Key Points

  • nm-PMBLsig+ tumors represent a distinct group of DLBCLs that share molecular features with bf-PMBL.

  • Mutational patterns and anatomic presentations suggest distinct evolutionary modes between nm-PMBLsig+ tumors and bf-PMBL.

Abstract

Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typically affects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas with gene expression features of PMBL have been described in nonmediastinal sites, raising questions about how these tumors should be classified. Here, we investigated whether these nonmediastinal lymphomas are indeed PMBLs or instead represent a distinct group within diffuse large B-cell lymphoma (DLBCL). From a cohort of 325 de novo DLBCL cases, we identified tumors from patients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature (nm-PMBLsig+; n = 16; 5%). A majority of these tumors expressed MAL and CD23, proteins typically observed in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig+ cases revealed close associations with DLBCL, and a majority displayed a germinal center B cell–like cell of origin (GCB). In contrast to patients with bf-PMBL, patients with nm-PMBLsig+ presented at an older age and did not show pleural disease, and bone/bone marrow involvement was observed in 3 cases. However, although clinically distinct from bf-PMBL, nm-PMBLsig+ tumors resembled bf-PMBL at the molecular level, with upregulation of immune response, JAK-STAT, and NF-κB signatures. Mutational analysis revealed frequent somatic gene mutations in SOCS1, IL4R, ITPKB, and STAT6, as well as CD83 and BIRC3, with the latter genes significantly more frequently affected than in GCB DLBCL or bf-PMBL. Our data establish nm-PMBLsig+ lymphomas as a group within DLBCL with distinct phenotypic and genetic features. These findings may have implications for gene expression– and mutation-based subtyping of aggressive B-cell lymphomas and related targeted therapies.

REFERENCES

1.
Swerdlow
SH
,
Campo
E
,
Harris
NL
, et al
.
WHO classification of tumours of haematopoietic and lymphoid tissues
. Revised 4th ed.
Lyon, France
:
IARC Press
;
2017
.
2.
Giulino-Roth
L
.
How I treat primary mediastinal B-cell lymphoma
.
Blood
.
2018
;
132
(
8
):
782
-
790
.
3.
Barth
TF
,
Leithäuser
F
,
Joos
S
,
Bentz
M
,
Möller
P
.
Mediastinal (thymic) large B-cell lymphoma: where do we stand?
Lancet Oncol
.
2002
;
3
(
4
):
229
-
234
.
4.
Isaacson
PG
,
Norton
AJ
,
Addis
BJ
.
The human thymus contains a novel population of B lymphocytes
.
Lancet
.
1987
;
2
(
8574
):
1488
-
1491
.
5.
Möller
P
,
Lämmler
B
,
Eberlein-Gonska
M
, et al
.
Primary mediastinal clear cell lymphoma of B-cell type
.
Virchows Arch A Pathol Anat Histopathol
.
1986
;
409
(
1
):
79
-
92
.
6.
Rosenwald
A
,
Wright
G
,
Leroy
K
, et al
.
Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma
.
J Exp Med
.
2003
;
198
(
6
):
851
-
862
.
7.
Savage
KJ
,
Monti
S
,
Kutok
JL
, et al
.
The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma
.
Blood
.
2003
;
102
(
12
):
3871
-
3879
.
8.
Mottok
A
,
Hung
SS
,
Chavez
EA
, et al
.
Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma
.
Blood
.
2019
;
134
(
10
):
802
-
813
.
9.
Chapuy
B
,
Stewart
C
,
Dunford
AJ
, et al
.
Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade
.
Blood
.
2019
;
134
(
26
):
2369
-
2382
.
10.
Sarkozy
C
,
Copie-Bergman
C
,
Damotte
D
, et al
.
Gray-zone lymphoma between cHL and large B-cell lymphoma: a histopathologic series from the LYSA
.
Am J Surg Pathol
.
2019
;
43
(
3
):
341
-
351
.
11.
Mottok
A
,
Wright
G
,
Rosenwald
A
, et al
.
Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens
.
Blood
.
2018
;
132
(
22
):
2401
-
2405
.
12.
Dubois
S
,
Viailly
PJ
,
Mareschal
S
, et al
.
Next-generation sequencing in diffuse large B-cell lymphoma highlights molecular divergence and therapeutic opportunities: a LYSA study
.
Clin Cancer Res
.
2016
;
22
(
12
):
2919
-
2928
.
13.
Yuan
J
,
Wright
G
,
Rosenwald
A
, et al;
Lymphoma Leukemia Molecular Profiling Project (LLMPP)
.
Identification of primary mediastinal large B-cell lymphoma at nonmediastinal sites by gene expression profiling
.
Am J Surg Pathol
.
2015
;
39
(
10
):
1322
-
1330
.
14.
Ennishi
D
,
Mottok
A
,
Ben-Neriah
S
, et al
.
Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact
.
Blood
.
2017
;
129
(
20
):
2760
-
2770
.
15.
Arthur
SE
,
Jiang
A
,
Grande
BM
, et al
.
Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma
.
Nat Commun
.
2018
;
9
(
1
):
4001
.
16.
Ennishi
D
,
Jiang
A
,
Boyle
M
, et al
.
Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma
.
J Clin Oncol
.
2019
;
37
(
3
):
190
-
201
.
17.
Wright
G
,
Tan
B
,
Rosenwald
A
,
Hurt
EH
,
Wiestner
A
,
Staudt
LM
.
A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma
.
Proc Natl Acad Sci USA
.
2003
;
100
(
17
):
9991
-
9996
.
18.
Li
H
,
Durbin
R
.
Fast and accurate long-read alignment with Burrows-Wheeler transform
.
Bioinformatics
.
2010
;
26
(
5
):
589
-
595
.
19.
Koboldt
DC
,
Zhang
Q
,
Larson
DE
, et al
.
VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing
.
Genome Res
.
2012
;
22
(
3
):
568
-
576
.
20.
Saunders
CT
,
Wong
WS
,
Swamy
S
,
Becq
J
,
Murray
LJ
,
Cheetham
RK
.
Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs
.
Bioinformatics
.
2012
;
28
(
14
):
1811
-
1817
.
21.
Cibulskis
K
,
Lawrence
MS
,
Carter
SL
, et al
.
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples
.
Nat Biotechnol
.
2013
;
31
(
3
):
213
-
219
.
22.
Cingolani
P
,
Platts
A
,
Wang
L
, et al
.
A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3
.
Fly (Austin)
.
2012
;
6
(
2
):
80
-
92
.
23.
Sherry
ST
,
Ward
MH
,
Kholodov
M
, et al
.
dbSNP: the NCBI database of genetic variation
.
Nucleic Acids Res
.
2001
;
29
(
1
):
308
-
311
.
24.
Tate
JG
,
Bamford
S
,
Jubb
HC
, et al
.
COSMIC: the Catalogue Of Somatic Mutations In Cancer
.
Nucleic Acids Res
.
2019
;
47
(
D1
):
D941
-
D947
.
25.
Schmitz
R
,
Wright
GW
,
Huang
DW
, et al
.
Genetics and pathogenesis of diffuse large B-cell lymphoma
.
N Engl J Med
.
2018
;
378
(
15
):
1396
-
1407
.
26.
Ennishi
D
,
Takata
K
,
Béguelin
W
, et al
.
Molecular and genetic characterization of MHC deficiency identifies EZH2 as therapeutic target for enhancing immune recognition
.
Cancer Discov
.
2019
;
9
(
4
):
546
-
563
.
27.
Anders
S
,
Pyl
PT
,
Huber
W
.
HTSeq—a Python framework to work with high-throughput sequencing data
.
Bioinformatics
.
2015
;
31
(
2
):
166
-
169
.
28.
Robinson
MD
,
McCarthy
DJ
,
Smyth
GK
.
edgeR: a Bioconductor package for differential expression analysis of digital gene expression data
.
Bioinformatics
.
2010
;
26
(
1
):
139
-
140
.
29.
Talevich
E
,
Shain
AH
,
Botton
T
,
Bastian
BC
.
CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing
.
PLOS Comput Biol
.
2016
;
12
(
4
):
e1004873
.
30.
Mermel
CH
,
Schumacher
SE
,
Hill
B
,
Meyerson
ML
,
Beroukhim
R
,
Getz
G
.
GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers
.
Genome Biol
.
2011
;
12
(
4
):
R41
.
31.
Viganò
E
,
Gunawardana
J
,
Mottok
A
, et al
.
Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation
.
Blood
.
2018
;
131
(
18
):
2036
-
2046
.
32.
Lenz
G
,
Wright
G
,
Dave
SS
, et al;
Lymphoma/Leukemia Molecular Profiling Project
.
Stromal gene signatures in large-B-cell lymphomas
.
N Engl J Med
.
2008
;
359
(
22
):
2313
-
2323
.
33.
Scott
DW
,
Wright
GW
,
Williams
PM
, et al
.
Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue
.
Blood
.
2014
;
123
(
8
):
1214
-
1217
.
34.
Bledsoe
JR
,
Redd
RA
,
Hasserjian
RP
, et al
.
The immunophenotypic spectrum of primary mediastinal large B-cell lymphoma reveals prognostic biomarkers associated with outcome
.
Am J Hematol
.
2016
;
91
(
10
):
E436
-
E441
.
35.
Gentry
M
,
Bodo
J
,
Durkin
L
,
Hsi
ED
.
Performance of a commercially available mal antibody in the diagnosis of primary mediastinal large B-cell lymphoma
.
Am J Surg Pathol
.
2017
;
41
(
2
):
189
-
194
.
36.
Hans
CP
,
Weisenburger
DD
,
Greiner
TC
, et al
.
Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray
.
Blood
.
2004
;
103
(
1
):
275
-
282
.
37.
Liston
P
,
Roy
N
,
Tamai
K
, et al
.
Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes
.
Nature
.
1996
;
379
(
6563
):
349
-
353
.
38.
Rahal
R
,
Frick
M
,
Romero
R
, et al
.
Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma
.
Nat Med
.
2014
;
20
(
1
):
87
-
92
.
39.
Li
X
,
Yang
Y
,
Ashwell
JD
.
TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2
.
Nature
.
2002
;
416
(
6878
):
345
-
347
.
40.
Hu
S
,
Du
MQ
,
Park
SM
, et al
.
cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas
.
J Clin Invest
.
2006
;
116
(
1
):
174
-
181
.
41.
Lopez
J
,
John
SW
,
Tenev
T
, et al
.
CARD-mediated autoinhibition of cIAP1’s E3 ligase activity suppresses cell proliferation and migration
.
Mol Cell
.
2011
;
42
(
5
):
569
-
583
.
42.
Mansouri
L
,
Noerenberg
D
,
Young
E
, et al
.
Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
.
Blood
.
2016
;
128
(
23
):
2666
-
2670
.
43.
Challa-Malladi
M
,
Lieu
YK
,
Califano
O
, et al
.
Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma
.
Cancer Cell
.
2011
;
20
(
6
):
728
-
740
.
44.
Steidl
C
,
Shah
SP
,
Woolcock
BW
, et al
.
MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers
.
Nature
.
2011
;
471
(
7338
):
377
-
381
.
45.
Khodabakhshi
AH
,
Morin
RD
,
Fejes
AP
, et al
.
Recurrent targets of aberrant somatic hypermutation in lymphoma
.
Oncotarget
.
2012
;
3
(
11
):
1308
-
1319
.
46.
Morin
RD
,
Mungall
K
,
Pleasance
E
, et al
.
Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing
.
Blood
.
2013
;
122
(
7
):
1256
-
1265
.
47.
Weniger
MA
,
Melzner
I
,
Menz
CK
, et al
.
Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation
.
Oncogene
.
2006
;
25
(
18
):
2679
-
2684
.
48.
Tiacci
E
,
Ladewig
E
,
Schiavoni
G
, et al
.
Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma
.
Blood
.
2018
;
131
(
22
):
2454
-
2465
.
49.
Mellert
K
,
Martin
M
,
Lennerz
JK
, et al
.
The impact of SOCS1 mutations in diffuse large B-cell lymphoma
.
Br J Haematol
.
2019
;
187
(
5
):
627
-
637
.
50.
Xie
K
,
Doles
J
,
Hemann
MT
,
Walker
GC
.
Error-prone translesion synthesis mediates acquired chemoresistance
.
Proc Natl Acad Sci USA
.
2010
;
107
(
48
):
20792
-
20797
.
51.
Teras
LR
,
DeSantis
CE
,
Cerhan
JR
,
Morton
LM
,
Jemal
A
,
Flowers
CR
.
2016 US lymphoid malignancy statistics by World Health Organization subtypes
.
CA Cancer J Clin
.
2016
;
66
(
6
):
443
-
459
.
52.
Ehrlich
M
,
Shmuely
A
,
Henis
YI
.
A single internalization signal from the di-leucine family is critical for constitutive endocytosis of the type II TGF-beta receptor
.
J Cell Sci
.
2001
;
114
(
Pt 9
):
1777
-
1786
.
53.
Huang
L
,
Kirschke
CP
.
A di-leucine sorting signal in ZIP1 (SLC39A1) mediates endocytosis of the protein
.
FEBS J
.
2007
;
274
(
15
):
3986
-
3997
.
54.
Kozik
P
,
Francis
RW
,
Seaman
MN
,
Robinson
MS
.
A screen for endocytic motifs
.
Traffic
.
2010
;
11
(
6
):
843
-
855
.
55.
Dierlamm
J
,
Baens
M
,
Wlodarska
I
, et al
.
The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas
.
Blood
.
1999
;
93
(
11
):
3601
-
3609
.
56.
Diop
F
,
Moia
R
,
Favini
C
, et al
.
Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia
.
Haematologica
.
2020
;
105
(
2
):
448
-
456
.
57.
Rossi
D
,
Deaglio
S
,
Dominguez-Sola
D
, et al
.
Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma
.
Blood
.
2011
;
118
(
18
):
4930
-
4934
.
58.
Yang
Y
,
Kelly
P
,
Shaffer
AL
III
, et al
.
Targeting non-proteolytic protein ubiquitination for the treatment of diffuse large B cell lymphoma
.
Cancer Cell
.
2016
;
29
(
4
):
494
-
507
.
59.
Chapuy
B
,
Stewart
C
,
Dunford
AJ
, et al
.
Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes [published corrections appear in Nat Med. 2018;24(8):1290-1291; Nat Med. 2018;24(8):1292]
.
Nat Med
.
2018
;
24
(
5
):
679
-
690
.
60.
Lacy
SE
,
Barrans
SL
,
Beer
PA
, et al
.
Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report
.
Blood
.
2020
;
135
(
20
):
1759
-
1771
.
61.
Zinzani
PL
,
Santoro
A
,
Gritti
G
, et al
.
Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large B-cell lymphoma: efficacy and safety from the phase II CheckMate 436 study
.
J Clin Oncol
.
2019
;
37
(
33
):
3081
-
3089
.
62.
Lenz
G
,
Wright
GW
,
Emre
NC
, et al
.
Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways
.
Proc Natl Acad Sci USA
.
2008
;
105
(
36
):
13520
-
13525
.
You do not currently have access to this content.

Sign in via your Institution

Sign In