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