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Review Article
Discordant bone marrow involvement in non-Hodgkin lymphoma
Jennifer Brudno,1,* Tamar Tadmor,2,3,* Stefania Pittaluga,4 Alina Nicolae,4 Aaron Polliack,5,† and Kieron Dunleavy1,†
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD; 2Hematology Unit, Bnai Zion Medical Center and
The Ruth and Bruce Rappaport Faculty of Medicine, Technion Haifa, Haifa, Israel; 4Hematopathology Section, Laboratory of Pathology, Center for Cancer
Research, National Cancer Institute, Bethesda, MD; and 5Department of Hematology, Hadassah University, Hospital and Hebrew University Medical
School, Jerusalem, Israel
3
A discordant lymphoma occurs where 2
distinct histologic subtypes coexist in at
least 2 separate anatomic sites. Histologic
discordance is most commonly observed
between the bone marrow (BM) and lymph
nodes (LNs), where typically aggressive
lymphoma is found in a LN biopsy with
indolent lymphoma in a BM biopsy. Although the diagnosis of discordance relied
heavily on histopathology alone in the
past, the availability of flow cytometry and
molecular studies have aided the identification of this entity. The true prevalence
and clinical ramifications of discordance
remain controversial as available data
are principally retrospective, and there is
therefore little consensus to guide optimal
management strategies. In this review,
we examine the available literature on discordant lymphoma and its outcome, and
discuss current therapeutic approaches.
Future studies in discordant lymphoma
should ideally focus on a large series of
patients with adequate tissue samples
and incorporate molecular analyses. (Blood.
2016;127(8):965-970)
Introduction
Bone marrow involvement (BMI) at diagnosis is present in the majority
of indolent B-cell lymphomas (BCLs), and in most studies is reported to
occur in ;10% to 15% of diffuse large BCL (DLBCL) cases.1,2 It is an
important clinical test and performed even when the likelihood of
involvement is low, as it may portend an inferior clinical outcome and
impact therapy selection.3 Although in most cases where BMI occurs,
histology is concordant among involved sites, “discordance” refers
to those lymphoma cases where the histology is distinctly different
between the bone marrow (BM) and other sites of involvement. It is
important to distinguish “discordant” from “composite,” where the
latter term refers to “lymphomas in which 2 or more distinct areas
of different histology can be appreciated in a single lymph node (LN)”
as opposed to these findings in separate anatomic sites as in the case
of “discordance.”4,5 Concordant and discordant clonality will also
be discussed here, but histologic discordance does not mandate
concordant clonality. In discussing “discordant” lymphomas, it is also
important to distinguish “discordance” from “transformation.” Transformed lymphomas are defined as indolent lymphoma cases that
undergo histologic transformation into aggressive lymphoma (usually
DLBCL) during the course of the disease. They include Richter
transformation or Richter syndrome, which describes cases of chronic
lymphocytic leukemia that transform into DLBCL or Hodgkin
lymphoma.6,7
There is a paucity of published experience on the biology,
diagnosis, treatment, and outcome of discordant lymphomas, and
data are mostly derived from single case reports and small retrospective studies.8-17 Consequently, the incidence, clinical behavior,
and optimal therapeutic approach to discordant lymphomas remain
controversial with little overall consensus. In this review, we analyze
the published literature on discordant non-Hodgkin lymphomas
(NHLs), with particular emphasis on DLBCL. The review of the
literature was performed by a search of the medical literature using
the PubMed database at www.pubmed.gov.
Submitted June 26, 2015; accepted December 14, 2015. Prepublished online
as Blood First Edition paper, December 17, 2015; DOI 10.1182/blood-201506-651968.
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
Diagnosis of discordant lymphoma
The diagnosis of discordant lymphoma is based on histologic
appearances but is challenging for the pathologist because no minimal
criteria to define discordance are rigorously established and/or uniformly used.1,18 Although morphology is the cornerstone of diagnosis,
the immunophenotypic and molecular characteristics of the lymphoma
subtype may be helpful in diagnosing discordance. Although BMI of
any histologic type has been found in an estimated 11% to 33% of
patients with aggressive BCLs, BMI with indolent NHL (discordance)
has ranged from between 5% to 24% in the limited studies that have
been performed (Table 1).1,2,4,19-22 Interestingly, in the post-rituximab
era, the incidence of discordance is reported to be less and 2 recent
analyses report indolent BMI with nodal DLBCL in 5% and 7% of
cases. This may reflect a reduction in the widespread use of bilateral BM
biopsies over time, and a resulting decreased detection of discordant
disease.2,21 Additionally, the definition of discordance has become
more refined with the availability of more sensitive methods for identifying lymphomatous involvement. Specifically, there are now improved immunohistochemical techniques as well as wider availability
of flow cytometry and polymerase chain reaction (PCR) to test for
clonality of B cells, and this has resulted particularly in the easier
identification of benign lymphoid aggregates.
Despite the availability of these technologies in recent times,
few studies have focused on the clonal relationship of discordant
lymphomas.23 Chigrinova et al performed genomic profiles using
high-density genome-wide single nucleotide polymorphism–based
arrays on 27 biopsies and predicted prognosis based on BMI, the
presence of specific cytogenetic aberrations, and the diagnosis of
concordant vs discordant histology. Samples with concordant BMI
had a distinct genetic profile, with low frequency gains of chromosome
7 or loss of 6q. There were too few cases of discordant BMI to
determine if the group had a significantly different molecular profile
*J.B. and T.T. contributed equally to this study.
†A.P. and K.D. contributed equally to the study.
965
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966
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
BRUDNO et al
Table 1. Discordant indolent BMI in patients with DLBCL
# of patients with any
# of patients with
Reference lymphomatous BMI (%) discordant BMI (%)
Treatment
Prognostic significance of discordant vs
concordant disease
25
22 (28%)
11 (14%)
CHOP, CVP, M-BACOD, and MACOP-B
2 y OS of 36% in discordant disease vs 11% in
4
43 (29%)*
21 (14%)*
Chlorambucil/vincristine/prednisone, or CAP-BOP Superior OS with discordant disease compared with
22
50 (N/A)
19 (N/A)
Anthracycline-based regimens
5 y OS of 79% with discordant disease vs 12% with
19
20 (34%)
14 (24%)
proMACE/MOPP, proMACE/cytaBOM, CHOP,
Mean OS of 47.7 mo in discordant disease vs 13.1 mo in
23
N/A
21 (N/A)
Unknown chemotherapy regimens 6 radiation
32
72 (16%)
18 (4%)
Not described
Not assessed
20
47 (27%)
34 (20%)
CHOP or CHOP-like regimens
Superior PFS and OS with discordant disease compared
concordant disease
concordant disease (P 5 .05)
concordant disease (P 5 .002)
CVP, M-BACOD, and COMLA
concordant disease (P , .05)
Not assessed
therapy
with concordant disease (P 5 .055 and .05,
respectively)
1
55 (11%)
26 (5%)
CHOP or CHOP-like regimens
5 y OS of 62% with discordant disease vs 10% with
2
125 (16%)
58 (7%)
R-CHOP
3 y PFS of 56% in discordant disease vs 37% in
concordant disease (multivariate P 5 .002)
concordant disease (multivariate P , .001); 3 y OS of
69% in discordant disease vs 49% in concordant
disease (multivariate P 5 .007)†
21
80 (13%)
32 (5%)
R-CHOP
3 y PFS of 57% in discordant disease vs 30% in
concordant disease (multivariate P , .001); 3 y OS of
64% in discordant disease vs 39% in concordant
disease (multivariate P 5 .011)†
CAP-BOP, cyclophosphamide-doxorubicin-procarbazine-bleomycin-vincristine-prednisone; COMLA, cyclophosphamide-vincristine-methotrexate-cytosine-arabinoside-leucovorin;
CVP, cyclophosphamide-vincristine-prednisone; M-BACOD, methotrexate-bleomycin-doxorubicin-cyclophosphamide-vincristine-dexamethasone; MACOP-B, methotrexatedoxorubicin-cyclophosphamide-vincristine-prednisone-bleomycin; N/A, not applicable or data not reported; OS, overall survival; PFS, progression-free survival; proMACE/CytaBOM,
cyclophosphamide-doxorubicin-etoposide-cytarabine-bleomycin-vincristine-methotrexate-leucovorin-trimethoprim-sulfamethoxazole; proMACE/MOPP, prednisone-methotrexateleucovorin-doxorubicin-cyclophosphamide-etoposide.
*For LN histology both DLBCL and immunoblastic lymphoma were included.
†Result controlled for IPI.
compared with patients without BMI.24 Kremer et al analyzed 21
cases of DLBCL with discordant BMI by PCR for immunoglobulin
(Ig) gene rearrangements and bcl-2 rearrangements with subsequent
sequencing in selected cases.23 To enrich for the tumor cells, laser
capture microdissection of formalin-fixed paraffin-embedded tissues
were used. Three of the original 19 histologically discordant cases
were excluded as they were found to be reactive lymphoid aggregates
on further review. A clonal relationship was identified in two-thirds
of discordant cases, with the remaining one-third exhibiting a different
clone. These data suggest that discordant BMI is overestimated, as a
subset of cases will be benign lymphoid aggregates and additionally,
a subset of discordant indolent disease found on BM biopsy will
be clonally related, suggesting transformation of the original indolent
neoplasm (Figure 1). Furthermore, it is unclear if the remaining patients
with non-clonally related lymphomas have particular risk factors for
developing two unrelated lymphomas, such as an underlying immunodeficiency. These interesting questions should prompt further investigation to better elucidate the clonal evolution and biology of discordance.
Impact of discordance on outcome
The prognostic significance of discordant disease in the pre-rituximab
era is limited by small sample sizes and the retrospective nature of the
analyses. However, some studies have shown that patients with
DLBCL and concordant BMI have an inferior OS compared with those
with discordant BMI (who interestingly have survival rates similar to
cases without lymphomatous BMI).4,19,25 In addition, a decrease in OS
has been observed when a greater proportion of large cells were present
in the marrow infiltrate.20,26 Interestingly, patients with concordant
histology had an inferior OS independent of the International Prognostic
Index (IPI), whereas those with discordant BMI had no significant
effect on survival even when accounting for IPI.1
The data regarding the rate of relapse following initial therapy in the
presence of discordant BMI are conflicting. In a small series of 13
patients with discordant BM histology, all documented recurrences
were of the original large cell lymphoma, rather than relapsed indolent
marrow disease. Six of 7 of these relapses occurred within the first
2 years after diagnosis.25 Conversely, others have reported that patients
with discordant marrow histology have a higher rate of late relapse, with
histology showing indolent disease in 7 of 10 relapsed patients. Over
half the cases with disease progression occurred more than 2 years after
diagnosis.22 At this point in the pre-rituximab era of therapy, it was
unclear whether a diagnosis of discordance truly implied a higher rate of
relapse, and if the relapse involved the aggressive or the indolent clone.
In the post-rituximab era, disparate outcomes of discordant and
concordant involvement are similar to in the pre-rituximab era. In
a recent retrospective analysis of patients with DLBCL receiving
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), those with concordant marrow involvement had a
worse OS and PFS than patients without BMI even after controlling for
IPI.2 In a univariate analysis, patients with discordant BMI had a
significantly worse PFS, but not OS, compared with patients with no
BMI. Discordant BMI was not an independent prognostic indicator
of either OS or PFS in this multivariate analysis when controlled for
IPI. Although these results are intriguing, it has been argued that this
particular study is limited by the lack of correlation with full gene
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BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
Figure 1. Discordant histology vs discordant clonality. For patients with DLBCL
at a nodal site, lymphomatous BMI may be either histologically concordant large
B-cell involvement or histologically discordant small B-cell involvement, which
suggests an indolent BCL involving the BM. Histologically discordant BMI may be
either clonally related or clonally unrelated to the nodal DLBCL with molecular
analysis.
expression profiling.27 Similarly, in the previously discussed analysis
of 133 patients with DLBCL treated with R-CHOP, concordant but not
discordant BMI also correlated with worse OS and PFS in a univariate
analysis, not controlling for IPI.24 A more recent study also showed that
concordant BMI was predictive of worse OS and PFS independent of
IPI score, whereas once again discordant BMI was not.21
In terms of patterns of relapsed disease in the post-rituximab era,
there is a clearer pattern of relapse, which is predominantly of the
aggressive large BCL rather than indolent disease. In 2011, Sehn
et al reported that the majority of patients with DLBCL having
discordant marrow involvement with relapsed disease had progression of the aggressive lymphoma rather than the indolent
lymphoma initially found in the marrow (92%; or 22 out of 24
patients), and in 88% of cases disease progression occurred in the
first 2 years after diagnosis.2 The above studies are summarized in
Table 1.
DISCORDANT NON-HODGKIN LYMPHOMA
967
lymphomatous involvement were reported.31 In a large series of 450
patients with NHL, including 345 cases with LN or other biopsy
material available to view, only 6 patients with FL on an
extramedullary biopsy specimen had DLBCL BMI by histology,
and no other discordant histologies were described.32 In a recent
British series of 345 patients with NHL for whom both LN and
BM biopsy were available, only 8 patients with FL were found to
have discordant marrow disease by histology, all of which were
classified as DLBCL.33
Discordant BMI in marginal zone lymphoma (MZL) appears to
be similarly infrequent. In a recent series, no cases of discordant
histology on BM biopsy of LN-diagnosed MZL or mantle cell
lymphoma were found.33 BM pathology was studied retrospectively by Boveri et al in 120 patients with nodal, extranodal, and
splenic MZL; prevalence of histologic BMI was 90% for splenic
MZL, 54% for nodal type, and 22% for extranodal MZL. In all these
subtypes, when BMI was found, the marrow showed similar
cytologic and immunophenotypic profiles to the original disease
site, suggesting that discordant BM histology is infrequent in this
subtype of NHL.34 As expected, concordant BMI was significantly
associated with more advanced Ann Arbor stage, presence of B
symptoms, presence of leukemic disease, higher number of nodal
and extranodal sites, and higher IPI and age-adjusted IPI. Twentyseven patients underwent repeat BM biopsy after diagnosis and 3
patients were then found to have discordant BM findings. Two
patients with previously negative BM biopsies showed a shift to
higher grade large BCL 12 and 6 years after diagnosis, and 1 patient
had a “myeloma” like infiltrate after receiving CHOP.34
Another possible rare presentation is the presence of 2 types of
indolent lymphomas diagnosed simultaneously from different sites.
Indeed, some case reports have described the diagnosis of mantle cell
lymphoma with MZL,35 or the association of mucosa-associated
lymphoid tissue lymphoma with FL.13,14
In summary, discordant BMI in indolent lymphomas has mostly
been described for FL, and even here the frequency appears to be low,
and mostly manifested as DLBCL on BM biopsy, probably indicative
of transformed disease.
Role of PET imaging as non-invasive evaluation
Discordant BMI in indolent BCL
Concordant BMI has long been known to predict worse survival
outcomes in patients with nodal follicular lymphoma (FL), as it
results in upgrading to an Ann Arbor stage of IV and thus a higher
FL IPI score.28 Concordant BMI has been estimated to occur in 40%
to 70% of patients with FL.29 In a study of discordant lymphomas
reported in 1995, 2 patients with FL thought to have discordant
lymphoma on BM biopsy were found to have bcl-2 gene rearrangements, suggesting the presence of FL in the marrow rather
than true discordance.30
Recently, in a Norwegian series of 96 patients with FL,
concordant BMI determined by Ig heavy and light chain gene
rearrangement analysis predicted worse survival, even when
present in the absence of histologically concordant BMI.29 No
cases of histologic discordance incidentally found on Ig chain
rearrangement PCR were reported, suggesting that clonally unrelated disease in the marrow is uncommon in FL. Similarly, in a
series of 91 patients with FL in which BMI was determined both
by histology as well as flow cytometry, no cases of discordant
A number of studies have suggested that fluorodeoxyglucose
(FDG) positron emission tomography (PET) can predict BMI with
high sensitivity in aggressive NHLs.36-40 In contrast, the literature
describing BMI in FL is more limited and suggests that PET is less
sensitive to detect concordant BMI by FL.41,42 In one study, only 13
of 24 patients with biopsy-proven BMI by FL had involvement by
PET evaluation, with PET findings suspicious for BMI being
defined as diffuse FDG uptake in hollow bones, pelvis, and spine or
diffuse uptake in hollow bones with focal uptake in spinal lesions.43
In another series, predominantly of patients with DLBCL, focal
areas of increased FDG uptake anywhere in the BM were considered
representative of disease. PET could not detect the established BMI
detected in the 4 cases with grades 1 to 2 FL.41 More recently, El-Najjar
et al, using a semi-quantitative analysis of PET images to assess BMI in
FL, showed an improved sensitivity (58% vs 31%) and specificity (96%
vs 92%) of detection when compared with visual inspection of the same
images by the radiologist.42
In a prospective analysis of 110 patients with newly diagnosed
DLBCL, 21 patients had a BM biopsy with evidence of lymphoma
(7 concordant and 14 discordant). Six of the 7 patients with concordant
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968
BRUDNO et al
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
PET scan is interpreted as negative for BMI. It is important to note
that the interpretation of the above studies is limited by the
heterogeneity in criteria used for PET positivity of the BM, with
some using comparison with normal liver uptake and others using
other subjective assessments.
Based on all the above and additional reports that support the
role of PET-CT in the diagnosis of BMI, updated guidelines have
recently been published by Cheson et al.47-50 According to these
recommendations, a BM biopsy is no longer indicated for the
routine staging of most DLBCL, if the PET-CT is negative for BMI.
However, in DLBCL cases with discordant BMI, FDG-PET avidity
of indolent lymphoma in the marrow may be very low and not detect
discordant disease. Therefore, in select cases where discordance is
suspected, cytopenias are found, or as part of clinical trials BM
biopsies should be performed even in the presence of negative
FDG-PET findings (Figure 2).
Therapeutic approach to discordant
lymphomas
Figure 2. Approach to the diagnosis of discordant lymphoma. In the staging
of DLBCL, a BM biopsy should be performed if there is increased PET-FDG
uptake or for other clinical reasons such as the presence of cytopenias. If
discordant indolent lymphoma is diagnosed in the BM, clonality studies should be
considered if available. In contrast to concordant BMI in DLBCL, studies suggest
that discordant involvement (with indolent disease in the BM) is not associated
with an increased risk of CNS disease.
BMI also had abnormal PET uptake, defined as at least one focus of
moderate or intense FDG uptake in a BM territory using a 3-point
system (1 5 low, 2 5 moderate, and 3 5 high). Conversely, only 4 of
14 patients with discordant involvement were PET positive. These
results suggest that PET can be helpful in predicting concordant BMI. It
is less clear if PET has any utility in predicting discordant BMI. Unlike
in previous studies, in this study there was no difference in survival
between patients with concordant or discordant involvement, possibly
in part due to the small sample size.44
A multinational study of 327 patients with DLBCL who
underwent PET and BM biopsy at diagnosis, in which PET
positivity was defined as focal BM FDG uptake greater than liver
uptake, revealed that only 10 of 241 patients with BM negativity
by PET had BM biopsy positivity for lymphoma.45 Two cases
were discordant and 8 were concordant. Interestingly, 6 of the
concordant cases demonstrated ,10% tumor cells in the BM,
presumably limiting detection on PET imaging. In a multivariate
analysis, BMI detected by both PET and biopsy was associated with
a significant decrease in OS. This effect was not seen with BMI
detected either by BM biopsy or PET alone, suggesting that BMI
identified by PET has independent prognostic value. Therefore, the
authors hypothesize that PET scans, which preferentially detect
concordant large cell BMI, are more specific indicators of poor
prognosis disease in the marrow.
Finally, a meta-analysis of 7 studies, including 654 patients
with newly diagnosed DLBCL, showed that FDG-PET computed tomography (CT) had a pooled estimate of 88.7% sensitivity and 99.8% specificity.46 This study further supports the view
that a BM biopsy positive for lymphoma, whether concordant or
discordant, does not change the management of a patient if the
There are no randomized trials or prospective studies addressing specific
treatments for either nodal DLBCL with discordant indolent BMI or
indolent nodal lymphomas with discordant aggressive lymphoma BMI.
The majority of patients with DLBCL and discordant BMI with indolent
lymphoma on biopsy are treated with anthracycline-based regimens,
such as R-CHOP. As referenced above, most retrospective analyses
demonstrate that the presence of indolent BMI does not affect prognosis for patients treated with aggressive immunochemotherapy. If discordant aggressive lymphoma is found on BM biopsy of a patient with
indolent nodal lymphoma, anthracycline-based treatment directed at the
aggressive histology is typically used but again this has been poorly
studied. Although a majority of histologically discordant lymphomas
in the BM are clonally related to the LN histology, a reasonable therapeutic approach is to target the aggressive histology, as described in
retrospective series (Figure 2).1,2,4,5,19-22,25 The role of upfront autologous stem cell transplant following first remission in transformed lymphomas has not been well established and there is no data assessing its
role in discordant cases.51,52
An increased risk of central nervous system (CNS) involvement and
CNS relapse in newly diagnosed patients with DLBCL who have
concordant BMI has been well described,53-55 and therefore cerebrospinal fluid sampling for lymphomatous involvement and prophylactic
CNS-directed therapy are common practice.56,57 In contrast, discordant
indolent BMI in patients with nodal DLBCL has not been associated
with an increased risk of CNS involvement/relapse and should not
mandate cerebrospinal fluid sampling in the absence of other high-risk
characteristics.2,19,22,25
Conclusion/summary
In summary, concordant BMI with DLBCL portends a worse outcome
and inferior OS compared with cases without BMI. In contrast, and
importantly, recognizing that this is a poorly studied area with a lack of
large or prospective data, discordant BMI with an indolent BCL in
newly diagnosed DLBCL does not appear to impact negatively on
prognosis. Although FDG-PET is a helpful tool in the diagnosis of
concordant BMI in DLBCL, it is probably much less sensitive in
detecting discordant BMI. Extrapolating from the limited number of
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BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
studies that have looked at Ig gene rearrangements in these cases, a high
proportion of histologically discordant lymphomas appear to be clonally related.23 The molecular biology of discordance has been poorly
studied and should be a focus of future studies in this area that aim at
defining optimal approaches for these diseases.
Acknowledgments
There were no funding sources for the preparation of this manuscript.
DISCORDANT NON-HODGKIN LYMPHOMA
969
Authorship
Contribution: All authors were involved in preparing the manuscript,
data analysis, and writing of the manuscript.
Conflict-of-interest disclosure: J.B. and K.D. received funding
from the Intramural Program of the National Cancer Institute. The
remaining authors declare no competing financial interests.
Correspondence: Kieron Dunleavy, Lymphoid Malignancies
Branch, National Cancer Institute, Building 10, Room 4N-115, 9000
Rockville Pike, Bethesda, MD 20892; e-mail: [email protected].
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From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
2016 127: 965-970
doi:10.1182/blood-2015-06-651968 originally published
online December 17, 2015
Discordant bone marrow involvement in non-Hodgkin lymphoma
Jennifer Brudno, Tamar Tadmor, Stefania Pittaluga, Alina Nicolae, Aaron Polliack and Kieron
Dunleavy
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