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NEOPLASIA
Concordant but not discordant bone marrow involvement in diffuse large B-cell
lymphoma predicts a poor clinical outcome independent of the International
Prognostic Index
Randy Chung,1,4 Raymond Lai,2,4 Peter Wei,1,4 Jason Lee,1,4 John Hanson,3 Andrew R. Belch,1,4 A. Robert Turner,1,4
and Tony Reiman1,4
1Department
of Medical Oncology, 2Department of Pathology, 3Department of Epidemiology, Cross Cancer Institute; and 4Faculty of Medicine and Dentistry,
University of Alberta, Edmonton, AB, Canada
In diffuse large B-cell lymphoma (DLBCL),
previous studies have suggested that, while
concordant bone marrow (BM) involvement
confers a poor prognosis, discordant BM
involvement does not. Whether this correlation is independent of the non-Hodgkin lymphoma International Prognostic Index (IPI)
was previously unknown. We reviewed all
DLBCL case histories from 1986 to 1997 at
our center with complete staging, IPI data,
and follow-up. A total of 55 (11.2%) of 489
patients had BM involvement, including 29
with concordant involvement and 26 with
discordant involvement. The 55 patients with
BM involvement had a poor prognosis compared with the uninvolved BM group (5-year
overall survival [OS], 34.5% versus 46.9%;
log-rank P ⴝ .019). However, concordant involvement portended a very poor prognosis
(5-year OS, 10.3%; P < .001), whereas discordant involvement did not (5-year OS, 61.5%,
P value nonsignificant). Compared with the
discordant subset, the concordant subset
patients were older, had a higher serum
lactate dehydrogenase level, and a significantly higher IPI. However, the poor survival
associated with concordant BM involvement was independent of the IPI score
(P ⴝ .002, Cox regression). We conclude
that in patients with DLBCL, concordant but
not discordant BM involvement confers a
very poor clinical outcome. Furthermore,
concordant BM involvement is an independent adverse prognostic factor. (Blood. 2007;
110:1278-1282)
© 2007 by The American Society of Hematology
Introduction
Bone marrow (BM) involvement in diffuse large B-cell lymphoma
(DLBCL) is often discordant, characterized by a BM infiltrate
composed of small lymphoid cells with cleaved nuclear contours
admixed with only rare large transformed lymphoid cells,
morphologically suggestive of a coexisting low-grade lymphoma.1-5 The mechanism for the morphologic discordance
remains unclear but may involve transformation of a low-grade
non-Hodgkin lymphoma, or alternatively the presence of 2 unrelated B-cell neoplasms.6 This is in contrast to DLBCL with
concordant BM involvement, where the marrow lymphoid
infiltrates are composed of a prominent component of large
transformed lymphoid cells. Various groups have shown that
concordant BM involvement carries a poor prognosis, whereas
discordant BM involvement does not.1-5 Interestingly, discordant BM involvement in large-cell lymphoma may be associated
with higher rates of late relapse.3
The non-Hodgkin lymphoma International Prognostic Index
(IPI) is a powerful tool for predicting clinical outcome in patients
with aggressive non-Hodgkin lymphoma on the basis of clinical
criteria, including age, stage, extranodal site involvement, lactate
dehydrogenase (LDH) level, and performance status.7 Most of the
previous studies examining prognosis in DLBCL with BM involvement were small and predated the introduction of the IPI, thus
making interpretation difficult. Therefore, until now it has remained unclear whether concordant BM involvement in DLBCL is
independent of the IPI in terms of survival prediction.
The intent of the present study was to examine the prognostic
impact of concordant versus discordant BM involvement in
DLBCL while controlling for the IPI. We have found that DLBCL
with concordant BM involvement carries a poor prognosis that is
independent of the IPI, whereas discordant BM involvement does
not confer poor prognosis.
Patients, materials, and methods
Patient population
A total of 624 consecutive patients with DLBCL initially diagnosed from
1986 to 1997 at the Cross Cancer Institute (Edmonton, AB, Canada) were
reviewed. Of these, 489 patients had complete clinical and pathologic data
for analysis and were therefore included in this study. Clinical data included
staging according to the Ann Arbor system and scoring using the IPI
criteria. All patients in our series were evaluated with history and physical
examination, computed tomography (CT) scanning, complete blood count
(CBC), LDH, serum biochemistry including liver enzymes and renal
function, and BM biopsy. Some patients also had plain radiographs,
lymphangiography, ultrasound, magnetic resonance imaging (MRI), bone
scans, lumbar puncture, or other investigations as clinically indicated.
Treatment protocols during this time period were in keeping with international standards and generally included intensive combination chemotherapy regimens (CHOP [cyclophosphamide/doxorubicin/vincristine/
prednisone ]–like regimens) for front-line therapy, and salvage chemotherapy
followed by autologous stem-cell transplantation. Institutional Review
Board approval for this study was granted by the Alberta Cancer Board
Submitted January 29, 2007; accepted April 20, 2007. Prepublished online as
Blood First Edition paper, May 2, 2007; DOI 10.1182/blood-2007-01-070300.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
The publication costs of this article were defrayed in part by page charge
© 2007 by The American Society of Hematology
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BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
MARROW INVOLVEMENT IN DLBCL AND OUTCOME
Research Ethics Committee. Informed consent was obtained in accordance
with the Declaration of Helsinki.
1279
were compared with the log-rank test. Cox regression was used to assess the
contribution of BM involvement to prognosis. Statistical significance was
set at a P value of .05 or less (2-sided).
Determination of BM involvement
All BM biopsy samples were reviewed in this study by a hematopathologist
(R.L.) for the presence or absence of BM involvement, extent of infiltration,
and histology of the lymphoid infiltrates (ie, discordant versus concordant
marrow involvement). The criteria used to distinguish benign lymphoid
infiltrates from lymphomatous involvement have been described in detail
elsewhere.8 Determination of the histology of the lymphoid infiltrates was
adopted and modified from a previously published method,3 which defined
BM involvement as small-cell type, mixed-cell type, and large-cell type
using the criteria of less than 5, 5 to 15, and more than 15 large, noncleaved
cells per high-power field, respectively, in a background of small cleaved
cells. Since our initial analysis revealed that patients with the mixed-cell
type of BM involvement were relatively uncommon and were similar
prognostically to those with large-cell involvement, we combined patients
with the mixed-cell type and large-cell type in 1 group. Thus, in this study,
we defined concordant marrow involvement when there were less than
5 large, noncleaved cells per high-power field, and discordant marrow
involvement when there were 5 or more large, noncleaved cells per
high-power field. The extent of the marrow involvement was estimated
based on the proportion of marrow space occupied by the neoplasm.
Statistical analysis
Univariate correlations between BM involvement and other known prognostic factors were examined at the time of diagnosis. Student t test, Fisher
exact test, or the chi-squared test was used as appropriate. Overall survival
(OS) was determined from the date of initial diagnosis until death from any
cause or to last follow-up evaluation for survivors. Survival curves were
constructed using the Kaplan-Meier method, and survival distributions
Results
Patient characteristics and prevalence of BM involvement
For the 489 patients with DLBCL who had complete data, median
follow-up was 995 days. A total of 55 (11.2%) had BM involvement. Of these 55 patients, 29 (52.7%) had concordant BM
involvement (including 9 with mixed-cell type and 20 with
large-cell BM involvement) and 26 (47.3%) had discordant BM
involvement. Table 1 summarizes the clinical characteristics for
each of these 2 groups. Patients with concordant BM involvement
(mean, 68.3 years; range, 41-92 years) were older than patients
without BM involvement (mean, 60.4 years; range, 3-94 years) and
were also older than patients with discordant BM involvement
(mean, 60.3 years; range, 41-85 years). Patients with BM involvement had higher IPI scores because both stage and extranodal site
scores reflect BM involvement, but also because LDH elevation
was more prevalent in this group compared with the BM-negative
group. There was no significant difference in sex, age, and Eastern
Cooperative Oncology Group (ECOG) performance status between
the BM-involved versus BM-uninvolved groups. Patients with
concordant BM involvement were older (P ⫽ .05) and more often
had elevated LDH levels (P ⫽ .008) and higher IPI scores
(P ⬍ .001) than patients with discordant BM involvement. No
significant difference was noted for sex, stage, extranodal sites, and
Table 1. Comparison of clinical features in the BMⴚ, BMⴙ, concordant BMⴙ, and discordant BMⴙ groups
Clinical features
BMⴚ, n ⴝ 434
BMⴙ, n ⴝ 55
Concordant BM involvement, n ⴝ 29
Discordant BM involvement, n ⴝ 26
Sex
Male, no. (%)
231 (53.2)
25 (45.5)
11 (37.9)
14 (53.8)
Female, no.
203
30
18
12
60 y and younger, no. (%)
183 (42.2)
19 (34.5)
Older than 60 y, no.
251
36
Age
6 (20.7)*
23
13 (50)†
13
Stage
1-2, no. (%)
261 (60.1)
3-4, no.
173
55
0 (0)‡
29
0 (0)*
26
0 (0)
1-2, no. (%)
261 (60.1)
38 (69.1)
19 (65.5)
19 (73.1)
3-4, no.
173
17
10
386 (88.9)
33 (60.0)‡
16 (55.2)*
22
13
51 (92.7)
25 (86.2)
Stage, excluding BM status
7
Extranodal sites
0-1, no. (%)
2 or more, no.
48
17 (65.4)
9
Extranodal sites, excluding BM
0-1, no. (%)
2 or more, no.
386 (88.9)
48
4
4
26 (100)
0
LDH
Normal, no. (%)
219 (50.5)
19 (34.5)‡
Elevated, no.
215
36
23
6 (20.7)*
13 (50)†
13
380 (87.6)
45 (81.8)
22 (75.9)
23 (88.5)
ECOG score
0-1, no. (%)
2-4, no.
54
10
7
3
IPI score, no. (%)
Low (0-1)
203 (46.8)
2 (3.6)
Intermediate (2-3)
198 (45.6)
41 (74.5)
High (4-5)
33 (7.6)
12 (21.8)‡§
0 (0)
20 (70.0)
9 (31.0)*§
*Statistically significant difference between concordant BM and BM-negative groups (P ⬍ .05).
†Statistically significant difference between discordant BM and concordant BM groups (P ⬍ .05).
‡Statistically significant difference between BM-positive and BM-negative groups (P ⬍ .05).
§Significant differences between 2 groups regarding IPI status were determined using 3 ⫻ 2 tables and the chi-squared test.
2 (7.7)
21 (80.8)
3 (11.5)†§
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1280
BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
CHUNG et al
100
100
BM negative
BM positive
< 15%
15% +
90
80
80
70
70
Percent Survival
Percent Survival
90
60
50
40
60
50
40
30
30
20
20
10
10
0
0
0
24
48
72
96
120
144
168
192
216
0
24
48
72
96
120
144
168
192
216
Months
Months
Figure 1. Kaplan-Meier survival curves comparing BM-negative versus BMpositive groups.
Figure 3. Kaplan-Meier survival curves comparing patients by extent of BM
involvement.
performance status between these 2 groups. Table 1 also includes
an assessment of stage that excludes the BM status, and a tabulation
of the number of extranodal sites other than the marrow; for both of
these modified parameters, there was no significant difference
among the groups.
Multivariate analysis incorporating IPI
Prognostic significance of BM involvement
BM involvement predicted poor survival compared with the
uninvolved BM group (5-year OS, 34.5% versus 46.9%; log-rank
P ⫽ .019; Figure 1). Importantly, concordant BM involvement
portended a very poor prognosis relative to patients without BM
involvement (5-year OS, 10.3%; log-rank P ⬍ .001) whereas
discordant BM involvement did not (5-year OS, 61.5%; log-rank
P value nonsignificant; Figure 2).
Extensive BM involvement was found to be a highly
significant negative prognostic factor. For the purposes of this
analysis, we defined extensive BM involvement at 15% and
higher because this cutoff was most prognostically significant in
our patient cohort on univariate analysis (5-year OS, 15.0%
versus 45.7%; log-rank P ⫽ .002; Figure 3). The concordant
subset had more patients with extensive BM involvement when
compared with the discordant subset (51.7% versus 19.2%;
P ⫽ .01; Table 2).
100
Negative
Discordant
Concordant
90
80
Percent Survival
70
The IPI was predictive of OS, with low (0-1), low-intermediate
(2), high-intermediate (3), and high (4-5) risk groups having
5-year survivals of 64.7%, 38.2%, 24.3%, and 26.7%, respectively (Figure 4). Patients with concordant BM involvement had
higher IPI scores compared with patients without BM involvement (P ⬍ .001), partly by definition and partly owing to their
aforementioned older age and increased LDH levels (Table 1).
To clarify the impact of concordant BM involvement, multivariate analysis was carried out to control for IPI. A Cox regression
model of OS was constructed including IPI and BM status as
covariates. Based on this analysis, concordant BM involvement
was a negative prognostic feature independent of the IPI score
(hazard ratio compared with BM-negative patients ⫽ 1.87; 95%
confidence interval [CI], 1.25-2.81; P ⫽ .002).
Discussion
We found that the prognostic significance of BM involvement in
DLBCL is dependent on the morphologic cell type at this site.
Whether this correlation is independent of the IPI was previously
unknown. Of the published studies examining the prognostic
significance of concordant versus discordant BM involvement in
large-cell lymphoma, it is worth noting that the analysis of some
studies included patients with various types of aggressive lymphoma in addition to DLBCL, and that the number of such patients
in each series was relatively small, ranging from 50 to 180 patients.1-5 In addition, most of these papers were published in the era
preceding the development of the IPI; the 1 paper in the post-IPI era
60
Table 2. The extent of BM involvement in concordant versus
discordant BM groups
50
40
30
20
Concordant BM
involvement,
n ⴝ 29
Discordant BM
involvement,
n ⴝ 26
14 (48.3)
21 (80.8)*
15 (51.7)
5 (19.2)
Minimal extent of BM involvement
10
⬍ 15%, no. (%)
0
0
24
48
72
96
120
144
168
192
216
Months
Figure 2. Kaplan-Meier survival curves comparing BM-negative, BM-discordant,
and BM-concordant groups.
Extensive BM involvement ⱖ 15%,
no. (%)
*Statistically significant difference between concordant and discordant BM
groups (Fisher exact test, P ⬍ .05).
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BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
100
MARROW INVOLVEMENT IN DLBCL AND OUTCOME
0-1
2-3
4-5
90
80
Percent Survival
70
60
50
40
30
20
10
0
0
24
48
72
96
120
144
168
192
216
Months
Figure 4. Kaplan-Meier survival curves for patients stratified by IPI.
included only 60 patients, and the authors recommended confirmation in a larger series.2
The IPI was originally defined and published in 1993 based on
mathematical modeling of candidate prognostic factors in 2031 patients with de novo, diffuse aggressive lymphoma.7 BM involvement was considered for inclusion in the IPI (and ultimately
rejected based on multivariate analysis), but the definitive study on
this topic did not report on the extent to which the BM biopsies
from these patients were reviewed.7 Despite the fact that it was
intended to report only on patients with de novo aggressive
lymphoma in the original IPI study, it remains possible that many
of those patients had discordant BM involvement. This seems
likely, given that the proportion of patients in that study reported to
have BM involvement was 22%. In our present series, 11% of
patients had BM involvement, and only half of these patients had
concordant BM involvement. Even at our own center, the concordance or discordance of the marrow involvement was not routinely
reported, particularly in the 1980s and early 1990s, and it was only
upon direct review of the archived BM specimens that we were
able to determine which cases of BM involvement were concordant
or discordant.
We chose to study patients from the era prior to the introduction
of rituximab in the treatment of DLBCL, and patients in our series
received treatment that was comparable to the treatment given to
patients in the original 1993 IPI study. We do not yet have enough
follow-up on patients at our center treated with rituximabcontaining regimens to make a determination of the prognostic
impact of BM involvement in these patients, which are expected to
have improved outcome relative to the patients reported here.9
The IPI was able to discriminate subgroups of patients with
differing prognosis in our study, reaffirming the utility of the IPI in
the evaluation of patients with DLBCL. Our 5-year OS estimates
for the patient subgroups defined by the IPI are comparable to those
cited in the original 1993 IPI study and confirmed by others.7,10,11
Despite the strong correlation between the presence of marrow
involvement and IPI score, multivariate analysis revealed that
concordant BM involvement is a negative prognostic factor
independent of the IPI. Therefore, the presence of concordant BM
involvement should be considered in the evaluation of prognosis of
patients with DLBCL in addition to the IPI.
Interestingly, extensive (ⱖ 15%) BM involvement was more
often seen with concordant rather than discordant BM involvement.
Therefore, when extensive BM involvement is present, there
should be heightened concern that concordant BM involvement is
also present, and vice versa.
1281
Of 489 patients with DLBCL, 55 (11.2%) had BM involvement. Others have reported BM involvement rates in their
diffuse large-cell lymphoma population studies between 17%
and 33%.1,5,7 This discrepancy may reflect differences in study
populations, or variations in biopsy sampling and reporting
methods. Our population represents the vast majority of patients
DLBCL from our geographic region that underwent BM biopsy
at a single institution for staging purposes. Therefore, there may
be less selection bias in our study compared with previous
reports that are referral population based. Importantly, most
previously reported series included aggressive lymphomas other
than DLBCL in the analysis, which may have affected the rate of
marrow positivity in those studies.
Our study has potential limitations. At our center, BM
biopsies are routinely unilateral, which might have reduced the
sensitivity of the test for the detection of marrow involvement.
This was a retrospective study that included patients from the
era prior to the introduction of the IPI, and so not all patients
during this time period had complete data for inclusion in our
study. We did not have reliable information on the rates of
relapse or causes of death in all patients, and so we could not
compute relapse-free survival or cause-specific mortality. This
is a single-institution study that may not completely reflect the
experience of other centers. Despite these limitations, the
findings from this large study are statistically robust and
consistent with prior, smaller studies in its findings.
In summary, we found that concordant BM involvement with
large cells in DLBCL is a negative prognostic feature that is
independent of the IPI, although the 2 parameters are correlated.
Identification of large cells in the BM is often associated with
extensive BM involvement. On the other hand, discordant BM
involvement had no adverse effect on survival in our study.
These findings are confirmed here in a large series of patients
and should be considered when assessing patient prognosis and
when considering inclusion criteria for clinical trials. Future
studies will address the impact of rituximab on the poor
prognosis associated with BM involvement, and on the relationship between BM involvement and newer, molecular predictors
of clinical outcome.10,11
Acknowledgment
This work was supported by a Clinical Investigator award from the
Alberta Heritage Foundation for Medical Research (T.R.).
Authorship
Contribution: R.C. and T.R. contributed to study design, analysis,
and writing. R.L. contributed to study design and analysis, and
performed the pathology reviews. P.W. and J.L. contributed to
study design and data collection/analysis. J.H. contributed to study
design and statistical analysis. A.R.B. and A.R.T. treated many of
the patients in this study and contributed to the analysis and
interpretation of the data. All authors checked the final version of
the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Tony Reiman, Cross Cancer Institute, 11560
University Ave, Rm 2229, Edmonton, AB, Canada T6G 1Z2;
e-mail: [email protected].
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CHUNG et al
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2007 110: 1278-1282
doi:10.1182/blood-2007-01-070300 originally published
online May 2, 2007
Concordant but not discordant bone marrow involvement in diffuse
large B-cell lymphoma predicts a poor clinical outcome independent of
the International Prognostic Index
Randy Chung, Raymond Lai, Peter Wei, Jason Lee, John Hanson, Andrew R. Belch, A. Robert
Turner and Tony Reiman
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