, biopsy was not feasible because of a rapidly declining performance status.
Table 2. Baseline Clinical Characteristics of Patients at the Time of Transformation to Aggressive Lymphoma and Treatment Received
CharacteristicNo. of Patients%
Time to transformation, years  
    Median8.1
    Range0.35-20.3
Age at transformation, years  
    Median42
    Range26-76
Diagnosis  
    DLBCL862
    TCRBCL215
    Aggressive lymphoma NOS18
    Clinical diagnosis215
Male1077
Elevated LDH969
B symptoms754
Performance status ≥ 21077
Any extranodal involvement862
    Liver431
    GI tract323
    Soft tissue323
    Bone18
Splenic involvement*778
Stage III or IV disease1077
IPI score  
    0-2323
    3-51077
Treatment of prior NLPHL  
    ABVD or equivalent alone754
    Radiotherapy alone539
    Surgery17
Treatment at time of transformation  
    Rituximab combination646
        R-CHOP5 
        R-GDP + HDC/ASCT1 
    CHOP (CHOP-like)323
    ICE + HDC/ASCT18
    Palliative chemotherapy or supportive care323
Abbreviations: DLBCL, diffuse large B-cell lymphoma; TCRBCL, T-cell rich B-cell lymphoma; NOS, not otherwise specified; LDH, lactate dehydrogenase; IPI, International Prognostic Index; NLPHL, nodular lymphocyte-predominant Hodgkin's lymphoma; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-GDP, rituximab plus gemcitabine, dexamethasone, and cisplatin; HDC, high-dose chemotherapy; ASCT, autologous stem-cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ICE, ifosfamide, carboplatin, and etoposide.
*
Four patients had a prior splenectomy with staging laparotomy at the time of diagnosis of NLPHL and were not assessable for splenic involvement at the time of transformation; thus the denominator is 9.
Two patients had etoposide substitution for the anthracycline.
The clinical features at the time of the development of secondary aggressive lymphoma are listed in Table 2. The median age at the time of transformation was 42 years (range, 26 to 76 years), with a male predominance (n = 10, 77%), and most patients had advanced-stage disease (77%), elevated LDH (69%), and overall, high-risk disease (International Prognostic Index ≥ 3; 77%). In the patients who had not undergone splenectomy with staging laparotomy at the time of diagnosis of NLPHL (n = 9), seven patients (78%) had splenic involvement based on computed tomography imaging or splenectomy at the time of transformation. Of note, only one patient had experienced a prior relapse of NLPHL; for the remainder, the transformation to aggressive lymphoma represented their first lymphoma relapse.
The actuarial risks of development of transformed lymphoma were 5%, 7%, 15%, 31%, and 36% at 5, 10, 15, 20, and 25 years, respectively, with no definite plateau, although the number of patients observed after 25 years is small (Fig 1). Interestingly, there was a cluster of early cases that occurred within 3 years or less (n = 5) and a cluster of late cases that occurred between 10 and 25 years (n = 7). Patients with transformed lymphoma were more likely to have had advanced-stage disease and splenic involvement at the time of diagnosis of NLPHL (Table 3). In univariate analysis, splenic involvement at diagnosis of NLPHL (P = .006) was a strong risk factor for future transformation, and there was a trend toward an increased risk with advanced-stage disease (P = .057; Table 4). In multivariate analysis, only splenic involvement (hazard ratio = 4.18; 95% CI, 1.37 to 12.69; P = .012) was predictive of future development of transformed lymphoma in patients with NLPHL.
Fig 1. Time to transformation in patients with nodular lymphocyte-predominant Hodgkin's lymphoma.
Table 3. Demographics and Clinical Characteristics of Patients With NLPHL at Diagnosis Who Subsequently Developed Transformation to Aggressive Lymphoma Compared With Patients Who Have Not Developed Transformation
CharacteristicTransformed (n = 13)Nontransformed (n = 82)P
No. of Patients%No. of Patients%
Age, years     
    Median3637
    ≥ 406463138.566
Sex    .709
    Male10775972 
    Female3232328 
Performance status    .518
    0/110776984 
    2381316 
Stage    .012
    I or II5386073 
    III or IV8622227 
Splenic disease    < .00001
    Yes64667 
    No7547893 
B symptoms    .919
    Yes7547592 
    No64678 
LDH elevated*    .099
    Yes21556 
    No11855871 
Bulk ≥ 5 cm    .708
    Yes3332027 
    No6675373 
Abbreviations: NLPHL, nodular lymphocyte-predominant Hodgkin's lymphoma; LDH, lactate dehydrogenase.
*
Nineteen patients were missing LDH (n = 19 nontransformed).
Thirteen patients were missing mass size (n = 4 transformed; n = 9 nontransformed).
Table 4. Univariate Analysis of Risk Factors for Transformation at Diagnosis of NLPHL
Clinical FeatureP
Age ≥ 40 years.556
Male sex.625
Performance status ≥ 2.522
Stage III or IV disease.057
Splenic disease.006
B symptoms.913
LDH elevated.526
Bulk ≥ 5 cm.331
Abbreviations: NLPHL, nodular lymphocyte-predominant Hodgkin's lymphoma; LDH, lactate dehydrogenase.
Given the eras that this study spanned, a variety of therapies were used at the time of transformation (Table 2). Most patients received multiagent chemotherapy with curative intent, and three patients received supportive care or palliative chemotherapy. Six patients received rituximab-containing regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] plus rituximab [R-CHOP]; n = 3; cyclophosphamide, doxorubicin, etoposide, and prednisone plus rituximab; n = 2; and gemcitabine, dexamethasone, and cisplatin plus rituximab; n = 2)23 followed by high-dose chemotherapy (HDC) and autologous stem-cell transplantation (ASCT). Three patients received CHOP or CHOP-like chemotherapy, and one patient received ICE ifosfamide, carboplatin, and etoposide24 followed by HDC and ASCT. Nine patients (69%) achieved a complete remission, three patients died of progressive disease, and one patient with a recent history of splenectomy for diagnosis died of sepsis after one cycle of R-CHOP. With a median follow-up time after the development of transformation of 8.1 years (range, 0.34 to 20.3 years), the 10-year PFS and OS rates were 52% and 62%, respectively (Fig 2). Two patients in complete remission experienced relapse after 1.5 years with aggressive lymphoma; one of the patients is alive on palliative chemotherapy, and the other died as a result of the lymphoma. There were no relapses after 2 years, including NLPHL (Fig 2).
Fig 2. (gold line) Progression-free survival and (blue line) overall survival after transformation of nodular lymphocyte-predominant Hodgkin's lymphoma to aggressive B-cell lymphoma.

Discussion

It has long been recognized that large-cell lymphoma can occur either at diagnosis or as a subsequent relapse in patients with NLPHL.10,11,16 The incidence has been reported to range up to 10%; however, in many cases, the diagnosis of NLPHL was based on obsolete classification systems, and follow-up has been quite limited. Thus, little is known about the actuarial long-term risk and cumulative incidence of this occurrence in NLPHL with mature follow-up.
The importance of pathologic rereview of older cases previously classified as NLPHL before the routine availability of immunohistochemistry cannot be overemphasized. The European Task Force study evaluated 388 patients that participating institutions had diagnosed as having NLPHL. However, with a combination of morphologic and immunophenotypic criteria, only 219 patients (56%) were found to have NLPHL by today's diagnostic standards.25 Depending on the population studied, the incidence of transformation may be reduced by inclusion of patients with lymphocyte-rich classical Hodgkin's lymphoma, or alternatively, it may be magnified if patients with TCRBCL are erroneously included. Similar to the European Task Force, on rereview of the older cases, we found that a large proportion of patients had a diagnosis other than NLPHL. Although not the focus of this study on pathologic rereview, five patients (5%) with NLPHL had a concurrent or overlapping diagnosis of DLBCL presenting either as a composite, transitional17 or discordant lymphoma, further highlighting the relationship between these diseases and providing some insight as to why there have been discrepancies in the literature.
The final cohort of 95 patients with NLPHL had the typical clinical features encountered in this disease, namely male predominance, early stage, and few adverse prognostic factors.2628 Consistent with prior reports, overall, the prognosis of our NLPHL patients was favorable, with a 10-year OS rate of 91%. In total, 13 patients developed transformed lymphoma with actuarial risks at 10 and 20 years of 7% and 30%, respectively. The high frequency of late events underscores the need to observe patients long term and ensure that a biopsy is obtained at the time of presumed relapse in all patients with NLPHL. The clinical features of the transformed patients were similar to the features of secondary DLBCL after NLPHL or classical Hodgkin's lymphoma that have been reported in previous studies28,29 (ie, predominantly male, the majority with advanced-stage disease and extranodal involvement). Interestingly, splenic involvement, independent of stage, at the time of diagnosis of NLPHL emerged as a strong risk factor for future transformation; this has not been previously reported and was seen regardless of whether the transformation occurred early or late. Furthermore, almost all assessable patients with transformed lymphoma had involvement of the spleen (78%), a relatively uncommon site in de novo DLBCL in which the frequency is approximately 20%.30 It is possible that splenic disease reflects the presence of occult large-cell lymphoma that is only partially treated with treatment regimens directed against NLPHL. In patients with NLPHL with findings suggestive of splenic involvement at diagnosis, strong consideration should be given to performing a splenectomy to rule out a concurrent diagnosis of either TCRBCL or DLBCL to ensure that appropriate therapy is delivered.
Despite the fact that most patients with transformed lymphoma presented with advanced-stage disease and a high International Prognostic Index score and less than half received rituximab in their treatment regimen, the outcome was favorable, with a 10-year PFS rate of 51% and 10-year OS rate of 61%, which are superior compared with rates associated with transformation that develops in the setting of follicular lymphoma.31 This may reflect a less heavily pretreated population, although the majority of patients with NLPHL had received prior combination chemotherapy. Thus, it more likely represents different disease biology. Consistent with this, there were no relapses seen after 2 years, highlighting a different natural history than de novo DLBCL or follicular lymphoma that subsequently transformed. However, for the NLPHL population as a whole, development of a secondary lymphoma was the most common cause of death and thus represents the major threat to morbidity and mortality.
It is unclear what the appropriate therapy is in patients with NLPHL who develop secondary DLBCL or TCRBCL. Given the expression of CD20, rituximab should provide the same magnitude of benefit as that observed in de novo DLBCL.32 However, the number of patients with transformed lymphoma in the present series is too small to determine the impact of rituximab or the role of consolidative HDC and ASCT.
Other studies evaluating the outcome of patients with Hodgkin's lymphoma who develop a secondary NHL have been discrepant, with some reporting a more favorable outcome than de novo DLBCL9,17 and others showing a similar or worse prognosis.11,33 In addition to the challenge of evaluating older studies using outdated classification systems, comparison of outcomes is also hampered by some analyses evaluating secondary NHL developing in all Hodgkin's lymphoma subtypes,7,33 and other studies have combined patients with concurrent lymphomas (ie, patients with composite or discordant lymphoma) and sequential lymphoma,9,11,17 which may obscure differences in these subgroups. It has been suggested that patients with concurrent NLPHL with DLBCL have a more favorable prognosis than sequential patients.9,17,34 However, it is unclear from some of these older series whether patients with sheets of LP cells may have been reported as having concurrent large-cell lymphoma but actually represent NLPHL, which, in turn, could explain the favorable prognosis in this group. Alternatively, some patients may represent NLPHL in transition to large-cell lymphoma, which has been described for TCRBCL and which may also represent a different disease state.29 The Nebraska study group reported on the outcome of concurrent and sequential patients with NLPHL DLBCL including TCRBCL and found no difference in outcome between patients with secondary and age/sex-matched de novo DLBCL, although survival in the former was reportedly much lower than in our study (5-year OS rate, 31%). Future studies should separate concurrent and sequential patients to further understand any prognostic differences.
Several cases in our study seemed to be related to TCRBCL. The histologic similarities between NLPHL and TCRBCL and their relationship have been previously well described.35 However, it is unknown whether secondary TCRBCL represents clonal progression of NLPHL or whether a common germinal center precursor exists. In one study, the transcription factor PU.1 was found to be expressed in all patients with NLPHL but reduced or absent in TCRBCL.36 However, genomic imbalances are more frequent in NLPHL than TCRBCL, which argues against direct evolution.
In summary, this large study with long-term follow-up confirms that patients with NLPHL have a substantial risk of future transformation to aggressive lymphoma, which can occur decades after the primary diagnosis of NLPHL with no apparent plateau in risk. Patients with splenic involvement at diagnosis of NLPHL seem to have an elevated risk and require close follow-up. Long-term surveillance and repeat biopsy at the time of relapse are imperative in this patient population to ensure that the appropriate therapy is delivered.

Authors' Disclosures of Potential Conflicts of Interest

The author(s) indicated no potential conflicts of interest.

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Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 793 - 799
PubMed: 20048177

History

Published online: January 04, 2010
Published in print: February 10, 2010

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Authors

Affiliations

Mubarak Al-Mansour
From the Departments of Medical Oncology and Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Joseph M. Connors
From the Departments of Medical Oncology and Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Randy D. Gascoyne
From the Departments of Medical Oncology and Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Brian Skinnider
From the Departments of Medical Oncology and Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Kerry J. Savage [email protected]
From the Departments of Medical Oncology and Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

Notes

Corresponding author: Kerry J. Savage, MD, MSc, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, British Columbia, V5Z 4E6; e-mail: [email protected].

Author Contributions

Conception and design: Kerry J. Savage
Provision of study materials or patients: Joseph M. Connors, Randy D. Gascoyne, Brian Skinnider
Collection and assembly of data: Mubarak Al-Mansour, Randy D. Gascoyne, Brian Skinnider, Kerry J. Savage
Data analysis and interpretation: Mubarak Al-Mansour, Joseph M. Connors, Randy D. Gascoyne, Brian Skinnider, Kerry J. Savage
Manuscript writing: Mubarak Al-Mansour, Kerry J. Savage
Final approval of manuscript: Mubarak Al-Mansour, Joseph M. Connors, Randy D. Gascoyne, Brian Skinnider, Kerry J. Savage

Disclosures

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Funding Information

Supported in part by the Turner Family Lymphoma Outcome Unit Fund.

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Mubarak Al-Mansour, Joseph M. Connors, Randy D. Gascoyne, Brian Skinnider, Kerry J. Savage
Journal of Clinical Oncology 2010 28:5, 793-799

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