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					Imperial College
London




        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
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 HIV-
           lymphomas 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
                                                                              Double hit
                                                                              None

                                                                   BCL2 11%
                                                        c-MYC 4%
                           Double hit 5%
               None, 53%                IGH only, 2%     BCL3 2%



                           iDLBCL (139 cases)
                 c-MYC,
                   8%                                                                        c-MYC ,
                                                                                               30%




                             c-MYC                                                                     c-MYC
                             None                                                                      double hits
                                                                                                       None




                                                           None, 62%
                                                                                            double
   None, 92%
                                                                                           hits, 8%
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 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.
•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
              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 EBV-
association 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 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.
 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

•   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

				
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posted:4/27/2014
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