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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 - PowerPoint PPT Presentation
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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, post-transplant 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
AWOD: alive without disease, AWD: alive with disease, NR: no response
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).
• 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 CHOP R-CHOP No chemo
N 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% -
OS 8 mos 20 mos 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 EBER-negative 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 subtypescattered distribution of Hodgkin andReed-Sternberg - like giant cells
CD 20 (+)
EBNA2 stain
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 age-related 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 EBV-positive 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 age-related 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).
24 mos
A significant difference was still found even when accounting for age
H-I/High IPI
Low/L-I IPI
score of 0 (n = 18), no adverse factors 56.3 mosscore of 1 (n = 39), one factor25.2 mosscore of 2 (n = 21) , two factors 8.5 mos Oyama
score
56 mos
25 mos8.5 mos
Switzerland, Austria, Italy
8/258 (3.1%)
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%
Median age: 67.5 y/o
no correlation between age and prevalence of EBV in any of the studied DLBCL collectives