VOLUME 28 䡠 NUMBER 5 䡠 FEBRUARY 10 2010

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Transformation to Aggressive Lymphoma in Nodular

From the Departments of Medical
Oncology and Pathology, British Colum-
bia Cancer Agency, Vancouver, British
Columbia, Canada.
Submitted July 1, 2009; accepted
September 4, 2009; published online
ahead of print at www.jco.org on
January 4, 2010.
Supported in part by the Turner Family
Lymphoma Outcome Unit Fund.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Kerry J. Savage,
MD, MSc, British Columbia Cancer
Agency, 600 West 10th Ave, Vancou-
ver, British Columbia, V5Z 4E6; e-mail:
ksavage@bccancer.bc.ca.
© 2010 by American Society of Clinical
Oncology
0732-183X/10/2805-793/$20.00
DOI: 10.1200/JCO.2009.24.9516
Lymphocyte-Predominant Hodgkin’s Lymphoma
Mubarak Al-Mansour, Joseph M. Connors, Randy D. Gascoyne, Brian Skinnider, and Kerry J. Savage
A B S T R A C T
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 underappreci-
ated. 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.

J Clin Oncol 28:793-799. © 2010 by American Society of Clinical Oncology

ferred to as lymphocytic and histiocytic or Reed-

INTRODUCTION
Nodular lymphocyte-predominant Hodgkin’s Lym-
phoma (NLPHL) accounts for approximately 5% of
all Hodgkin’s lymphoma (HL). NLPHL was identi-
fied as a distinct subtype of HL in the Revised
European-American Lymphoma (REAL) classifica-
tion and in the WHO classification of lymphomas1
based on unique histopathologic and clinical char-
acteristics that distinguish it from classical HL. Pa-
tients with NLPHL are usually male, with a median
age of 30 to 40 years, and usually present with
slowly progressive, localized peripheral lymphad-
enopathy.2 Bulky disease, “B” symptoms, medias-
tinal 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 re-
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 mem-
brane antigen, but they do not express CD15 and
CD30.3 This B-cell phenotype and demonstration of
clonally arranged immunoglobulin genes with on-
going mutations suggest a close relationship with
B-cell non-Hodgkin’s lymphoma (NHL).5
Despite a favorable outcome, previous ob-
servations suggest that there is an inherent ten-
dency of NLPHL to develop secondary NHL,
typically diffuse large B-cell lymphoma (DLBCL),
either concurrently or subsequently.2,6-13 The inci-
dence 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,

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 Al-Mansour et al

particularly in older studies before diagnoses were based on the REAL/ P ⬍ .1 from the univariate analysis. All statistical analyses were performed
WHO classification, as well as limited follow-up because this event can using SPSS, version 11.5 (SPSS, Chicago, IL).
occur years later. Molecular studies have demonstrated a clonal rela-
tionship between the LP cells of NLPHL and the cells of the associated RESULTS
DLBCL in at least some patients,14-18 suggesting that the large-cell
lymphoma may evolve from the same germinal center precursor that
Clinical Features, Primary Therapy, and Outcome
has developed into a more aggressive disease manifestation.
of NLPHL
The purpose of this study was to evaluate the frequency of trans-
At diagnosis of NLPHL, the median age was 37 years (range, 15 to
formation to aggressive lymphoma in patients with NLPHL, diag-
77 years), and the majority of patients were male (73%) with stage I or
nosed by the REAL/WHO classification, and to evaluate the outcome
II disease (67%) and a good performance status (0 or 1; 91%; Table 1).
of patients with transformed lymphoma.
Of the patients with advanced-stage disease, only one had stage IV
disease. A small proportion of patients had B symptoms (8%) or an
PATIENTS AND METHODS 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.
The British Columbia Cancer Agency Lymphoid Cancer Hodgkin’s Lym-
phoma Database was searched to identify all patients more than 15 years of age
None of the patients had bulky disease (mass ⱖ 10 cm).
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 rou- Table 1. Baseline Demographics and Clinical Characteristics of Patients With
Nodular Lymphocyte-Predominant Hodgkin’s Lymphoma at
tine immunophenotyping. On pathologic reassessment, 55 patients were ex- Diagnosis (N ⫽ 95)
cluded for the following reasons: classical Hodgkin’s lymphoma (total, n ⫽ 20;
No. of
mixed cellularity, n ⫽ 7, lymphocyte rich, n ⫽ 9; lymphocyte depleted, n ⫽ 1;
Characteristic Patients %
nodular sclerosis, n ⫽ 1; not classifiable, n ⫽ 2); composite or gray-zone
lymphoma (n ⫽ 4) or discordant lymphoma (n ⫽ 1); NHL (DLBCL, n ⫽ 4; Follow-up, years
not classifiable, n ⫽ 1); and paraffin blocks and/or slides not available for Median 6.5
review (n ⫽ 25). Range 2.5-33
Of the remaining 95 patients with NLPHL available for further analysis, Age, years
the diagnosis was confirmed in all patients based on the established WHO Median 37
criteria with both morphology and immunophenotyping analysis, with the Range 15-77
exception of six patients in whom the diagnosis was based only on morphology Sex
alone on pathologic rereview because the original material was not available Male 69 73
for immunohistochemistry. Female 26 27
Clinical information at the time of diagnosis of both NLPHL and sec- ECOG performance status
ondary NHL was recorded, including age, sex, Eastern Cooperative Oncology 0 66 69
Group performance status, B symptoms, stage, extranodal and/or splenic 1 21 22
involvement, and lactate dehydrogenase (LDH). Limited stage was defined as 2 8 9
stage IA or IIA and the absence B symptoms or bulky disease ⱖ 10 cm. As of Splenic involvement 12 13
November 2001, rare patients with nonbulky, stage IB Hodgkin’s lymphoma Pathologic (splenectomy) 6
have also been considered to have limited-stage disease. Imaging 6
B symptoms
Definition of Transformation A 90 92
Patients were diagnosed with transformed disease based on biopsy con- B 8 8
firmation with the finding of DLBCL or other aggressive lymphoma. If a Stage
biopsy was not feasible, a clinical diagnosis was made based on one or more of I or II 64 67
the following: a sudden increase in LDH ⱖ 2⫻ the upper limit of normal III or IV 31 33
(ULN), rapid clinical deterioration, new B symptoms, or involvement of Elevated LDHⴱ 7 7
unusual extranodal sites. Initial therapy
Limited state (n ⫽ 64)
Statistical Analysis RT alone 24 38
The primary end point was the time to development of a secondary ABVD or MOPP/ABV ⫾ RT† 38 59
DLBCL or transformation to aggressive lymphoma and was measured from Surgery alone 2 3
the initial pathologic diagnosis of NLPHL. Overall survival (OS) was calculated Advanced stage (n ⫽ 31)
from the date of diagnosis of NLPHL (or transformation to DLBCL) to the RT 2 6
date of last follow-up or death from any cause. Progression-free survival (PFS) ABVD or MOPP/ABV 23 74
was determined in patients with transformed lymphoma from the date of MOPP ⫹ RT 3 10
diagnosis of transformation to the date of relapse or progression of lymphoma Other 3 10
(including NLPHL) or death as a result of acute treatment toxicity. The
Kaplan-Meier method was used for calculation of survival and time to devel- Abbreviations: ECOG, Eastern Cooperative Oncology Group; LDH, lactate
dehydrogenase; RT, radiotherapy; ABVD, doxorubicin, bleomycin, vinblastine,
opment of transformation.19 Survival comparisons were performed using the
and dacarbazine; MOPP/ABV, mechlorethamine, vincristine, procarbazine,
log-rank test. Baseline characteristics between patient groups were compared prednisone doxorubicin, bleomycin, and vinblastine.
using the ␹2 test. Risk factors for development of transformation were analyzed ⴱ
LDH level is missing in 19 patients.
using univariate analysis. Multivariate analysis was performed using a Cox †Eight patients received chemotherapy alone.
proportional hazards model and forward selection including factors with a

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 Transformation of NLPHL to Aggressive Lymphoma

Patients with limited-stage NLPHL (n ⫽ 64) received radiother-

Table 2. Baseline Clinical Characteristics of Patients at the Time of
apy alone (1965 to 1993; n ⫽ 24) or chemotherapy ⫾ radiotherapy Transformation to Aggressive Lymphoma and Treatment Received
(1993 to 2006; n ⫽ 38). Two patients underwent surgery alone for
No. of
stage IA disease because the diagnosis of NLPHL was established Characteristic Patients %
retrospectively on pathologic rereview (Table 1). In the chemotherapy Time to transformation, years
treatment era, the exceptional patient with stage IA disease and high Median 8.1
neck node involvement received involved-field radiotherapy. Chem- Range 0.35-20.3
otherapy for limited-stage disease typically consisted of doxorubicin, Age at transformation, years
Median 42
bleomycin, vinblastine, and dacarbazine (ABVD), but four patients
Range 26-76
received mechlorethamine, vincristine, procarbazine, and prednisone
Diagnosis
(MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) or cyclo- DLBCL 8 62
phosphamide, vincristine, procarbazine, and prednisone/ABV.20 TCRBCL 2 15
The majority of patients with advanced-stage disease (n ⫽ 31) Aggressive lymphoma NOS 1 8
received chemotherapy (n ⫽ 29, 94%). Two patients received Clinical diagnosis 2 15
extended-field radiotherapy alone. Most patients received an ABVD- Male 10 77
Elevated LDH 9 69
like regimen (ABVD, n ⫽ 19; or MOPP/ABV, n ⫽ 4), and three
B symptoms 7 54
patients received MOPP followed by radiotherapy. Two elderly pa- Performance status ⱖ 2 10 77
tients (ⱖ 65 years old) received vincristine, doxorubicin, bleomycin, Any extranodal involvement 8 62
etoposide, and prednisone,21 and one patient received vinblastine, Liver 4 31
etoposide, cyclophosphamide, doxorubicin, bleomycin, vincristine, GI tract 3 23
and prednisone.22 Soft tissue 3 23
Bone 1 8
The 5- and 10-year PFS rates for the whole cohort of patients with
Splenic involvementⴱ 7 78
NLPHL were 85% and 73%, respectively, and the 5- and 10-year OS Stage III or IV disease 10 77
rates were 94% and 91%, respectively. In total, 16 patients have died, IPI score
and the most common cause of death was secondary NHL (n ⫽ 5, 0-2 3 23
31%). There was one toxic death as a result of febrile neutropenia 3-5 10 77
during therapy for NLPHL and no deaths as a result of refractory Treatment of prior NLPHL
ABVD or equivalent alone 7 54
NLPHL. The remaining causes of death were cardiac (n ⫽ 4), second-
Radiotherapy alone 5 39
ary malignancies other than NHL (n ⫽ 4), and other (n ⫽ 2). Surgery 1 7
Treatment at time of transformation
Transformation in NLPHL Rituximab combination 6 46
R-CHOP† 5
With a median follow-up time of living patients of 6.5 years
R-GDP ⫹ HDC/ASCT 1
(range, 2.5 to 32 years), 13 patients (14%) experienced transformation CHOP (CHOP-like) 3 23
to aggressive lymphoma have (Table 2). The median time to transfor- ICE ⫹ HDC/ASCT 1 8
mation was 8.1 years (range, 0.35 to 20.3 years; Table 2). Ten patients Palliative chemotherapy or
had a pathologic diagnosis of DLBCL (DLBCL, n ⫽ 8; T-cell–rich supportive care 3 23

B-cell lymphoma [TCRBCL], n ⫽ 2), and in one patient, a fine-needle
aspiration was performed that demonstrated an aggressive B-cell lym-
phoma, but further subclassification was not possible as a result of
limited pathologic material. Clinically, the latter patient had an
LDH ⱖ 4⫻ ULN and rapid clinical deterioration. In two patients, the
clinical picture suggested an aggressive transformation (LDH ⱖ 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.
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 ⱖ 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 in-
volvement based on computed tomography imaging or splenectomy
at the time of transformation. Of note, only one patient had experi-
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 dacar-
bazine; 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 trans-
plantation; CHOP, cyclophosphamide, doxorubicin, vincristine, and pred-
nisone; ICE, ifosfamide, carboplatin, and etoposide.
ⴱ
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.
enced 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

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 Al-Mansour et al

1.0 Table 3. Demographics and Clinical Characteristics of Patients With

NLPHL at Diagnosis Who Subsequently Developed Transformation to
0.9 Aggressive Lymphoma Compared With Patients Who Have Not
Developed Transformation
0.8
Non-
0.7 Transformed transformed
(n ⫽ 13) (n ⫽ 82)
Proportion

0.6
No. of No. of
0.5 Characteristic Patients % Patients % P
0.4 Age, years
++ ++ + + + + + +
+
Median 36 37 —
0.3
+ ⱖ 40 6 46 31 38 .566
0.2 Sex .709
+ +
++++++ +++
Male 10 77 59 72
0.1 +
+
+ + +++ +++
++ Female 3 23 23 28
+
Performance status .518
0 5 10 15 20 25 30 35 40 0/1 10 77 69 84
Time to Transformation (years) 2 3 8 13 16
Stage .012
Fig 1. Time to transformation in patients with nodular lymphocyte-predominant I or II 5 38 60 73
Hodgkin’s lymphoma. III or IV 8 62 22 27
Splenic disease ⬍ .00001
Yes 6 46 6 7
No 7 54 78 93
likely to have had advanced-stage disease and splenic involvement B symptoms .919
at the time of diagnosis of NLPHL (Table 3). In univariate analysis, Yes 7 54 75 92
splenic involvement at diagnosis of NLPHL (P ⫽ .006) was a strong No 6 46 7 8
LDH elevatedⴱ .099
risk factor for future transformation, and there was a trend toward
Yes 2 15 5 6
an increased risk with advanced-stage disease (P ⫽ .057; Table 4). No 11 85 58 71
In multivariate analysis, only splenic involvement (hazard ratio ⫽ Bulk ⱖ 5 cm† .708
4.18; 95% CI, 1.37 to 12.69; P ⫽ .012) was predictive of future Yes 3 33 20 27
development of transformed lymphoma in patients with NLPHL. No 6 67 53 73
Given the eras that this study spanned, a variety of therapies Abbreviations: NLPHL, nodular lymphocyte-predominant Hodgkin’s lympho-
were used at the time of transformation (Table 2). Most patients ma; LDH, lactate dehydrogenase.
ⴱ
Nineteen patients were missing LDH (n ⫽ 19 nontransformed).
received multiagent chemotherapy with curative intent, and three †Thirteen patients were missing mass size (n ⫽ 4 transformed;
patients received supportive care or palliative chemotherapy. Six pa- n ⫽ 9 nontransformed).
tients received rituximab-containing regimens (cyclophosphamide,
doxorubicin, vincristine, and prednisone [CHOP] plus rituximab [R-
CHOP]; n ⫽ 3; cyclophosphamide, doxorubicin, etoposide, and pred-
however, in many cases, the diagnosis of NLPHL was based on obso-
nisone plus rituximab; n ⫽ 2; and gemcitabine, dexamethasone, and
lete classification systems, and follow-up has been quite limited. Thus,
cisplatin plus rituximab; n ⫽ 2)23 followed by high-dose chemother-
little is known about the actuarial long-term risk and cumulative
apy (HDC) and autologous stem-cell transplantation (ASCT). Three
incidence of this occurrence in NLPHL with mature follow-up.
patients received CHOP or CHOP-like chemotherapy, and one pa-
The importance of pathologic rereview of older cases previously
tient received ICE ifosfamide, carboplatin, and etoposide24 followed
classified as NLPHL before the routine availability of immunohisto-
by HDC and ASCT. Nine patients (69%) achieved a complete remis-
chemistry cannot be overemphasized. The European Task Force study
sion, 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 develop-
Table 4. Univariate Analysis of Risk Factors for Transformation at
ment of transformation of 8.1 years (range, 0.34 to 20.3 years), the Diagnosis of NLPHL
10-year PFS and OS rates were 52% and 62%, respectively (Fig 2). Two
Clinical Feature P
patients in complete remission experienced relapse after 1.5 years with
Age ⱖ 40 years .556
aggressive lymphoma; one of the patients is alive on palliative chem-
Male sex .625
otherapy, and the other died as a result of the lymphoma. There were Performance status ⱖ 2 .522
no relapses after 2 years, including NLPHL (Fig 2). Stage III or IV disease .057
Splenic disease .006
B symptoms .913
DISCUSSION LDH elevated .526
Bulk ⱖ 5 cm .331
It has long been recognized that large-cell lymphoma can occur Abbreviations: NLPHL, nodular lymphocyte-predominant Hodgkin’s lympho-
either at diagnosis or as a subsequent relapse in patients with ma; LDH, lactate dehydrogenase.
NLPHL.10,11,16 The incidence has been reported to range up to 10%;

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 Transformation of NLPHL to Aggressive Lymphoma
1.0
Cumulative Survival (proportion)
0.9
0.8
0.7 ++
0.6 +++ + +
++ + +
0.5
0.4
0.3
0.2
0.1
0 2 4 6 8 10
Time (years)
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.
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 ei-
ther 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 predomi-
nance, early stage, and few adverse prognostic factors.26-28 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 devel-
oped 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, in-
dependent of stage, at the time of diagnosis of NLPHL emerged as a
strong risk factor for future transformation; this has not been previ-
ously 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 rela-
tively uncommon site in de novo DLBCL in which the frequency is
approximately 20%.30 It is possible that splenic disease reflects the
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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 lym-
+ +
phoma presented with advanced-stage disease and a high Interna-
tional 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 pa-
12 tients 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 lym-
phoma 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 ex-
pression 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 classifica-
tion 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 dis-
cordant 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 favor-
able 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 lym-
phoma but actually represent NLPHL, which, in turn, could ex-
plain the favorable prognosis in this group. Alternatively, some
patients may represent NLPHL in transition to large-cell lym-
phoma, 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 un-
derstand any prognostic differences.
Several cases in our study seemed to be related to TCRBCL.
The histologic similarities between NLPHL and TCRBCL and their
© 2010 by American Society of Clinical Oncology 797
 Al-Mansour et al

relationship have been previously well described.35 However, it is

unknown whether secondary TCRBCL represents clonal progres-
sion 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 con-
firms 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 impera-
tive 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.
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

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