Use of MYC, BCL2 and BCL6 FISH for investigations of high grade B cell lymphoma

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1 Use of MYC, BCL2 and BCL6 FISH for investigations of high grade B cell lymphoma Dr Anthony Bench Haematopathology and Oncology Diagnostic Service Cambrıdge Unıversıty Hospitals NHS Foundatıon Trust Cambridge UK

2 Use of MYC, BCL2 and BCL6 FISH for investigations of high grade B cell lymphoma Dr Hongxiang Liu Prof. Ming Q. Du Baljinder Matharu Bridget Manasse Dr George Follows

3 High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH)

4 Frequency of BL and HGBL-DH/TH HGBL-DH constitute around 5% of all DLBCL At least 250 predicted cases HGBL-DH per year in the UK Annual rate per 100,000 Median age at diagnosis Expected UK cases per year 5-Year Relative Survival (%) Non-Hodgkin lymphoma Marginal zone lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Burkitt lymphoma T-cell lymphoma Hodgkin lymphoma

5 FISH panel to aid diagnosis of Burkitt s lymphoma and DLBCL To confirm a diagnosis of BL MYC break apart probe MYC-IGH fusion probe IGK break apart probe IGL break apart probe For differential diagnosis of BL and High grade B cell lymphoma MYC break apart probe MYC-IGH fusion probe BCL2 break apart probe BCL6 break apart probe

6 High grade B cell lymphoma FISH panel 582 high grade B-cell NHL cases tested since 2008 successfully analysed, -> 97%. 564 cases No cases MYC-R MYC- IGH MYC- Amp BCL2-R BCL6-R MYC-R BCL2-R MYC-R BCL6-R MYC-R BCL2-R BCL6-R CNV at any locus BL DLBCL HGBL

7 Burkitt s lymphoma with MYC-IGH t(8;14) rearrangement Normal cells t(8;14)(q24:q32) MYC-IGH dual colour dual fusion MYC dual colour

8 Burkitt s lymphoma with MYC-IGL t(8;22) rearrangement Normal cells t(8;14)(q24:q32) MYC-IGH triple colour dual fusion MYC dual colour

9 Burkitt s lymphoma with MYC-IGL t(8;22) rearrangement MYC-IGH triple colour dual fusion MYC dual colour IGK dual colour IGL dual colour

10 Burkitt s lymphoma FISH panel? Burkitt s lymphoma MYC break apart MYC-IGH fusion MYC break apart : POSITIVE MYC-IGH fusion : POSITIVE MYC break apart : NEGATIVE MYC-IGH fusion : NEGATIVE MYC break apart : POSITIVE MYC-IGH fusion : NEGATIVE IGK or IGL : POSITIVE Review diagnosis Consider : Unusual MYC breakpoint Burkitt-like lymphoma with 11q aberration

11 High grade B cell lymphoma FISH panel 582 high grade B-cell NHL cases tested since 2008 successfully analysed, -> 97%. 564 cases No cases MYC-R MYC- IGH MYC- Amp BCL2-R BCL6-R MYC-R BCL2-R MYC-R BCL6-R MYC-R BCL2-R BCL6-R CNV at any locus BL DLBCL HGBL

12 High grade B cell lymphoma with MYC rearrangement MYC dual colour MYC-IGH dual colour dual fusion MYC-IGH rearrangement observed

13 High grade B cell lymphoma with MYC rearrangement MYC dual colour MYC-IGH dual colour dual fusion MYC-IGH rearrangement with MYC breakpoint 5 of MYC probes

14 High grade B cell lymphoma with MYC rearrangement MYC dual colour MYC-IGH dual colour dual fusion MYC-IGH rearrangement with MYC breakpoint within 5 MYC probe

15 High grade B cell lymphoma FISH panel 582 high grade B-cell NHL cases tested since 2008 successfully analysed, -> 97%. 564 cases No cases MYC-R MYC- IGH MYC- Amp BCL2-R BCL6-R MYC-R BCL2-R MYC-R BCL6-R MYC-R BCL2-R BCL6-R CNV at any locus BL DLBCL HGBL

16 High grade B cell lymphoma with MYC and BCL2 rearrangement 83/female, LN CD20+, CD10+, BCL6+, BCL2+, Ki67~90% MYC dual colour BCL2 dual colour BCL2-IGH dual colour dual fusion

17 High grade B cell lymphoma with MYC and BCL2 and BCL6 rearrangement 48/male, LN CD20+, CD10+, CD79a+, BCL6+, BCL2+, Ki67~90% MYC dual colour BCL2 dual colour BCL6 dual colour

18 High grade B cell lymphoma FISH panel 582 high grade B-cell NHL cases tested since 2008 successfully analysed, -> 97%. 564 cases No cases MYC-R MYC- IGH MYC- Amp BCL2-R BCL6-R MYC-R BCL2-R MYC-R BCL6-R MYC-R BCL2-R BCL6-R CNV at any locus BL DLBCL HGBL

19 HGBL / DLBCL FISH panel? Burkitt s lymphoma / HGBL / DLBCL MYC : POSITIVE MYC-IGH : POSITIVE BCL2 : NEGATIVE BCL6 : NEGATIVE No significant CNV MYC break apart MYC-IGH fusion BCL2 break apart BCL6 MYC : POSITIVE BCL2 or BCL6: POSITIVE May have CNV MYC : NEGATIVE May have CNV Favours Burkitt s lymphoma Favours HGBL with MYC and BCL2 and/or BCL6 Favours HGBL, NOS or DLBCL, NOS IMPORTANT : Integrate with morphogical and IHC information e.g. Ki67

20 Burkitt s lymphoma MYC and high grade B cell lymphoma MYC translocations are usually the sole chromosomal aberration or are associated with few additional alterations MYC translocations involve IGH or IGK or IGL High grade B cell lymphoma MYC translocation may be single hit or double hit MYC translocations may involve partners other than IG loci. Frequently associated with complex cytogenetic karyotype. Generally felt to be associated with a less favourable outcome compared to MYC-negative cases

21 Prognostic relevance of MYC, BCL2 and BCL6 rearrangements in high grade B cell lymphoma Presence of MYC rearrangement associated with less favourable outcome in DLBCL

22 Prognostic relevance of MYC, BCL2 and BCL6 rearrangements in high grade B cell lymphoma HGBL with MYC and BCL2 may represent a less favourable group compared to HGBL with MYC and BCL6 Ye et al 2016

23 MYC+, non-ig DH+, non-ig DH- MYC- MYC+, IG DH+, IG

24 High grade B cell lymphoma with MYC and BCL2 or BCL6 HGBL with MYC and BCL2 or BCL6 double hit generally felt to perform less well on standard chemotherapy R-CHOP But : MYC + BCL2 + : Unfavourable MYC + BCL6 + : No difference MYC-IG : MYC-non-IG : Unfavourable No difference May explain why some studies do not find a less favourable outcome for double hit lymphoma More intensive chemotherapy regimes (e.g. DA-EPOCH-R) give better response to induction and improves progression free survival BUT overall survival is not improved