SH Comprehensive Molecular Profiling of an ALK-Negative, Anaplastic Large Cell Lymphoma with DUSP22 rearrangement

Transcription

1 SH Comprehensive Molecular Profiling of an ALK-Negative, Anaplastic Large Cell Lymphoma with DUSP22 rearrangement Caleb Ho, M.D.; Alexander Chan, M.D., Yanming Zhang, M.D.; Lu Wang, M.D., Ph.D; Maria E. Arcila, M.D.; Ahmet Dogan, M.D., Ph.D

2 Clinical History 50 year old man with PMH of asthma, GERD, and Lyme disease 6 yrs ago Noted right submandibular mass while shaving First underwent FNA, then excisional biopsy

3 H&E 2X 2.5cm Submandibular Mass

4 H&E 10X 2.5cm Submandibular Mass

5 H&E 40X 2.5cm Submandibular Mass

6 CD3 CD20

7 CD4 CD8

8 CD2 CD7 CD5 TCR Beta

9 CD30 ALK-1

10 TIA-1 Ki-67

11 Summary of All Immunostains Positive for: o CD3, CD4, CD2, CD30 (Strong, diffuse), BCL-2 (weak), MUM-1, TCR-Beta Negative for: o CD20, CD8, CD5, CD7, CD10, CD56, ALK-1, TIA-1, Granzyme B, EMA, BCL-6, Cyclin D1 EBV LMP-1 and EBER ISH are negative Ki-67 Proliferation index: >90%

12 Cytogenetics/FISH Studies IRF4 gene rearrangement detected in 68% of the cells (100 cells analyzed) The findings are supportive of DUSP22-IRF4 (6p25.3) gene rearrangement

13 Final Diagnosis Right Submandibular Lymph Node, Excision Anaplastic Large Cell Lymphoma (ALCL), ALK- Negative, with DUSP22-rearrangement

14 Genetic Alterations in ALK-Negative ALCL Parrilla Castellar ER, et al. Blood 2014 Aug28; 124(9): /73 (30% of cases) harbor DUSP22 (6p25.3) rearrangements 6/73 (8% of cases) harbor TP63 (3q28) rearrangements Mutually exclusive gene rearrangements Not found in ALK-Positive ALCL cases DUSP22 rearrangements in T cell lymphoma first described in 2011 (Feldman AL, et al. Blood 2011 Jan 20;117(3):915-9) TP63 rearrangements in T cell lymphoma first described in 2012 (Vasmatzis G, et al. Blood 2012 Sep 13; 120(11):2280-9)

15 Doughnut cell in DUSP22-rearranged ALCL King RL, et al. Am J Surg Pathol 2016 Jan;40(1): DUSP22-rearranged ALCL are: More likely to exhibit Doughnut cell morphology Less likely to have pleomorphic cell More likely to have sheet-like growth Less likely to have admixed granulocytes or eosinophils

16 Cytotoxic Markers in DUSP22-Rearranged ALCL DUSP22-Rearranged ALCL are more likely to lack TIA1 and Granzyme B expression Parrilla Castellar ER, et al. Blood 2014 Aug 28;124(9):

17 Survival Differences among ALCL subgroups Parrilla Castellar ER, et al. Blood 2014 Aug 28;124(9):

18 Survival Differences among ALCL subgroups Pedersen MB, et al. Blood 2017 Jul 27;130(4):

19 Screening for DUSP22- and TP63-Rearranged ALCL DUSP22-Rearranged ALCL Characteristic morphology ( Doughnut cell, sheet-like growth pattern) Tend to lack TIA1 and Granzyme B expression by IHC FISH for DUSP22-IRF4 (6p25.3) TP63-Rearranged ALCL Overexpression of p63 by IHC FISH for TP63 (3q28) RNA sequencing for fusion detection

20 Back to our Case - Molecular Findings Hybridization-capture based assay, targeting 400 genes, sequencing on an Illumina HiSeq2500 instrument Patient s Nail DNA was used as Matched Normal control to filter out germline variants. Mean Overall Coverage: 1089X Variants detected: 1. CARD11 (NM_032415) exon5 p.k215del (c.645_647delgaa) (136/1523 reads, VAF=0.09) 2. CARD11 (NM_032415) exon6 p.k254n (c.762g>t) (90/1209 reads, VAF=0.07) 3. GRIN2A (NM_ ) exon13 p.f1135c (c.3404t>g) (304/1426 reads, VAF=0.21) 4. PIK3R1 (NM_181523) exon15 splicing variant p.x662_splice (c t>c) (138/638 reads, VAF=0.22) Lenz G, et al. Science 2008 Mar 21;319(5870):

21 CARD11 is linked to both B- and T-cell receptor Signaling NF-κB Pathway Activation Turvey SE, et al. J Allergy Clin Immunol 2014 Aug; 134(2):

22 Case Follow-up Diagnosed with Stage III disease (>1 extranodal site), IPI score of 1 Bone marrow: No evidence of lymphoma involvement Underwent CHOEP X 4 cycles Complete Response (CR) by PET/CT Patient was offered consolidation therapy with autologous stem cell transplant. However, since DUSP22-rearranged ALK-Negative ALCL has better prognosis than other ALK-Negative ALCL cases, the patient decided that he would hold off undergoing marrow transplant.

23 Final Panel Diagnosis Right Submandibular Lymph Node, Excision Anaplastic Large Cell Lymphoma (ALCL), ALK- Negative, with DUSP22-rearrangement

24 The End Thank You

25 References Feldman AL, Dogan A, Smith DI, et al. Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood 2011 Jan 20;117(3): King RL, Dao LN, McPhail ED, et al. Morphologic features of ALK-negative anaplastic large cell lymphomas with DUSP22 rearrangements. Am J Surg Pathol 2016 Jan;40(1): Len G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008 Mar 21;319(5870): Parrila Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood 2014 Aug28; 124(9): Pedersen MB, Hamilton-Dutoit SJ, Bendix K, et al. DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study. Blood 2017 Jul 27;130(4): Turvey SE, Durandy A, Fischer A, et al. The CARD11-BCL10-MALT1 (CBM) signalosome complex: stepping into the limelight of human primary immunodeficiency. J Allergy Clin Immunol 2014 Aug; 134(2): Vasmatzis G, Johnson SH, Knudson RA, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood 2012 Sep 13; 120(11):