Daniel Martinez
Hospital Clínic, Barcelona, Spain
Post-transplant lymphoproliferative disorders (PTLD)
Historia Clínica
• Hombre 41años
• Antecedentes médicos de: – Diabetes tipo I desde los 7 años
• Complicaciones micro y macroangiopáticas – Retinopatía
– Neuropatía
– Nefropatía
– Amputación por isquemia de dedos del pie
– Hemodiálisis 2000
– Doble Trasplante reno-pancreático 2007 con posterior pérdida del injerto renal
• Actualmente en diálisis
• Cuadro de alucinaciones, orientado como meningitis linfocitaria
• Parada cardiorrespiratoria y éxitus a las dos semanas
CD 20 CD 79a
Ki67
EBV: EBER 1,2
EBV: LMP-1 EBV: EBNA-2
EBV: LATENCY IIA
DIAGNOSTICO
LINFOMA DIFUSO DE CELULAS GRANDES DE FENOTIPO
B PRIMARIO DEL SNC,
EBV POSITIVO ASOCIADO A INMUNODEFICIENCIA
POR TRANSPLANTE RENAL
LINFOMATOSIS CEREBRAL
DIFUSA
¿SINDROME LINFOPROLIFERATIVO
POST-TRANSPLANTE?
¿LINFOMA PRIMARIO
DEL SNC?
Hochberg FM et al. Nat Clin Pract Neurol 2007 3: 24–35 Reimersema S et al J Pathol. 2005;206:328-36.
DLBCL Central Nervous System
• Immunocompetent host
• 2-3% of all NHL
• > 60 yr
• History of autoimmune
disorders neurological or
systemic
• EBV negative
• Deletions HLA Class I and II
• Immunosuppresed host
• Younger patients
• Low CD4 counts
• EBV positive
Hochberg FM et al. Nat Clin Pract Neurol 2007 3: 24–35 Reimersema S et al J Pathol. 2005;206:328-36.
Primary DLBCL of Central Nervous
System WHO 2008
• Immunocompetent host
• Primary intracerebral or
intraocular
• Exclude: dura, intravascular,
secondary involvement
• 2-3% of all brain tumors
• > 60 yr
• History of autoimmune
disorders neurological or
systemic
• EBV negative
• Deletions HLA Class I and II
1: Ferry et al Mod Pathol. 1989;2(6):583-92. 2: Nalesnik et alAm J Pathol. 1988;133(1):173-92. 3: Webber et al . Lancet. 2006;367(9506):233-9. 4. Cabalieri et al, Cancer 2010; (116): 863-870 5. Phan TG, et al Neuro Oncol. 2000; 2: 229-238. 6. Snanoudj R, et al . Transplantation. 2003; 76: 930-937. 7. Castellano-Sanchez et al. Am J Clin Pathol. 2004; 121: 246-253
CNS INVOLVEMENT IN PTLPD
• Rare 0-3.6% (2/56; 0/43) 1-3
• EBV associated (latency??)
• 45 cases 1970-20105-7
19/20 EBV
PTLD- WHO 2008
Monomorphic PTLD
(Classify according to lymphoma they resemble)
B-cell lymphomas
Diffuse large B-cell lymphoma Burkitt lymphoma
Plasma cell myeloma
Plasmocytoma-like lesion
Other (indolent small B-cell lymphomas excluded)
T-cell lymphomas:
PTCL, NOS,
Hepatosplenic TCL
Other,
Polymorphic PTLD
“Early lesions”
Plasmacytic hyperplasia,
Infectious mononucleosis-like PTLD
Classical Hodgkin Lymphoma-type PTLPD
Ng and Khoury, Adv Anat Pathol, January 2009
Epstein-Barr virus: latency patterns
Results
• Median age 54 years (26-77)
• Male predominance (26M:9F)
6 polymorphic PTLD
• Diagnosis 27 monomorphic PTLD
2 classical Hodgkin lymphoma-type
26 DLBCL
1 plasmacytoma-like
12 HSCT
23 solid organ tx
7 liver
11 kidney
5 heart
• Type of transplant
• Type of immunosupression cyclosporine
mycophenolate
Gonzalez, Meeting European Society Pathology, Prague 2012
EBV status
28 (80%) EBV +
7 (20%) EBV -
•PB 7/11
•CSF 6/6
•Biopsy site 2/2
PCR study in 19 EBV+ pt
21%
32%
47%
Latency I Latency II Latency III
EBV latency program
Relation between groups and type of
transplant
8
4
9
7
7
0% 50% 100%
EBV+ w R
EBV + w/o R
EBV -
HSCT
SOT
Groups based on replication status
Cases were separated into replicative or non-replicative
based on Zebra expression
• 17/28 (60%) replicative
• 11/28 (40%) non-replicative ZEBRA
ZEBRA
p=0.086
Groups based on replication status
EBV latency program with and without
replication
Patients with replication develop an early onset latency III
EBV+ PTLD
p=0.017
121,17
209,6
255,77
1,53 4,33
46,8720,97
64,93
138,16
0
50
100
150
200
250
300
EBV+ w R EBV+ w/o R EBV-
Mo
nth
s
Time from transplant
p<0.00
0
2
4
6
8
10
12
Latency I Latency II Latency III
EBV+ w /o R EBV+ R
Replication status and clinical presentation
Disease
Involvement
EBV + with replication
EBV + without replication
EBV -
Bone marrow 0 1 0
Brain 3 2 0
GI tract 2 2 1
Liver 2* 1 1
Lung 1 1 1
Lymph node 3 2 2
Kidney 1* 0 0
Urinary bladder 0 1 1
Skin 1 0 0
Soft tissue 1 0 1
Waldeyer ring 1 1 0
Disseminated disease (OS<1wk)
2 0 0
Latency III pattern and EBV replication
Latency III & R
Others
p= 0.04 Latency
III+R Others p-value
CMV reactivation 7/11 5/21 0.034
GVHD/Rejection 7/11 14/21 0.582
Rejection 3/5 8/15 0.6
GVHD 4/6 6/6 0.23
- Patients with latency III pattern and replication have significantly lower OS
- They show higher rates of CMV reactivation and lower rates of
GVHD/rejection than the others PTLD patients
- More immunosuppressed patients?
years
Ov
era
ll s
urv
ival
Conclusions
1. Intratumoral EBV replication occurs in human PTLD as shown in mouse
models
2. EBV replication is independent of the kind of immunosuppression and the
type of transplant
3. EBV replication is associated with early onset LPD, latency III EBV
infection pattern and tend to have a more aggressive clinical course with
shorter survival and higher rates of disseminated disease
4. The combination of a latency III with viral replication can be used as a
biomarker of the extent of immunossuppression in individual cases in
order to select patients that may benefit from antiviral therapy or higher
reduction of immunosuppression (RIS)