review
How I manage patients with grey zone lymphoma
Athena Kritharis,1 Monika Pilichowska2 and Andrew M. Evens1
1
Division of Hematology/Oncology, Tufts Medical Center, and 2Department of Pathology, Tufts Medical Center, Boston, MA, USA
Summary
Since grey zone lymphoma (GZL) was originally included in
the 2008 World Health Organization classification as a B-cell
lymphoma unclassifiable with features intermediate between
diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin
lymphoma (cHL), new biological and clinical knowledge have
been learned. It is important to highlight that diagnosis of this
entity is complex and involvement by haematopathologists
with expertise in this disease is recommended. It is recognized
now that patients with GZL may present clinically with pri-
mary mediastinal localization or systemic disease without
mediastinal involvement. Regardless of clinical presentation,
patients with GZL have relatively high relapse rates, especially
compared with primary mediastinal DLBCL or cHL. Interest-
ingly, relapsed/refractory GZL patients appear to be salvaged
fairly successfully, especially with haematopoietic stem cell
transplantation (HSCT). Off of a clinical trial, we recommend
R-CHOP (rituximab, cyclophosphamide, doxorubicin,
oncovin, prednisolone) or dose-adjusted EPOCH-R (etopo-
side, prednisolone, oncovin, cyclophosphamide, doxorubicin,
rituximab) for frontline treatment of GZL. Additionally, we
advocate use of consolidative radiotherapy for localized and/or
bulky disease. For patients with relapsed/refractory GZL, sal-
vage chemotherapy followed by consolidative autologous
HSCT should be considered. Finally, continued biological and
pathologic examination of this unique disease entity is war-
ranted as well as exploration towards the integration of tar-
geted therapeutic agents (e.g., brentuximab vedotin,
programmed cell death 1inhibitors, B-cell receptor inhibitors,
proteasome inhibitors, etc.) into the treatment paradigm of
GZL.
Keywords: Grey/gray zone lymphoma, classical Hodgkin
lymphoma, diffuse large B-cell lymphoma, prognosis,
treatment.
Grey zone lymphoma (GZL) is a disease entity that was first
recognized in the World Health Organization (WHO)
Correspondence: Dr. Andrew M. Evens, Professor of Medicine and
Chief, Division of Hematology/Oncology, Tufts Medical Center, 800
Washington Street, Boston, MA 02111, USA.
E-mail: AEvens@tuftsmedicalcenter.org
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 174, 345–350
classification in 2008 as a B-cell lymphoma, unclassifiable,
with features intermediate between diffuse large B-cell lym-
phoma (DLBCL) and classical Hodgkin lymphoma (cHL)
(Swerdlow et al, 2008). Collectively, there has been increasing
knowledge learned regarding clinical data of GZL, especially
the non-mediastinal systemic subtype. Although initially
described as primarily involving the mediastinum (Garcia
et al, 2005; Traverse-Glehen et al, 2005; Grant et al, 2011),
further analyses have identified both primary mediastinal and
non-mediastinal disease presentations of GZL (Evens et al,
2015).
Mediastinal GZL (MGZL) is similar clinically in presenta-
tion to cHL and primary mediastinal B-cell lymphoma
(PMBCL), as it typically occurs in young adults in the third
and fourth decade. Conversely, patients with non-mediastinal
GZL (NMGZL) are typically older and more often present
with advanced-stage disease. Furthermore, unlike cHL and
PMBCL, MGZL and NMGZL both have a more aggressive
clinical course with comparatively inferior outcomes. Given
its relatively new recognition and general paucity of associ-
ated clinical data, additional description of GZL management
is warranted. The following is a detailed review of the litera-
ture and description of the diagnosis, biology, prognosis, and
treatment of GZL.
Biology
Grey zone lymphoma is thought to arise from a common
precursor (e.g., thymic B-cell), which partly explains why
cHL, PMBCL or GZL may relapse as the other related entity
(Dunleavy & Wilson, 2015). The exact mechanism for trans-
formation of the B-cell is not known. Interestingly, gene
expression signatures of PMBCL and cHL are similar, as are
numerous genetic abnormalities, such as gains in chromo-
some 9p and 2p (Eberle & Jaffe, 2011). However, as GZL
may differentiate in either direction (e.g., Reed-Sternberg
cell/variant or DLBCL), epigenetic changes as opposed to
genetic aberrations may influence the final morphology and
immunophenotype.
Eberle et al (2011a) performed a large-scale DNA methyla-
tion analysis of 30 cases including cHL, PMBCL as well as
GZL. They demonstrated a close relationship between the
three diseases but with unique signatures that distinguished
GZL from HL and PMBCL. These included lack of de novo
hypomethyation in CHL, hypomethylation of HOXA5 in
First published online 15 June 2016
doi: 10.1111/bjh.14174
Review
MGZL, and hypermethylation of EPHA7 and DAPK1 in
PMBCL. In addition, the nuclear factor jB (NFjB) pathway
was significantly enriched and appeared important to the
pathogenesis of all three entities.
Diagnosis
The diagnosis of GZL should be made by expert pathological
evaluation of the involved tissue, preferably obtained by an
excisional or incisional resection/biopsy. Researchers from the
National Institutes of Health (NIH) first described the mor-
phology and immunophenotype of MGZL in 2005 (Traverse-
Glehen et al, 2005). Three years later, the diagnostic category
was formally included in the WHO classification with defining
histological and immunophenotypic criteria (Swerdlow et al,
2008). GZL is highly variable, with each tumour displaying a
unique set of features. A spectrum of morphologies known
with cHL and PMBCL can occur and divergent morphological
areas can be seen within the same tumour, necessitating exten-
sive sampling for the correct diagnosis. Similar to morphology,
the immunophenotype of GZL has transitional features
between cHL and PMBCL. Tumours resembling cHL will show
prominent CD20, weaker/absent CD30 and absent CD15
whereas tumours resembling PMBCL will be strongly positive
for CD30 and CD15 with negative CD20 and CD79a (Fig 1).
As the B-cell programme is preserved, B-cell transcription fac-
tors, such as PAX5, OCT2 and BOB1, are positive in neoplastic
cells (Dunleavy & Wilson, 2015). In comparison to a cohort of
51 patients with PMBCL, MGZL patients were more often
male, expressed CD15, and had lower expression of CD20
(Dunleavy & Wilson, 2015).
In a retrospective multicentre study of 112 GZL patients
(Evens et al, 2015), the immunophenotype of MGZL appeared
concordant with prior studies. In addition, there was no
apparent significant difference in immunophenotype between
MGZL versus NMGZL. The most prevalent immunopheno-
types were: CD20+ (93%), CD30+ (89%), CD79a+ (78%),
PAX5+ (98%), OCT2+ (96%) and MUM1+ (100%). CD15
(46%) and CD45 (67%) staining were more variable, whereas
only 11% and 28% of patients were positive for CD10 and
Epstein–Barr virus (EBV), respectively [the latter by EBV-
encoded small RNA (EBER) in situ hybridization staining]. It
should be highlighted, however, that central pathological
review was not performed for this retrospective multicentre
study with pathological workup and diagnoses were completed
at the local academic centres.
Overall, the diagnosis of GZL remains challenging; workup
and/or consultation at a centre with haematopathology
expertise of this particular entity is highly recommended. We
advocate detailed review of B-cell markers (e.g. CD20, PAX5,
CD79a, BOB1, OCT2) along with CD30, CD15 and MUM1
when GZL is suspected. Furthermore, for T-cell markers,
CD3 should be included as a minimum in the workup of
every case presenting with sheets of large CD30 positive and
CD20 negative cells to partly rule out anaplastic large cell
346
lymphoma. EBER in situ hybridization should also be
included. Collectively, the diagnosis of GZL should be con-
sidered if strong expression of CD20 is identified in cHL or
strong CD15 expression is seen in an otherwise typical
PMBCL.
Clinical characteristics
The original descriptions of GZL were primarily of patients
with mediastinal involvement presenting similarly to PMBCL.
Subsequent analyses have shown a distinctive non-mediastinal
presentation of GZL. Wilson et al (2014) recently reported
outcomes among 24 patients with MGZL diagnosed and trea-
ted over an approximate 20-year period at the NIH. The med-
ian age of these patients was 33 years and approximately two-
thirds were male. Of these patients, nearly half had a bulky
mediastinal mass >10 cm, while a minority of patients had
extranodal involvement and only 13% had stage IV disease.
In terms of clinical comparison of MGZL versus NMGZL
in the series reported by Evens et al (2015), NMGZL patients
presented significantly less often with bulky disease, but they
were significantly older and presented more often with extra-
nodal involvement and advanced-stage disease (Table I). Due
in part to these latter features, NMGZL patients had signifi-
cantly worse prognostic scores [(International Prognostic
Score (IPS) and International Prognostic Index (IPI)] com-
pared with MGZL patients. It is not known whether NMGZL
has different biology compared with MGZL. Continued bio-
logical analyses and clinical characterization of patients with
MGZL and NMGZL are warranted.
Primary management
There are no standard management guidelines for GZL
patients in the up-front or the relapsed/refractory setting.
This is partly due to the small number of analyses examining
therapeutic approaches for GZL as well as challenges in
diagnosis, as discussed before. From the aforementioned
prospective NIH study, 24 mediastinal GZL patients were
treated with dose-adjusted etoposide, prednisone, oncovin,
cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-
R) and outcomes were compared with similarly treated
PMBCL patients (Wilson et al, 2014). MGZL patients had
significantly inferior outcomes compared with PMBCL [5-
year event-free survival (EFS) of 62% vs. 93% and 5-year
overall survival (OS) 74% vs. 97%, respectively] (Dunleavy
et al, 2011; Wilson et al, 2014).
Among the 112 GZL patients treated across 19 North
American centres over a recent ten-year period (Evens et al,
2015), the two most common therapeutic approaches were
cyclophosphamide, doxorubicin, oncovin and prednisone
(CHOP) +/ rituximab and doxorubicin, bleomycin, vin-
blastine and dacarbazine (ABVD) +/ rituximab, with only a
handful of patients treated with DA-EPOCH-R. Approxi-
mately two-thirds of patients received rituximab as part of
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 174, 345–350
 Review

(A) (B) (C)

(D) (E) (F)

Fig 1. B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL), also
known as grey zone lymphoma (GZL). Different morphologies and immunophenotypes can be seen within the same neoplasm; transitional fea-
tures occur. Biopsy of a bulky mediastinal mass in a 36-year-old female. Areas resembling cHL (A), with the neoplastic forms showing
immunophenotype of Reed-Sternberg cells, CD20 (B) and CD30 + (C) are seen, together with areas resembling primary mediastinal DLBCL
(D) with neoplastic forms being strong CD20 + (E) and mainly CD30 (F). A and D: haematoxylin and eosin 9 200; B, C, E and F:
Immunoperoxidase 9 200.

their frontline therapy. The overall response rates (ORR) and
complete remission (CR) rates for all patients were 71% and
59%, respectively, with 33% of patients having primary
refractory disease (no difference identified between MGZL
versus NMGZL). The ORR and CR rates for patients who
received rituximab as part of frontline therapy were 82% and
73%, respectively, versus 59% and 43%, respectively, without
rituximab (P = 0
02 and P = 0
008, respectively).
At 31 months median follow-up, the 2-year PFS and OS
for all patients were 40% and 88%, respectively (Fig 2). The
2-year PFS rate for patients with stage I/II versus III/IV dis-
ease was 54% vs. 30%, respectively, and the corresponding
OS rates were 94% vs. 76%. Interestingly, despite a compara-
tive preponderance of early-stage disease and lower IPI, the
survival rates were not statistically different for patients with
MGZL versus NMGZL. In terms of frontline chemotherapy
regimens in this retrospective series, PFS rate appeared sig-
nificantly inferior for patients treated with ABVD +/
rituximab versus treatment with a DLBCL-based regimen
(i.e., CHOP+/-R and DA-EPOCH-R) with corresponding 2-
year rates of 23% vs. 52%, respectively (Fig. 2). It is impor-
tant to highlight that this finding persisted on multivariate
Cox regression, including when controlling for IPI and
receipt of rituximab.
Role of radiotherapy
There are minimal prospective, and no randomized, data
regarding the utility of radiotherapy in GZL. Treatment para-
digms for GZL in the series reported by Evens et al (2015)
resembled typical PMLCL and cHL management with radio-
therapy usually given to patients with bulky disease after
R-CHOP. Radiotherapy was not routinely given for patients
treated with DA-EPOCH-R in the series reported by Wilson
et al (2014), as is standard practice with this therapeutic reg-
imen for patients with PMLCL (Dunleavy et al, 2013). In the

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Table I. Patient characteristics: Mediastinal versus Non-Mediastinal on multivariate analyses controlling for IPI and response to
GZL. pre-HSCT salvage therapy (Evens et al, 2015). This improve-
Mediastinal Non-mediastinal ment, however, probably reflected that fit patients with
(n = 48) (n = 64) P* chemotherapy-sensitive disease underwent SCT. Nevertheless,
given these findings, there should be consideration for sal-
Age, years 12% 47% 0
0001
vage combination chemotherapy followed by autologous
>45
HSCT for patients with relapsed/refractory GZL. Addition-
Bone marrow involvement 0 20% 0
001
ally, as described before for localized relapse in the
Present
Extranodal sites present 8% 37% 0
014 mediastinum, there may be consideration for radiotherapy
>1 (+/ chemotherapy) without HSCT (Wilson et al, 2014).
Stage 13% 81% 0
0001 Clinical data regarding the use of biological agents for
III/IV GZL is highly limited. Brentuximab vedotin is an attractive
Bulky disease 44% 8% 0
0001 targeted therapy, given the CD30 positivity seen in many
Yes GZL cases. In a small subset of relapsed/refractory GZL
IPI 7% 35% 0
001 patients, brentuximab vedotin demonstrated activity in a
3–5 CD30+ relapsed/refractory DLBCL study (i.e., one CR and
IPS 6% 27% 0
002
two partial remissions in six patients) (Jacobsen et al, 2015).
4–7
Functionally active transcription pathways have not been
GZL, grey zone lymphoma; IPI, International Prognostic Index; IPS, clearly delineated in GZL, however data from PMBCL may
International Prognostic Score. be extrapolated. NF-jB is constitutively active in PMBCL
*Comparing mediastinal versus non-mediastinal. (Feuerhake et al, 2005) and thus inhibitors to this pathway,
as well as treatment approaches targeting B-cell receptor
series by Evens et al (2015), more patients with MGZL (BCR)-mediated activation should be considered (Gebauer
received radiotherapy versus NMGZL; this was probably dic- et al, 2014). Additionally, checkpoint inhibition may be a
tated by the much higher frequency of early-stage and bulky valid pathway to partially pursue, given the previously identi-
disease for MGZL patients in that analysis. When comparing fied amplification of chromosome 9p24.1 in PMBCL, which
response and survival rates, there did not appear to be a ben- was associated with activation of Janus kinase 2 (JAK2) and
efit to radiotherapy, however, caution should be applied to programmed cell death 1 ligand (Green et al, 2010). These
this finding given the retrospective nature and relatively data are also supported by findings from the NIH where
small patient numbers. alterations affecting the JAK2/PDL2 (also termed
Notably, relapses localized to the mediastinum may be PDCD1LG2) locus in 9p24.1 were seen in the majority of
curative. Wilson et al (2014) demonstrated that 44% (four of MGZL cases (Eberle et al, 2011b).
nine) patients achieved continuous remission with salvage
radiation therapy alone. It is not known if outcomes would
Prognostication
be improved for MGZL if adjuvant radiotherapy was more
routinely used following DA-EPOCH-R therapy. However, The prospective DA-EPOCH-R study identified serum abso-
given the currently defined outcomes for newly diagnosed lute lymphocyte count, presence of tumour-infiltrating den-
GZL, in what appears to be a relatively chemotherapy-resis- dritic cells, CD15 immuno-expression on malignant cells and
tant disease, we advocate use of consolidative radiotherapy tumour morphology as prognostic makers for MGZL out-
after chemo-immunotherapy for localized and/or bulky come (Wilson et al, 2014). Due to the smaller size of this
(>10 cm) disease. study, these associations were identified on univariate analy-
ses. Predominant PMBL-like morphology and presence of
CD68+ tumour-associated macrophages were associated with
Relapsed/Refractory disease
EFS. Additionally, they showed that a gene signature encod-
Among available data, the ability to salvage GZL patients ing for dendritic cell–specific intercellular adhesion molecule-
with relapsed/refractory disease appears fairly good. In 3-grabbing non-integrin (DC-SIGN, also termed CD209),
the series reported by Evens et al (2015), the median which is a marker of dendritic cells and activated macro-
time to relapse for GZL patients was 7 months (range, phages, was associated with OS. Furthermore, low absolute
1–64 months); most of these patients were treated with stan- lymphocyte count and increased staining of CD15 in malig-
dard combination chemotherapy salvage regimens. Further- nant cells were both associated with inferior EFS and OS
more, the majority of patients were taken to haematopoietic (Wilson et al, 2014).
stem cell transplantation (HSCT), usually autologous (Evens Analysis of clinical prognostic factors in the most recent
et al, 2015). The 2-year OS rate for relapsed/refractory GZL series showed that poor performance status, increased lactate
patients who underwent HSCT was 88%, which compared dehydrogenase (LDH), anaemia and advanced stage disease
with 67% for patients who did not have HSCT; this persisted were associated with PFS on univariate analyses, while only

348 ª 2016 John Wiley & Sons Ltd

British Journal of Haematology, 2016, 174, 345–350
 Review

Fig 2. Outcomes in grey zone lymphoma (GZL). (A, B) The 2-year progression-free survival (PFS) and overall survival (OS) rates for 112
patients with GZL were 40% and 88%, respectively, in a recently reported multicentre retrospective series (Evens et al, 2015). (C) The outcome
based on frontline therapeutic regimen; 2-year PFS for patients who received a standard frontline DLBCL regimen (i.e., CHOP+/ R and DA-
EPOCH-R) versus ABVD+/ R were 52% vs. 23%, P = 0
03. (D) Kaplan–Meier curves for patients who received rituximab as a part of frontline
therapy versus not; 2-year PFS were 51% vs. 22%, respectively, P = 0
01. Adapted from and reprinted with permission from: Evens et al, 2015. ©
John Wiley & Sons Inc. (A) All patients. (B) Mediastinal versus Non-Mediastinal. (C) PFS comparison of frontline therapeutic regimens for GZL.
(D) Impact on PFS of rituximab as a part of frontline therapy. R, rituximab; CHOP, cyclophosphamide, doxorubicin, oncovin, prednisone;
EPOCH, etoposide, prednisolone, oncovin, cyclophosphamide, doxorubicin; ABVD, doxorubicin, bleomycin, vinblastine and dacarbazine.

stage was prognostic for OS (Evens et al, 2015). Both the IPI
and IPS scoring systems were also prognostic for PFS and
OS (as categorical and continuous variables). Multivariate
analyses identified performance status as the most dominant
prognostic factor for PFS, whereas increased LDH was bor-
derline. For OS, advanced stage disease (i.e., III/IV) was the
only significant prognostic factor (i.e., hazard ratio, 4
89;
P < 0
05). Interestingly, CD20 positivity in malignant cells
also independently predicted PFS on Cox regression control-
ling for receipt of rituximab (i.e., 88% of the CD20-negative
GZL patients experienced progressive disease).
Conclusions
Since its original description in 2005 and its inclusion in the
WHO classification in 2008, there has been significant bio-
logical and clinical knowledge learned regarding GZL.
Despite the increased recognition of this disease as a distinct
pathological and clinical entity, it is important to highlight
that diagnosis of this disease is complex and requires the
involvement of a haematopathologist with expertise in this
area. Furthermore, there remains a critical need for harmo-
nization and consensus diagnostic criteria as well as for con-
tinuing to examine the biology of this disease entity. It is
fully recognized that clinically, patients with GZL may pre-
sent with primary mediastinal localization or with systemic
disease. Pathological or biological differences between these
varied clinical presentations remain to be elucidated. Regard-
less of clinical presentation, patients with GZL have been
noted to have relatively high relapse rates, especially com-
pared with PMLCL and cHL. Interestingly, GZL patients
appear to be salvaged successfully with salvage therapy
including HSCT. Further examination of the most optimal
chemotherapy regimen and appropriate timing of HSCT,
whether allogeneic or autologous, is essential.
Off of a clinical trial, we recommend therapy with either
R-CHOP or DA-EPOCH-R for the treatment of MGZL or
NMGZL. Additionally, given the relative chemotherapy-

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British Journal of Haematology, 2016, 174, 345–350
Review

resistant nature of this disease, we advocate the use of con-
solidative radiotherapy for localized and/or bulky (>10 cm)
disease. For patients with relapsed or refractory GZL, there
should be consideration to proceed with salvage chemother-
apy followed by consolidation with autologous HSCT.
Finally, there should be continued exploration towards the
use and integration of novel targeted therapeutic agents (e.g.,
brentuximab vedotin, new generation CD20 antibodies,
programmed cell death 1 inhibitors, BCR inhibitors, protea-
some inhibitors, etc.) into the treatment paradigm of GZL.
Author contributions
AK designed, drafted, analysed and wrote the paper. MP edi-
ted, wrote and contributed essential data and figures to the
paper. AE wrote and critically revised the paper.

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