To the editor:

Peripheral T-cell lymphomas (PTCLs) represent a group of rare hematological cancers of mature T-cell or natural killer cell origin accounting for 10% to 15% of all lymphomas.1  Although many patients have poor outcomes, some achieve long-term survival.2,3  Thus, identifying prognostic biomarkers is important to facilitate risk-adapted therapy.

Chromosomal rearrangements are critical in the molecular pathogenesis of nearly all types of hematologic neoplasms.4  The best-characterized rearrangements in PTCLs involve the anaplastic lymphoma kinase (ALK) gene, which result in oncogenic ALK fusion proteins and define a specific World Health Organization (WHO) subtype (ALK-positive anaplastic large cell lymphoma [ALCL], representing 6% to 8% of PTCLs).2,5,6  ALK also serves as a prognostic marker: patients with ALK-positive ALCLs have better outcomes than those with ALK-negative ALCLs or other nodal PTCLs, including angioimmunoblastic T-cell lymphoma (AITL) and PTCL, not otherwise specified (NOS).2,7  The molecular pathogenesis of other PTCLs is being elucidated.8  Recurrent chromosomal rearrangements involving the DUSP22-IRF4 locus on 6p25.3 (DUSP22 rearrangements) and the TP53 homolog TP63 on 3q28 recently were reported in ALK-negative ALCL.9-12 DUSP22 rearrangements are associated with decreased expression of dual-specificity phosphatase-22, an enzyme that regulates mitogen-activated protein kinase signaling.10,13,14  A retrospective study found that DUSP22 rearrangements were associated with favorable outcomes in ALK-negative ALCL.12 TP63 rearrangements encoding p63 fusion proteins were associated with aggressive clinical behavior and poor outcomes.11,12 

In the present study, we evaluated the prognostic impact of DUSP22 and TP63 rearrangements in diagnostic tumor biopsy specimens from a population-based Danish cohort of 138 patients with nodal PTCLs. Formalin-fixed, paraffin-embedded tumors from patients diagnosed with PTCL between 1984 and 2011 were retrieved from the pathology departments at 3 Danish tertiary referral centers (Aarhus, Herlev, and Odense University Hospitals). Specimens were pretreatment biopsy specimens from newly diagnosed PTCL patients aged ≥16 years for whom pre- and posttreatment clinical information was available. Clinicopathological data were obtained from the population-based database of the Danish National Lymphoma Registry, supplemented by medical records. Cases were reviewed and classified by expert hematopathologists, and re-reviewed to assure concordance with current WHO criteria.15  The study was approved by The Central Denmark Region Committees on Health Research Ethics (record 1-10-72-392-12), the Danish Data Protection Agency (record 1-16-02-26-11), and the institutional review boards at the participating institutions and was conducted in accordance with the Declaration of Helsinki.

Fluorescence in situ hybridization was performed on sections of previously constructed tissue microarrays16  using break-apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion (inv(3)(q26q28)) as previously described.10,11 DUSP22 and TP63 rearrangements were assessed in a blinded fashion without knowledge of PTCL subtype, clinical course, or outcome. Differences between groups of categorical and continuous variables were tested using Fisher’s exact test, Wilcoxon rank-sum test, and Kruskal-Wallis equality-of-populations rank test as appropriate. Overall survival (OS) was defined as the time from diagnosis to last follow-up or death from any cause. Association of genetic subtype with OS was assessed using Kaplan-Meier curves and Cox proportional hazards models. Significant differences were defined as P < .05. Statistical analyses were performed using STATA IC 11 (StataCorp, College Station, TX).

Of 169 PTCLs evaluated, 138 had sufficient material for DUSP22 and TP63 assessment. Subtypes, demographics, and clinical characteristics are shown in Table 1. Median age was 60 years (range, 16-92 years) with a male to female ratio of 1.6:1. Most patients (86%) received curative-intent anthracycline-containing combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], CHOP + etoposide, or other CHOP-like regimens). ALK-positive ALCL patients were younger (P = .07) and had better outcomes (5-year OS, 85%; 95% confidence interval [CI], 51% to 96%; P < .002) than patients with PTCL, NOS, AITL, and ALK-negative ALCL (Figure 1A).

Table 1.

Clinical characteristics of the study cohort (N = 138)

Characteristic PTCL, NOS (n = 71) AITL (n = 27) ALK-positive ALCL (n = 13) ALK-negative ALCL All PTCL (n = 138) 
DUSP22 (n = 5) TP63 (n = 2) −/−/− (n = 20)* 
Age, y        
 Median 61 64 46 49 44 61 60 
 Range 20-92 43-89 19-85 35-85 16-71 34-89 16-92 
Sex        
 Female 31 11 54 
 Male 40 16 14 84 
Ann Arbor stage        
 I 11 23 
 II 15 
 III 20 12 42 
 IV 29 11 53 
 Unclear 
Performance status        
 0-1 52 17 10 14 98 
 ≥2 18 10 39 
 Unknown 
Extranodal sites        
 ≤1 56 20 16 106 
 >1 15 32 
Skin involvement        
 No 60 23 10 17 114 
 Yes 11 
 Unknown 13 
LDH > upper normal limit        
 Yes 43 17 76 
 No 25 10 57 
 Missing 
IPI        
 1-2 32 12 10 12 71 
 3-4 26 14 49 
 Missing 13 18 
Initial treatment        
 CHOP/CHOP-like 59 23 13 16 118 
 Other 12 20 
 HDT/ASCT 10 23 
Response        
 CR 36 18 10 79 
 PR 10 17 
 NC 
 PD 12 
 Not evaluated 17 
 No treatment 
Outcome        
 5-y OS, % 26 28 85 80 33 35 
 95% CI 16-37 12-46 51-96 20-97 — 14-54 27-43 
Characteristic PTCL, NOS (n = 71) AITL (n = 27) ALK-positive ALCL (n = 13) ALK-negative ALCL All PTCL (n = 138) 
DUSP22 (n = 5) TP63 (n = 2) −/−/− (n = 20)* 
Age, y        
 Median 61 64 46 49 44 61 60 
 Range 20-92 43-89 19-85 35-85 16-71 34-89 16-92 
Sex        
 Female 31 11 54 
 Male 40 16 14 84 
Ann Arbor stage        
 I 11 23 
 II 15 
 III 20 12 42 
 IV 29 11 53 
 Unclear 
Performance status        
 0-1 52 17 10 14 98 
 ≥2 18 10 39 
 Unknown 
Extranodal sites        
 ≤1 56 20 16 106 
 >1 15 32 
Skin involvement        
 No 60 23 10 17 114 
 Yes 11 
 Unknown 13 
LDH > upper normal limit        
 Yes 43 17 76 
 No 25 10 57 
 Missing 
IPI        
 1-2 32 12 10 12 71 
 3-4 26 14 49 
 Missing 13 18 
Initial treatment        
 CHOP/CHOP-like 59 23 13 16 118 
 Other 12 20 
 HDT/ASCT 10 23 
Response        
 CR 36 18 10 79 
 PR 10 17 
 NC 
 PD 12 
 Not evaluated 17 
 No treatment 
Outcome        
 5-y OS, % 26 28 85 80 33 35 
 95% CI 16-37 12-46 51-96 20-97 — 14-54 27-43 

—, Not evaluable. CR, complete response; HDT, high-dose therapy; IPI, International Prognostic Index; LDH, lactate dehydrogenase; NC, no change; PD, progressive disease; PR, partial response.

*

−/−/−, triple-negative ALCL.

Figure 1.

Outcomes in patients with PTCL. (A) Five-year OS rates (Kaplan-Meier estimates) stratified by PTCL subtype and ALK status only (current WHO classification). (B) Five-year OS rates with ALK-negative ALCL stratified by genetic subtype. ALK-pos ALCL, anaplastic lymphoma kinase–positive anaplastic large cell lymphoma; ALK-neg DUSP22 ALCL, anaplastic lymphoma kinase–negative DUSP22-rearranged anaplastic large cell lymphoma; ALK-neg TP63 ALCL, anaplastic lymphoma kinase–negative TP63-rearranged anaplastic large cell lymphoma; −/−/− ALCL, triple-negative anaplastic large cell lymphoma (negative for ALK, DUSP22, and TP63).

Figure 1.

Outcomes in patients with PTCL. (A) Five-year OS rates (Kaplan-Meier estimates) stratified by PTCL subtype and ALK status only (current WHO classification). (B) Five-year OS rates with ALK-negative ALCL stratified by genetic subtype. ALK-pos ALCL, anaplastic lymphoma kinase–positive anaplastic large cell lymphoma; ALK-neg DUSP22 ALCL, anaplastic lymphoma kinase–negative DUSP22-rearranged anaplastic large cell lymphoma; ALK-neg TP63 ALCL, anaplastic lymphoma kinase–negative TP63-rearranged anaplastic large cell lymphoma; −/−/− ALCL, triple-negative anaplastic large cell lymphoma (negative for ALK, DUSP22, and TP63).

Of 27 ALK-negative ALCLs, 5 (19%) had DUSP22 rearrangements, 2 (7%) had TP63 rearrangements, and 20 (74%) were triple negative (ie, in addition to being ALK negative, they lacked DUSP22 and TP63 rearrangements). One PTCL, NOS with some ALCL-like features had rearrangements of both DUSP22 and TP63 (supplemental Figure 1, available on the Blood Web site). No DUSP22 or TP63 rearrangement was detected in the remaining cases of PTCL, NOS or in any ALK-positive ALCL or AITL.

Differences in OS among PTCL subtypes were significant when ALK-negative ALCLs were stratified by genetics (P = .008; Figure 1B) and varied widely among genetic subgroups of ALCL (P = .01; supplemental Figure 2). Patients with DUSP22-rearranged ALK-negative ALCL had a 5-year OS rate of 80% (95% CI, 20% to 97%), similar to that of ALK-positive ALCL patients (85%; P = .85). Both ALCL patients with TP63 rearrangements died with progressive disease within 2 years of initial diagnosis, despite favorable International Prognostic Index scores. Patients with triple-negative ALCLs were slightly older (median age, 61 years) than patients with ALK-positive, DUSP22-rearranged, and TP63-rearranged ALCLs (46, 49, and 44 years, respectively, P = .1). They had an intermediate 5-year OS rate (33%; 95% CI, 14% to 54%), which was poorer than ALK-positive ALCL and DUSP22-rearranged ALCL, better than TP63-rearranged ALCL, and similar to ALK-negative ALCL as a whole (5-year OS, 40%; 95% CI, 22% to 58%). All 5 patients with DUSP22-rearranged ALCLs achieved complete remission; the only death was from a non–lymphoma-related cause. Both ALCL patients with TP63 rearrangements and the PTCL, NOS patient with DUSP22 and TP63 rearrangements had primary refractory disease and died of lymphoma progression.

This study is the first to independently confirm that DUSP22 and TP63 rearrangements predict outcome in ALK-negative ALCL. It is also the first study to examine the prognostic significance of these rearrangements in a prospectively accrued, population-based patient cohort representing all major categories of PTCL. In concordance with Parrilla Castellar et al,12 DUSP22-rearranged ALCL had an excellent prognosis similar to that of ALK-positive ALCL. TP63 rearrangements were rare and were associated with chemotherapy refractoriness and poor outcome. Triple-negative ALCLs had intermediate OS rates inferior to those of DUSP22-rearranged ALCLs and superior to those of TP63-rearranged cases. The PTCL, NOS with rearrangements of both DUSP22 and TP63 had a poor clinical outcome. A previously reported primary cutaneous ALCL with both rearrangements also had an aggressive clinical course11 ; co-occurrence of DUSP22 and TP63 rearrangements has not been reported in systemic ALCL.12  These findings suggest that cases with both rearrangements may behave more similarly to cases with TP63 rearrangements than to those with DUSP22 rearrangements. The current series also confirms the absence of DUSP22 and TP63 rearrangements in ALK-positive ALCL and adds novel information regarding the absence of the rearrangements in AITL and most cases of PTCL, NOS. The genetic profile of triple-negative ALCLs and the distribution of other genetic findings in ALCL (including alterations of ERBB4, ROS1, TYK2, and VAV1 and genes in the JAK-STAT3 pathway17-20 ) merit further study.

This study represents an important first independent validation of the relative frequencies and prognostic significance of DUSP22 and TP63 rearrangements in ALCL. The overall number of cases in each genetic subtype was limited, and thus this series lacked power to formally test survival differences among the ALK-negative genetic subgroups. However, the striking reproducibility of the outcomes after genetic stratification provides a compelling rationale to study the implications of genetic status for clinical management further in larger population-based cohorts and in the clinical trial setting. For example, it has been suggested that DUSP22-rearranged ALCLs may not derive additional benefit from autologous stem cell transplantation in first remission.12  Accordingly, the predictive significance of DUSP22 and TP63 rearrangements currently is being evaluated further in the setting of a large Nordic PTCL trial of upfront autologous stem cell transplantation (NLG-T-01).21 

The online version of this article contains a data supplement.

Authorship

Acknowledgments: The authors thank Kristina Lauridsen (Laboratory of Molecular Pathology, Aarhus University Hospital), Lindsay B. Emanuel (Department of Health Sciences Research, Mayo Clinic), and Kathryn E. Pearce (Department of Laboratory Medicine and Pathology, Mayo Clinic) for excellent technical and logistic assistance.

This work was supported by grants from the Institute of Clinical Medicine, Aarhus University/Aarhus University Hospital, The Karen Elise Jensen Foundation, The A. P. Møller and Chastine Mc-Kinney Møller Foundation for General Purposes, The Eva and Henry Frænkel Foundation, The Mimi & Victor Larsens Fund, the National Institutes of Health, National Cancer Institute (R01 CA177734 and P50 CA97274), and the Department of Laboratory Medicine and Pathology, Mayo Clinic.

Contribution: M.B.P., F.d’A. and A.L.F. drafted the manuscript; F.d’A. and A.L.F. designed the study. R.P.K., P.P.B., I.M.L., and C.A.S. scored and interpreted fluorescence in situ hybridization testing; R.L.B. and N.N.B. contributed to data interpretation; S.J.H.-D., K.B., P.N., M.B.M., and T.S. provided samples and provided pathology review; M.B.P. performed statistical analysis; and all authors approved the final manuscript.

Conflict-of-interest disclosure: A.L.F. and R.P.K. are inventors of technology discussed in this manuscript for which Mayo Clinic holds an unlicensed patent (A.L.F.) or has submitted a patent application (A.L.F. and R.P.K.). The remaining authors declare no competing financial interests.

Correspondence: Andrew L. Feldman, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: feldman.andrew@mayo.edu; and Francesco d’Amore, Department of Hematology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark; e-mail: frandamo@rm.dk.

References

References
1.
Armitage
JO
.
The aggressive peripheral T-cell lymphomas: 2015
.
Am J Hematol
.
2015
;
90
(
7
):
665
-
673
.
2.
Vose
J
,
Armitage
J
,
Weisenburger
D
;
International T-Cell Lymphoma Project
.
International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes
.
J Clin Oncol
.
2008
;
26
(
25
):
4124
-
4130
.
3.
Mak
V
,
Hamm
J
,
Chhanabhai
M
, et al
.
Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors
.
J Clin Oncol
.
2013
;
31
(
16
):
1970
-
1976
.
4.
Rowley
JD
.
Chromosomal translocations: revisited yet again
.
Blood
.
2008
;
112
(
6
):
2183
-
2189
.
5.
Pedersen
MB
,
Hamilton-Dutoit
SJ
,
Bendix
K
, et al
.
Evaluation of clinical trial eligibility and prognostic indices in a population-based cohort of systemic peripheral T-cell lymphomas from the Danish Lymphoma Registry
.
Hematol Oncol
.
2015
;
33
(
4
):
120
-
128
.
6.
Delsol
G
,
Falini
B
,
Muller-Hermelink
HK
, et al
.
Anaplastic large cell lymphoma, ALK-positive. In: Swerdlow S, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:312-316
.
7.
Gascoyne
RD
,
Aoun
P
,
Wu
D
, et al
.
Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma
.
Blood
.
1999
;
93
(
11
):
3913
-
3921
.
8.
Sandell
RF
,
Boddicker
RL
,
Feldman
AL
.
Genetic landscape and classification of peripheral T-cell lymphomas
.
Curr Oncol Rep
.
2017
;
19
(
4
):
28
.
9.
Feldman
AL
,
Law
M
,
Remstein
ED
, et al
.
Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas
.
Leukemia
.
2009
;
23
(
3
):
574
-
580
.
10.
Feldman
AL
,
Dogan
A
,
Smith
DI
, et al
.
Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing
.
Blood
.
2011
;
117
(
3
):
915
-
919
.
11.
Vasmatzis
G
,
Johnson
SH
,
Knudson
RA
, et al
.
Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas
.
Blood
.
2012
;
120
(
11
):
2280
-
2289
.
12.
Parrilla Castellar
ER
,
Jaffe
ES
,
Said
JW
, et al
.
ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes
.
Blood
.
2014
;
124
(
9
):
1473
-
1480
.
13.
Alonso
A
,
Merlo
JJ
,
Na
S
, et al
.
Inhibition of T cell antigen receptor signaling by VHR-related MKPX (VHX), a new dual specificity phosphatase related to VH1 related (VHR)
.
J Biol Chem
.
2002
;
277
(
7
):
5524
-
5528
.
14.
Mélard
P
,
Idrissi
Y
,
Andrique
L
, et al
.
Molecular alterations and tumor suppressive function of the DUSP22 (Dual Specificity Phosphatase 22) gene in peripheral T-cell lymphoma subtypes
.
Oncotarget
.
2016
;
7
(
42
):
68734
-
68748
.
15.
Swerdlow
SH
,
Campo
E
,
Pileri
SA
, et al
.
The 2016 revision of the World Health Organization classification of lymphoid neoplasms
.
Blood
.
2016
;
127
(
20
):
2375
-
2390
.
16.
Pedersen
MB
,
Danielsen
AV
,
Hamilton-Dutoit
SJ
, et al
.
High intratumoral macrophage content is an adverse prognostic feature in anaplastic large cell lymphoma
.
Histopathology
.
2014
;
65
(
4
):
490
-
500
.
17.
Crescenzo
R
,
Abate
F
,
Lasorsa
E
, et al
;
European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies”
.
Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma
.
Cancer Cell
.
2015
;
27
(
4
):
516
-
532
.
18.
Velusamy
T
,
Kiel
MJ
,
Sahasrabuddhe
AA
, et al
.
A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders
.
Blood
.
2014
;
124
(
25
):
3768
-
3771
.
19.
Scarfò
I
,
Pellegrino
E
,
Mereu
E
, et al
;
European T-Cell Lymphoma Study Group
.
Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts
.
Blood
.
2016
;
127
(
2
):
221
-
232
.
20.
Boddicker
RL
,
Razidlo
GL
,
Dasari
S
, et al
.
Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma
.
Blood
.
2016
;
128
(
9
):
1234
-
1245
.
21.
d’Amore
F
,
Relander
T
,
Lauritzsen
GF
, et al
.
Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01
.
J Clin Oncol
.
2012
;
30
(
25
):
3093
-
3099
.

Author notes

*

F.d’A. and A.L.F. contributed equally to this study.