EBV positive DLBCL of the
elderly
2013/04/01
住院總醫師 王智慧 報告
感謝 蕭樑材大夫 指導
Am. J. Hematol. 86:663–667, 2011.
• diffuse large B-cell lymphoma (DLBCL)~
31% of all non-Hodgkin lymphoma
• Burkitt , plasmablastic, NK/T-cell,
angioimmunoblastic, Hodgkin, hydroa-like
T-cell lymphoma and lymphomas
associated with HIV infection, posttransplant lymphoproliferations, and after
exposure to certain cytotoxic or
immunomodulator agents.
Patients and Methods
• January 2002-December 2009,
• all newly diagnosed DLBCL from the
medical records
• CD20，CD10，bcl-6，MUM1/IRF4 (cutoff:
30%)
• EBER in ≧20% of malignant cells
• EBV-positive DLBCL of the elderly were
defined:
• (1) age ≧ 50 years,
• (2) no clinical and/or laboratory evidence
of immunodeficiency,
• (3) diffuse large cell morphology with
positive expression of CD20,
• (4) EBV-encoded RNA positivity in the
tumor cells.
-exclusion• Transformed and primary cutaneous variants of
DLBCL
• coinfection by HIV, hepatitis B, hepatitis C, or
human T-lymphotrophic virus-1
• clinical suspicion of immunodeficiency such as
chronic infections, chronic diarrhea, and chronic
eczema
• chronic disease associated with leucopenia or
lymphopenia, or low immunoglobulin levels
Oyama score includes age≧
70 years and presence of B
symptoms as adverse risk
factors three risk groups,
low (0 factors), intermediate
(1 factor), and high risk (2
factors).
AWOD: alive without disease, AWD: alive with disease, NR: no response
• Multivariate survival analyses were not
attempted due to the small number of
cases.
Results
• A total of 199 new cases of DLBCL were
identified, 28 patients met the criteria, incidence
rate of 14% .
• Median age at diagnosis: 75 years (51~95) .
• 17 men, 11 women (61% and 39%) 1.5:1.
• Hb <10 g/dL, platelets <150 x 10^9/L,
lymphocytes <1.0x 10^9/L in 61%, 21%, and
37% of the patients, respectively.
• ECOG >1  18 patients (64%),
• LDH levels elevated in 11 (41%),
• advanced clinical stages (Stage III or IV) in
14 (50%).
• N=14 (50%) presented exclusively with
nodal disease,
• n=11 (39%) had nodal and extranodal
involvement,
• n=3 (11%) had primary extranodal
disease, involving the stomach in all
cases.
• extranodal sites of involvement were GI
tract (n=6), lung (n=3), oropharynx (n=3),
bone marrow (n =2), adrenals (n=1), skin
(n=1), bone (n=1).
• B symptoms in 12 cases (43%)
• IPI scores >2 in 16 cases (57%).
• Low, intermediate, high Oyama scores in 5
(18%), 12 (43%), and 11 (39%) patients
Histology
• diffuse pattern, large cells
• (68%) Monomorphic with a centroblastic or
immunoblastic morphology, frequent
mitoses, usually necrosis
• (32%) polymorphic large neoplastic cells
with immunoblastic morphology admixed
with variable amounts of small
lymphocytes and histiocytes.
• All cases showed scattered RS- like cells.
• 19 patients (68%) had a non-germinal
center (NGC) and 9 (32%) had a germinal
center (GC)-like phenotype.
Blood. 2004;103:275-282
Blood. 2004;103:275-282
Therapy
N
CHOP
R-CHOP
No chemo
12
8
8
CR 50% (n= 10)
PR 5% (n= 1)
NR 45% (n= 9)
Rapid progress or
poor PS
CR
CR 33%
(p= 0.3) CR 63%
-
Alive
33%
(p= 0.17) 75%
-
8 mos
20 mos
OS
1.5 mos (p=0.002)
• median follow up of 32 months, 18
patients (64%) have died; 83% from
lymphoma progression.
• OS for the entire group was 5 months and
3-year OS was 33%
Worse OS
• age ≥70 years (n= 14; P= 0.002),
advanced clinical stage (n= 9; P= 0.02),
ALC <1.0x10^9/L (n= 4; P= 0.004).
• ECOG performance status > 1,
hemoglobin <10 g/dL , platelets <200x
10^9/L, elevated LDH levels showed a
trend
64 mos
5 mos
64 mos
8 mos
Discussion
• age >70, advanced stage and ALC <1.0 3
109/L ~ a worse OS rate,
• R-CHOP may derive better CR and OS
rates than CHOP
• Asian studies, incidence 5 ~11%
• in Western populations, incidence < 5%
• Immunosenescence characterized by
decreased number and function of T-cells
in peripheral blood and lymph nodes,
apoptosis dysregulation, and elevation of
levels of proinflammatory molecules
• Park et al. showed that EBER-positive
DLBCL patients showed poorer clinical
response and worse OS rates than EBERnegative patients
• In a prior study from our group, the
presence of EBER in DLBCL patients was
also independently associated with a
worse prognosis
• these studies did not include patients
treated with rituximab-containing regimens
Clin Cancer Res 2007;13:5124–5132.
Materials and Methods
• Diagnosis. when more than 50% of the
proliferating, often neoplastic appearing
cells showed both of the expression of one
or more pan–B cell antigens
(CD20/CD79a) and/or light-chain
restriction and positive signal for in situ
hybridization using EBV-encoded small
nuclear early region (EBER)
oligonucleotides on paraffin section for
patients more than 40 y/o without
predisposing immunodeficiency
• Among 149 cases fulfilling these criteria,
96 cases with available clinical data set
were enrolled
• For the control group, 107 patients aged
over 40 years with EBV-negative DLBCL
treated consecutively at Aichi Cancer
Center between 1993 and 2000.
Sites of extranodal involvement
• N= 17 (20%), limited to extranodal sites.
• N= 27 (31%) had only lymphadenopathies
without extranodal involvement,
• N= 43 (49%) had lymphadenopathies with
extranodal involvement.
polymorphic subtype
scattered distribution of Hodgkin and
Reed-Sternberg - like giant cells
EBNA2 stain
CD 20 (+)
Histologic features
• diffuse and polymorphic proliferation of
large lymphoid cells with a varing degree
of reactive components such as small
lymphocytes, plasma cells, histocytes, and
epithelioid cells ,sometimes accompanied
by necrosis and an angiocentric pattern.
• Often featured by a broad range of B-cell
maturation, containing morphologic
centroblasts, immunoblasts, and Hodgkin
and Reed-Sternberg (HRS)–like giant cells
with distinct nucleoli
• morphologically divided into two subtypes:
• large cell lymphoma (LCL): n=34, having
notably dominant areas where large
lymphoid cells with relatively monomorphic
appearance.
• polymorphic LPD subtypes: n=62,
scattered distribution of large cells in the
polymorphous composition.
• The histology was frequently varied from
area to area, indicating a continuous
spectrum
• no significant difference in any clinical
characteristics and immunophenotype
between these two groups
Phenotypic features
• LMP1 was positive on the large atypical
cells in 67 (94%) out of 71 tested cases.
• EBNA2 was detected in the nuclei of 16
(28%) of 57 tested cases
• CD30 was stained more common in agerelated EBVpositive B-cell LPDs than in
EBV-negative DLBCL (75% vs 13%, P <
0.0001).
• CD10 expression (18% vs 38%, P =
0.015)
Response to treatment and
Kaplan-Meier survival estimates
• chemoregimens containing anthracycline
for 62 patients (79%) and without
anthracycline for 7 patients (9%)~EBV+
• 40 (63%) of 64 evaluable patients with
achieved a CR with initial therapy~EBV+
• 95 (91%) of 104 evaluable cases with
DLBCL achieved a CR (P < 0.0001).
• 57 deaths in 96 cases of age-related EBVpositive B-cell LPDs , 34 deaths in 107
cases of DLBCL.
• causes of death available for 47 cases for
age-related EBV-positive B-cell LPDs and
29 for DLBCL.
• Deaths (PD and complications such as
infections) in 38 and 9 cases, in agerelated EBV-positive B-cell LPDs, 23 and
6 cases in EBVDLBCL.
• The observed differences between two
disease groups were not significant (P =
0.870).
– more than 70 y/o- not significant (P = 0.747).
A significant difference was
still found even when
accounting for age
24 mos
H-I/High IPI
Low/L-I IPI
score of 0 (n = 18), no adverse factors 56.3 mos
score of 1 (n = 39), one factor25.2 mos
Oyama
score of 2 (n = 21) , two factors 8.5 mos
score
56 mos
25 mos
8.5
mos
Switzerland, Austria, Italy
8/258 (3.1%)
Median age: 67.5 y/o
OS: 5.5 mos (EBNA2+): 103 mos (DLBCL > 50 y/o)
EBV-positive DLBCL of the elderly in the Asian population
seems to be more frequent at extranodal sites, e.g. up to 80%
no correlation between age and prevalence of EBV in
any of the studied DLBCL collectives