Daniel Martinez

Hospital Clínic, Barcelona, Spain

dmartin1@clinic.ub.es

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)