Leukemia (2007) 21, Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas

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3 Leukemia (2007) 21, Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas

4 Clinical presentation Mean age: 55.8 years (range: 16-87). M/F: 1.42/1 Primary site: skin: 27 lymph node: 15 intestine, testis (each): 6 bone, CNS: 3 anterior mediastinum, biliary ducts, pancreas, serosa,, breast, (each): 2 auditory canal, heart, kidney, lung, salivary gland, spleen, tonsil, uterus, gingiva, soft tissue (each): 1 more than one site involved 12

5 Testis

6 Extra-hepatic bile ducts

7 Kidney

8 Clinical features Patients with a concomitant neoplasm: 32/92-26 AML - 1 MPN - 5 MDS Patients with a previous history of neoplasm: 35/92-15 AML - 13 MPN (7 CML, 3 IMF, 2 PV, 1 TE) - 7 MDS Patients without an associated neoplasm: 25/92

9 Morphologic findings At extra-nodal sites: indian-file growth pattern + varying degrees of fibrosis. In the lymph node: either intra-sinusoidal diffusion or para-cortical involvement with some residual follicles. Medium-large sized elements with round-oval oval nuclei, rather dispersed chromatin, one or more prominent nucleoli, and basophilic cytoplasm.

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13 Monoblastic appearance Myelo-monocytic appearance

14 Phenotypic profile Commonest phenotypic profile: MPO +, CD68/KP-1 +, CD68/PG-M1 -, CD163 -, GlyA -, MKC -, CD3 -, and CD79a -. In 20 cases, myelo-monocytic monocytic features: MPO +/ -, CD68/ KP-1 +, CD68/PG-M1 -/+, CD163 -/+. In 20 cases, pure monoblastic population: MPO -, CD68/ KP-1 +, CD68/ PG-M1 +, CD CD117: : in 71.7% of cases (17/20 MØM cases negative). CD34 + and TdT + in 28.3% and 21.4% of cases. CD99 + in 53.4% of cases. CD56 + in 16.9% (with negativity of pdc markers!). Ki-67: high.

15 MPO pdc nodule

16 CD117 pdc nodule

17 CD34 pdc nodule

18 Plas.. mono. nodules in 3 cases (blastic type) CLA/HECA452 Inv16 CD68/PG-M1

19 MPO CD68/PG-M1

20 CD99

21 CD % CD123 - /HECA 452 -

22 Cytogenetics 7/56 (12.5%) were not evaluable by FISH analysis. 34/56 sarcoma samples could be fully analysed (60.7%), while in the remaining 15 (26.8%) the success rate of FISH analysis varied within the different probe analysed. Clonal abnormalities in 22/49 (44.8%) sarcomas fully or partially analysed. 12.8% for monosomy 7; 8.5% for MLL rearrangement; 8.3% for trisomy 8; 5% for monosomy 5q (1 case of monosomy and 1 of 5q deletion); 4.5% for inversion 16; 4.5% for trisomy 4; 4.4% for del CBF-Beta Beta (incidentally observed while scoring INV-16); 2.7% for 20q-; 2.2% for AML1/ETO fusion; 2.1% for trisomy 11. In 2 cases two different aberrations were observed: 20q- and CBF- Beta deletion in E1263/02; trisomy 4 and 5q- in E232/02.

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24 MLL

25 INV16

26 16% Leukemia (2007) 21, Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas

27 ACUTE MYELOID LEUKEMIA WITH MUTATED NPM1 ABOUT ONE-THIRD OF ADULT AML FREQUENCY INCREASES WITH AGE (ONLY 7% IN CHILDREN) HIGHER INCIDENCE IN FEMALE USUALLY DE-NOVO LEUKEMIA CLOSE ASSOCIATION WITH NORMAL KARYOTYPE (85% CASES) 15% CASES CARRY CHROMOSOME ABERRATIONS DIFFERENT FROM AML RECORRENT GENETIC ABNORMALITIES ( WHO ) OFTEN M4 or M5 (also( M1, usually up-like nuclei, M2, M6) MULTILINEAGE INVOLVEMENT NEGATIVITY FOR CD34 (>95% CASES) DISTINCT GEP (UP-REGULATION OF HOX GENES) and mirna PROFILES HIGH FREQUENCY OF FLT3 FLT3-ITD (about( 40%) GOOD RESPONSE TO INDUCTION THERAPY FAVOURABLE PROGNOSIS (in absence of FLT3-ITD) (Falini B, NEJM 2005)

28 Misdiagnoses Diffuse large B-cell B lymphoma: Small lymphocytic lymphoma: Peripheral T-cell T lymphoma, NOS: T-cell precursor lymphoma/leukemia: Anaplastic large cell lymphoma: Myeloid metaplasia: 5 cases 1 case 1 case 1 case 1 case 1 case 10/25 cases without a previous or contemporary malignancy.

29 Extra-medullary haematopoiesis Haemoglobinopathies (ß-thalassaemia) Haemolytic anaemia Splenic cavernous haemangioma IMF G-CSF prolonged administration*. *Friedman HD et al, Ann Hematol 1998, 77: 79-83

30 Spleen: cavernous haemangioma

31 Spleen: IMF

32 Extra-medullary haematopoietic mass following prolonged G-CSF administration

33 Clinical outcome Patients with a concomitant neoplasm: 32/92-26 AML - 1 MPN - 5 MDS Patients with a previous history of neoplasm: 35/92-15 AML - 13 MPN (7 CML, 3 IMF, 2 PV, 1 TE) - 7 MDS Patients without an associated neoplasm: 25/92

34 Clinical outcome Follow-up available in 67 patients 47 CHT 10 BMT (6 allobmt,, 4 autobmt) 5 surgery 3 imatinib-mesylate mesylate 1 radiotherapy 1 no treatment 60 DOD 7 RC (6 AlloBMT,, 1 CHT) 1 MS de novo 4 AML 1 MDS 1 PV

35 Clinical outcome BMT overall survival Other treatments

36 PP Piccaluga, E Sabattini, F Bacci, C Agostinelli, M Rossi, C Sagramoso, S Righi, A Gazzola,, T Sista, M Piccioli, MR Sapienza, C Mannu,, F Fuligni,, F Sandri,, P Artioli,, G De Biase,, G Da Pozzo, C Tigrini,, M Monari and D Bignami