Department of Histopathology & Cytopathology , Hammersmith Hospital
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Transcript of Department of Histopathology & Cytopathology , Hammersmith Hospital
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A comparison of the frequency of common lymphoma-associated gene rearrangements among B-Post transplant
lymphoproliferative disorders (B-PTLD), B-cell HIV-lymphomas 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
Imperial College London
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Background
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Post-transplant lymphoproliferative disorders (PTLD)
• Early lesions
• Polymorphic PTLD
• Monomorphic PTLD
• Classical Hodgkin lymphoma-type PTLD
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Monomorphic PTLD
• B-cell neoplasmsDLBCL
Burkitt lymphomaPlasmacytoma / plasma cell
myeloma Plasmacytoma-likeOthers
• T-cell neoplasms (~15%)Peripheral T-cell lymphoma,
NOS Hepatosplenic T-cell lymphoma Others
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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.
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Aetiology
• Viruses: 1) EBV
2) HHV-8
• Genetic changes (translocation, Mutation,......)
• Antigen stimulation
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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
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Question ?
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Do common lymphoma-associated gene rearrangements differ among B-PTLDs, B-cell HIV-
lymphomas and iDLBCL?
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Materials & Methods
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H&EISH
Serial sections
TMA
FISH
IHC
Tissue microarray
• 64 B-PTLD
• 41 HIV-BCL
• 139 iDLBCL
Cases collected
BCL2, BCL3, BCL6, c-MYC, PAX5, MALT1 and IGH
Genes investigated
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Results
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c-MYC 8%
None 92%
c-MYCNone
c-MYC 30%
double hits 8%
None 62%
c-MYC double hitsNone
BCL6 23%
BCL2 11%
c-MYC 4%
BCL3 2%
IGH only 2%
Double hit 5%
None 53%
BCL6BCL2c-MYCBCL3IGH onlyDouble hitNone
Percentage involvement of rearrangements of different genes among DLBCLs in different settings
HIV-DLBCL(39cases)PTLD-DLBCL(24 cases)
iDLBCL (139 cases)
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• BCL2 and BCL6 rearrangements were predominantly restricted to GC and AGC/non-GC subtypes respectively.
• 8% PT-DLBCLs and 30% HIV-DLBCLs showed c-MYC rearrangement.
• PT-DLBCLs and HIV-DLBCLs lacked BCL2 and BCL6 rearrangements.
• Seven iDLBCLs (5%) and 2 HIV-DLBCLs (8%) had rearrangements of two oncogenes.
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• 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.
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BCL2
BCL2
BCL6
BCL6
BCL3
BCL3
c-MYC
c-MYC
Double hit
Double hit
IGH only
IGH only
Negative
Negative
0% 10% 20% 30% 40% 50% 60%
GC (MUM-neg)
AGC/non GC (MUM1-pos)
Rearrangements of different genes among iDLBCL subsets
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• 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.
EBV association
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• None of the cases with either BCL2 or BCL6 rearrangement showed EBV-association (p=0.031 & p<0.001 respectively).
• No significant correlation between EBV-association and c-MYC or IGH rearrangement.
Correlation of rearrangements of c-MYC, BCL2 and BCL6 genes among the EBV-positive cases
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Dual-colour break-apart probes
EBER
IGH C-MYC
Monomorphic PTLD, plasmablastic lymphoma
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Summary and Conclusion
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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 B-PTLD.
• 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.
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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.
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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
References
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Acknowledgements
• 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.
The Egyptian Government
All members of the Department of Histopathology, of Hammersmith Hospital.
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Thank you