Imperial College
London
A comparison of the frequency of common lymphomaassociated gene rearrangements among B-Post transplant
lymphoproliferative disorders (B-PTLD), B-cell HIVlymphomas and diffuse large B-cell lymphoma in immune
competent patients (iDLBCL).
Hazem AH Ibrahim, Michael J Neat, Mufaddal Moonim, Amen Furrat, Lia Menasce, Sabine Pomplun,
Margaret Burke, Donald Macdonald, Ed Kanfer, Mark Bower, Paul Fields, Nicola Foot, Alistair Reid and Kikkeri N Naresh.
Department of Histopathology & Cytopathology,
Hammersmith Hospital
Background
Post-transplant lymphoproliferative
disorders (PTLD)
• Early lesions
• Polymorphic PTLD
• Monomorphic PTLD
• Classical Hodgkin lymphoma-type PTLD
Monomorphic PTLD
• B-cell neoplasms
DLBCL
Burkitt lymphoma
Plasmacytoma / plasma cell myeloma
Plasmacytoma-like
Others
• T-cell neoplasms (~15%)
Peripheral T-cell lymphoma, NOS
Hepatosplenic T-cell lymphoma
Others
HIV-LPDs
•
•
•
•
•
•
Burkitt lymphoma.
Diffuse large B-cell lymphoma (DLBCL).
Primary effusion lymphoma (PEL).
Plasmablastic lymphoma.
HHV-8-associated LPDs in patients of MCD.
Polymorphic lymphoid proliferations resembling
PTLDs.
Aetiology
• Viruses:
1) EBV
2) HHV-8
• Genetic changes (translocation, Mutation,......)
• Antigen stimulation
 20-40% of iDLBCL and HIV-related DLBCLs
harbour BCL6 rearrangement that are very rarely
seen in PTLDs.
 Post-transplant Burkitt lymphomas (PT-BL),
similar to HIV-BL and iBL, display chromosomal
breaks at 8q24 involving the c-MYC oncogene.
 Very few reports investigated chromosomal
translocations among PTLDs
Question ?
Do common lymphoma-associated gene
rearrangements differ among B-PTLDs, B-cell HIVlymphomas and iDLBCL?
Materials & Methods
Tissue microarray
Cases collected
• 64 B-PTLD
TMA
• 41 HIV-BCL
Serial sections
• 139 iDLBCL
IHC
ISH
H&E
FISH
Genes investigated
BCL2, BCL3, BCL6, c-MYC, PAX5, MALT1 and IGH
Results
Percentage involvement of rearrangements of
different genes among DLBCLs in different settings
BCL6
23%
BCL6
BCL2
c-MYC
BCL3
IGH only
BCL2
11%
None 53%
Double hit
5%
IGH only 2%
c-MYC
4%
BCL3
2%
Double hit
None
iDLBCL (139 cases)
c-MYC 8%
c-MYC
30%
c-MYC
c-MYC
double hits
None
None
None 62%
double hits
8%
None 92%
PTLD-DLBCL(24 cases)
HIV-DLBCL(39cases)
•BCL2 and BCL6 rearrangements were
predominantly restricted to GC and AGC/non-GC
subtypes respectively.
•8% PT-DLBCLs and 30% HIV-DLBCLs showed cMYC rearrangement.
•PT-DLBCLs and HIV-DLBCLs lacked BCL2 and
BCL6 rearrangements.
•Seven iDLBCLs (5%) and 2 HIV-DLBCLs (8%)
had rearrangements of two oncogenes.
•Among Burkitt lymphoma (BL), 2/2 PT-BL
and 12/13 (92%) HIV-BL had c-MYC
rearrangement.
•Among plasmablastic lymphoma (PL), 2/6
(33%) PT-PL and 1/2 HIV-PL had c-MYC
rearrangement.
Rearrangements of different genes among iDLBCL subsets
Negative
AGC/non GC (MUM1-pos)
IGH only
Double hit
c-MYC
BCL3
BCL6
BCL2
Negative
GC (MUM-neg)
IGH only
Double hit
c-MYC
BCL3
BCL6
BCL2
0%
10%
20%
30%
40%
50%
60%
EBV association
•EBV-association was noted in 6%, 67% and 54% of
iDLBCLs, PT-DLBCLs and HIV-DLBCLs
respectively.
•100% PT-BL and 63% HIV-BL had EBV-association.
•83% PT-PL and 100% HIV-PL had EBV-association.
Correlation of rearrangements of c-MYC, BCL2
and BCL6 genes among the EBV-positive cases
•None of the cases with either BCL2 or BCL6
rearrangement showed EBV-association (p=0.031
& p<0.001 respectively).
• No significant correlation between EBVassociation and c-MYC or IGH rearrangement.
EBER
Dual-colour break-apart probes
C-MYC
IGH
Monomorphic PTLD, plasmablastic lymphoma
Summary and Conclusion
1- Gene rearrangements
• Gene rearrangement, apart from c-MYC-IGH
(characteristically seen in BL and PL), appear
to be very rare among both HIV-BCL and BPTLD.
• HIV-DLBCL is more frequently associated
with c-MYC rearrangement than iDLBCL.
• BCL6 rearrangement is frequently seen in
iDLBCL of AGC and non-GC subtypes.
• None of the cases with either BCL2 or BCL6
rearrangement showed EBV-association.
2- Alternate pathogenetic pathways in immune
deficiency LPDs
• Other (cyto)genetic abnormalities that are that
are not conventionally associated primary
abnormalities in lymphomas
• Aberrant somatic hypermutation of critical
genes.
• Aberrant hypermethylation of critical genes.
References
1. Jaffe ES, Harris NL, Stein H et al: World Health Organization Classification of Tumour: Pathology and
Genetics, Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon,
2008.
2. Vega F, Medeiros LJ: Chromosomal translocations involved in non-Hodgkin lymphomas. Arch Pathol Lab
Med 127:1148-1160, 2003.
3. Tibiletti MG, Martin V, Bernasconi B et al: BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in
nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of
fluorescent in situ hybridization probes and correlation with clinical outcome. Hum
Pathol 40:645-652, 2009.
4. Vakiani E, Nandula SV, Subramaniyam S et al: Cytogenetic analysis of B-cell posttransplant
lymphoproliferations validates the World Health Organization classification and
suggests inclusion of florid follicular hyperplasia as a precursor lesion. Hum Pathol
38:315-325, 2007.
5. Gaidano G, Lo CF, Ye BH et al: Rearrangements of the BCL-6 gene in acquired immunodeficiency
syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell
subtype. Blood 84:397-402, 1994
6. Windebank K, Walwyn T, Kirk R et al: Post cardiac transplantation lymphoproliferative disorder
presenting as t(8;14) Burkitt leukaemia/lymphoma treated with low intensity
chemotherapy and rituximab. Pediatr Blood Cancer 53:392-396, 2009.
7. Capello D, Rossi D, Gaidano G: Post-transplant lymphoproliferative disorders: molecular basis of disease
histogenesis and pathogenesis. Hematol Oncol 23:61-67, 2005
Acknowledgements
The Egyptian Government
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Prof. Kikkeri Naresh
Prof. Gordon Stamp.
Dr Roberto Dina
Mahrokh Nohdani.
Donna Homcastle, Pritesh Trivedi, Tyler Lloyd & Kay
Elderfield.
• William Mathieson
• John Brennan and David Peston.
• Prof. Letizia Foroni, Alistair Raid, and Jamshid Sorouri.
All members of the Department of
Histopathology, of Hammersmith Hospital.
Thank you