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

2. 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

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

4. Pathologic Fracture: Femur (10/2009)

5. Pathologic Fracture: Femur
CD34
MPO
Tryptase
CD117

6. Maxillofacial CT (11/2009)

7. Left Orbital Mass (11/2009)

8. Left Orbital Mass

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

10. 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

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

12. FICTION on Orbital Mass

13. 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

14. Posterior Iliac Crest BM (11/2009)

15. Posterior Iliac Crest BM
CD34

16. Sclerotic area
CD117
Tryptase
Cellular area
CD117
Tryptase

17. Sclerotic area
CD117
Tryptase
CD25
CD2

18. 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 (-)

19. 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

20. 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

21. 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?

22. 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

23. 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

24. 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)

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

26. 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)

27. 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

28. 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?

29. 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

30. 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?

31. 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

32. Acknowledgement
Keyur P Patel, MD PhD

33. Thank You