Session 7, case 171 Extramedullary Manifestations of Myeloid Neoplasms Sanam Loghavi, MD Roberto N. Miranda, MD

Clinical History 50 y/o man Palpable supraorbital mass Progressive leg pain Imaging: pathological fracture of the left femur with multiple lytic lesions in the pelvis

Laboratory Data WBC 8.7 x 109/L Hgb 11.7 g/dL Plt 370 x 109/L Normal differential Hgb 11.7 g/dL Plt 370 x 109/L Tryptase 12.8 ng/mL (< 11.5) LDH 321 IU/L (< 618)

Pathologic Fracture: Femur (10/2009)

Pathologic Fracture: Femur CD34 MPO Tryptase CD117

Maxillofacial CT (11/2009)

Left Orbital Mass (11/2009)

Left Orbital Mass

Left Orbital Mass CD34 (~15%) MPO Tryptase CD117

Flow Cytometry, Orbital Mass Positive CD13, CD25 CD117 bright CD59, CD63 dim CD69 very dim Negative CD2, CD34 SSC CD45 CD34 CD25 CD117 CD117 Blasts with mast cell/basophilic phenotype

Molecular Studies, Orbital Mass FISH for BCR-ABL (+): Double nuclear fusion (89% of cells) FISH for PDGFRA: Failed RT-PCR for KIT D816V: Negative

FICTION on Orbital Mass

RT-PCR on Orbital Mass and PB ICEPlex analysis demonstrated an e6a2 BCR-ABL fusion transcript in orbital mass and PB   Orbital mass ABL e6a2 e6a2 PB ABL

Posterior Iliac Crest BM (11/2009)

Posterior Iliac Crest BM CD34

Sclerotic area CD117 Tryptase Cellular area CD117 Tryptase

Sclerotic area CD117 Tryptase CD25 CD2

BM: Cytogenetics and Molecular 46,XY [5] BCR-ABL FISH: (+) in 30% of cells RT-PCR for BCR-ABL1 (-) (p190, p210, p230) KIT D816V (-) JAK2 V617F (-)

Diagnosis Proposed Consensus Philadelphia chromosome-positive myeloid neoplasm with increased blasts and associated aggressive systemic mastocytosis vs. myelomastocytic differentiation (myeloid sarcoma) involving an orbital mass Consensus Aggressive systemic mastocytosis associated with BCR-ABL1-positive myeloproliferative disorder, involving an orbital mass with 15% blasts

Therapy and Follow up Chemotherapy (dasatinib + low-dose Ara-C) Complete remission Bone lesions, orbital mass, bone marrow FISH (-) in BM Matched unrelated donor allogeneic stem cell transplant Day 32 BM: normal Microsatellite polymorphism identical to donor Expired on day 76 post transplant with severe acute GVHD

Discussion Q1. What is the significance of numerous mast cells? Q2.    Do the findings also support coexistent CML? Q 3. Does extramedullary disease warrant the classification and therapy as blast phase?

Increased Mast Cells in BM or Extramedullary Sites Systemic mastocytosis (SM) SM with associated clonal hematological non-mast-cell lineage disease (SM-AHNMD) Other variants Myelomastocytic leukemia

Systemic Mastocytosis (SM) Criteria Major Multifocal, dense infiltrates of mast cells (≥ 15) in BM or other extracutaneous organ Minor > 25% atypical KIT D816V mutation CD2+ or CD25+ Tryptase > 20 ng/mL

Systemic Mastocytosis In Favor Numerous atypical mast cells Mast cells positive for CD117, tryptase, CD25 Mast cells negative for MPO and CD34 Osteosclerotic lesions and pathologic fractures Clusters of aberrant mast cells with associated sclerosis Unusual features Diffuse pattern of involvement in BM and orbit in addition or discrete clusters of mast cells in BM Negative KIT D816V (Orbital mass and BM)

SM-AHNMD Meets criteria for SM and AHNMD MDS MPN (e.g., CML) AML Lymphoma Others

Myelomastocytic Leukemia Myeloid neoplasm with marked increase in immature mast cells Diagnostic of AML, RAEB, or blast phase of MPN Mast cells express tryptase and CD117 Criteria of SM are not fulfilled Diffuse infiltration instead of multifocal aggregates Therapy not well understood Our case responded to dasatinib (presence of BCR-ABL)

Myelomastocytic Leukemia In favor Diffuse increase of mast cells CD117+, tryptase+ Associated myeloid component with mast cell differentiation Both myeloid and mast cell components disappeared with dasatinib Against Not well defined underlying myeloid neoplasm (CML) Clusters of mast cells positive for CD117 and CD25 Features supportive of aggressive systemic mastocytosis

Q1.    What is the significance of numerous mast cells?  Q2.    Do the findings also support coexistent CML? Q 3. Does extramedullary disease warrant the classification and therapy as blast phase?

In Favor of CML Against CML Ph+ by FISH in orbit and BM ICEPlex positive for e6a2 BCR-ABL Extramedullary myeloid proliferation with marked eosinophilia Complete response to TKI (dasatinib) Against CML Presentation: pathologic fractures & osteosclerosis PB: no leukocytosis, neutrophilia or basophilia Histopathology: necrosis & mast cell differentiation BM: no increased neutrophils or megakaryocytes Karyotype: diploid

Q1.    What is the significance of numerous mast cells?  Q2.    Do the findings also support coexistent CML? Q 3. Does extramedullary disease warrant the classification and therapy as blast phase/myeloid sarcoma?

CML Blast Phase Definition Current therapy ≥ 20% blasts in PB or BM Extramedullary blast proliferation Is 15% sufficient? no criteria by WHO Blasts occupying significant areas of BM Current therapy TKI, HSCT (if feasible), +/- AML induction chemo

Acknowledgement Keyur P Patel, MD PhD

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