1. Coding Haematological Malignancies in Cancer Registries part I : Myeloid malignancies Pr Marc Maynadié Registre des Hémopathies Malignes de Côte d'Or Faculté de Médecine de Dijon marc.maynadie@u-bourgogne.fr

2. Four types of disorders  Acute transformation of a precursor ± differentiated  Acute Myeloid Leukemia (AML)  Proliferation of all stages of differentiation without major cytological abnormalities  Chronic myeloproliferative neoplasm (CMN)  Proliferation with marked cytological abnormalities  Myelodysplastic Syndromes (MDS) Mixed proliferation :  Myelodysplastic/myeloproliferative neoplasm

3. Acute Myeloid leukemia Proliferation of blast cells with blocking of differentiation

4. EntitiesICD-O- 3 codesn%Incidence RateSex RatioMean Age RHEMCO 1980-2004 /100.000 inhabitants /year MenWomenallMenWomen AML with recurrent cytogenetic abnormalities 5611.90.4 0.954642 AML with t(8;21) (q22;q22)989691.90.1 0.95831 AML with 11q23 abnormalities989720.40.0- -32- AML with inv(16)(p13;q22) or t(16;16)(p13;q11)9871112.30.1 1.62644 AML with t(15;17)(q22;q11-12)9866347.30.20.30.20.75244 AML with Multilineage Dysplasia 989511524.60.5 16970 AML and MDS, Therapy Related 9920, 9987153.20.1 0.75*7464 AML not otherwise categorised 23049.11.511.21.56164 AML, minimal differentiated9872194.00.1 16561 AML, without maturation9873194.00.1 1.35061 AML, with maturation98748217.50.40.30.41.36567 Acute Myelomonocytic Leukemia98674810.20.30.2 2.0 *6267 Acute Monoblastic and Monocytic Leukemia9891326.80.30.10.21.9 *56 Acute erythroid Leukemia9840142.90.1 1.66062 Acute megakaryoblastic Leukemia991000------ Acute basophilic Leukemia987000------ Acute panmyelosis with myelofibrosis9931142.90.10.00.11.46573 Myeloid sarcoma993020.400.00.01--67 AML, nos and AL of ambiguous lineage 9861, 98055211.10.30.2 1.8 *65 All Acute Myeloid Leukemia4681002.82.22.51.3***6263

5. Acute myeloid leukemia Proliferation of myeloid blast cells  Blasts : Seen on blood or bone marrow smears = cytology  Myeloid : Cytological specific stains : Peroxydases  Immunophenotyping : – myeloid markers : CD13, CD33, CD15, CD65, CD177, MPO.

6. List of AML in 2000 4 categories of AML  AML with recurrent cytogenetic abnormalities  AML with multilineage dysplasia  AML post therapy  Other

7. AML in 2008 1. AML with recurrent cytogenetic abnormalities 2. AML with myelodysplasia-related changes9895/3 3. Therapy-related myeloid neoplasms (AML and MDS)9920/3 4. AML, NOS 5. Myeloid sarcoma9930/3 6. Myeloid leukemia associated with Down syndrome (trisomy 21) 7. Blastic plasmocytoid dendritic cell neoplasm9727/3

8. AML with recurrent cytogenetic abnormalities 1. AML with t(8;21)(q22;q22)[RUNX1-RUNX1T1]9896/3 Acute Leukemia: blasts in bone marrow or blood smears Myeloid:  auer rods  or peroxydase  ex M2  or immunophenotype: CD13, CD33, MPO Karyotype: t(8;21)(q22;q22) Molecular Biology: AML 1/ETO Mandatory

9. AML with recurrent cytogenetic abnormalities 2. AML with t(15;17)(q22;q22)[PML/RAR  ]9866/3 Abnormal promyelocytesM3, Promyelocytic AML Auer rods +++ Karyotype: t(15;17)(q22;q12) Molecular Biology: PML/RAR  Variants: t(11;17) ; t(5;17) ; t(11;17) Mandatory

10. AML with recurrent cytogenetic abnormalities 3. AML with inv(16) or t(16;16) [CBF  /MYH11] 9871/3 Myeloid blasts with abnormal eosinophilsM4-Eo Karyotype: inv(16) (p13;q22) or t(16;16) (p13;q22) Molecular Biology: CBF  /MYH11 Mandatory

11. AML with recurrent cytogenetic abnormalities 4. AML with 11q23 abnormalities AML with t(9;11)(p22;q23) [MLLT3-MLL]9897/3 Myeloid blast cells Cytogenetic abnormalities in 11q23 Molecular Biology: MLL abnormalities Mandatory

12. AML with recurrent cytogenetic abnormalities AML with t(8;21)(q22;q22)9896/3 AML with inv(16)(p13.1;q22)or t(16;16) 9871/3 AML with t(15;17)9866/3 AML with t(9;11)(p22;q22) 9897/3 AML with (6;9)(p23;q34) [DEK-NUP]9865/3 AML with inv(3) or t(3;3) [RPN1-EVI1]9869/3 AML (megakaryoblastic) with t(1;22)9911/3 AML with mutated NPM19861/3 AML with mutated CEPB  9861/3

13. AML with multilineage dysplasia9895/3 After a pre-existing myelodysplastic syndrome or not  Myelogram: deep dysplasia  Medical chart  Myeloid markers: CD13, CD33, CD34  Cytogenetic: -7, del(7q), -5, +8, +9, +21

14. AML and MDS secondary to treatment History of treatment:  alkylating agents (5-6 years)  topoisomerase II inhibitors (2-3 years)  radiotherapy and chemotherapy Bone marrow blast cells Medical history 9920/3

15. AML, NOS (AML without other characteristic) 9861/3 AML with minimal differentiation9872/3 AML without maturation9873/3 AML with maturation9874/3 Acute myelomonocytic leukaemia9867/3 Acute monoblastic or monocytic leukaemia9891/3 Acute erythroid leukaemia9840/3 Acute megakaryoblastic leukaemia9910/3 Acute basophilic leukaemia9870/3 Acute panmyelosis with myelofibrosis9931/3

16. AML, NOS 1. AML with minimal differentiation9872/3 Ex M0 Myelogram: blasts cells peroxydase Θ Markers: CD117, CD34, CD13, CD33, MPO 

17. 2. AML without maturation9873/3 Ex M1 Myelogram: blastes ≥ 90%, peroxydases  Phenotype: CD34, CD13, CD33, CD117, MPO  AML, NOS

18. 3. AML with maturation9874/3 ex M2 Myelogram: blastes < 90%, peroxydase  Phenotype: CD13, CD33, CD65, CD15, MPO 

19. AML, NOS 4. Acute myelomonocytic leukaemia9867/3 Ex M4 Presence of ≥ 20% blastes peroxydases  and monocytes or monoblastes Phenotype: CD13, CD33 and CD14, CD4, CD64

20. AML, NOS 5. Acute monoblastic and monocytic leukaemia9891/3 Ex M5a and M5b Myelogram: monoblasts or monocytes, promocytes > 80% Phenotype: CD13, CD33 and CD 14, CD4, CD64

21. AML, NOS 6. Acute erythroid leukemia9840/3 Ex M6a and M6b, pro-erythroblastic leukaemia Myelogram: erythroblasts at all stages of differentiation in varying proportions Phenotype: CD36, glycophorine A

22. AML, NOS 7. Acute megakaryoblastic leukemia9910/3 Ex M7 Myelogram: megakaryoblasts ≥ 50%, peroxydases Θ Phenotype: CD36, CD61, CD41, CD42 Karyotype: t(1,22);inv(3);… 9911/3; 9869/3

23. Acute basophilic leukemia9870/3 Acute panmyelosis with myelofibrosis9931/3  or acute myelofibrosis  or acute myelosclerosis Osteo medullary biopsy  or myelofibrosis AML, NOS

24. Myeloid Sarcoma Myeloid sarcoma9930/3  or extramedullary myeloid tumor  or granulocytic sarcoma  or chloroma Osteo medullary Biopsy mandatory

25. Acute leukemia of ambiguous lineage Acute undifferentiated leukemia9801/3 Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL19806/3 Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged9807/3 Mixed phenotype acute leukemia B/myeloid, NOS9808/3 Mixed phenotype acute leukemiaT/myeloid, NOS9809/3 Natural killer (NK) / cell lymphoblastic leukemia/lymphoma

26. Registration Diagnostic bases  can only be5 (cytology) or 7 (histology)  No 4 : cytology is mandatory to say that there are blasts cells Archive: essential exams that have made the diagnosis Morphology code: ICD-O-3 Topography code: C42.1 always except granulocytic sarcoma

27. Myeloproliferative neoplasms Proliferation of cells at all stages of differentiation without major cytological abnormalities

28. Epidemiology of MPN IncidenceSex ratio Mean age 5-y RS20-y RS CML0.91.55660%18% PV0.61.36597%47% ET 1.2 (increasing) 0.96593%50% MF0.437055%4% All3.21.46379%34% Données RHEMCO, 1980-2004

29. Myeloproliferative neoplasms Chronic myelogenous leukemia, BCR-ABL1 positive9875/3 Chronic neutrophilic leukemia9963/3 Polycythemia vera9950/3 Primary myelofibrosis9961/3 Essential thrombocythemia9962/3 Chronic eosinophilic leukemia, NOS9964/3 Mastocytosis Systemic mastocytosis9741/3 Mast cell leukaemia9742/3 Myeloproliferative neoplasm, unclassifiable9975/3

30. Chronic myelogenous leukaemia 9875/3 Blood  Hyperleukocytosis made of neutrophils  Myelemy, eosinophilia, basophilia  Accelerated phase: blasts 10-19% Myelogram: very rich, granular Karyotype: t(9;22)(q34;q11) Molecular Biology: BCR/ABL

31. Polycytemia vera9950/3 Diagnosis according to many criteria  Red Blood cells mass > 25%  Hb > 18.5 g/dl (M) and 16.5 g/dl (W)  EPO collapsed  Myelogram: no positive sign  Karyotype: no t(9;22)(q34;q11)  Molecular biology: no BCR/ABL... JAK2 mutated (V617F) in 95% of cases

32. Essential thrombocythemia9962/3 Diagnosis according to many criteria  Platelets > 450 000 x 10 6 /L  No sign of PV or other MPN  Myelogram: no positive sign  Karyotype: no t(9;22)(q34;q11)  Molecular biology: no BCR/ABL...  No MDS, other cause of thrombocytosis  Diagnosis of exclusion JAK2 mutated in 65% of cases

33. Primary myelofibrosis9961/3 Proliferation of platelet with rapid progression to fibrosis and development of extramedullary hematopoiesis Diagnosis:  blood signs: poïkylocytosis  splenomegaly  bone marrow biopsy +++ Phenotype, karyotype, molecular biology: nothing

34. Other MPN Chronic neutrophilic leukaemia9963/3 Chronic eosinophilic leukaemia9964/3 Myelodysplastic/myeloproliferative neoplasm, unclassifiable9975/3 Mastocytoma

35. Systemic mastocytoma9741/3 Mast cell leukaemia9742/3 Mast cell sarcoma9740/3 Extracutaneous/cutaneous mastocytoma9740/ 1

36. Registration Diagnostic bases  can only be5 (cytology) or 7 (histology)  No 4 or 6 : not useful in hematology Archive: essential exams that have made the diagnosis Morphology code: ICD-O-3 Topography code: C42.1

37. Myelodysplastic syndromes Proliferation with major cytological abnormalities

38. Myelodysplastic syndromes Refractory cytopenia with unilineage dysplasia  Refractory anemia9980/3  Refractory neutropenia9991/3  Refractory thrombocytopenia9992/3 Refractory anemia with ring sideroblasts9982/3 Refractory cytopenia with multilineage dysplasia9985/3 Refractory anemia with excess blasts9983/3 Myelodysplastic syndrome associated with isolated del(5q)9986/3 Myelodysplastic syndrome, unclassifiable9989/3 Childhood myelodysplastic syndrome  Refractory cytopenia of childhood9985/3 ! !

39. Epidemiology of MDS IncidenceSex ratio Mean age 5-y RS20-y RS RA0.261.37557%20% RAS0.41.8**7770%- RAEB0.552.5**7422%- 5q-0.040.28047%- All1.352***7545%6% Données RHEMCO, 1980-2004

40. Refractory anemia9980/3 Aregenerative anemia, normochromic mormocytic, isolated No sign of positive diagnosis  Myelogram: erythroblasts at all stages of differentiation in varying proportions  Normal karyotype in 50% of cases  Culture of progenitor cells: normal in 50% of cases Diagnosis of elimination

41. Refractory anaemia with ring sideroblasts 9982/3 Aregenerative anemia, normochromic mormocytic or macrocytic, isolated No sign of positive diagnosis  Over 15% of ringed sideroblasts in the Perls staining in erythroblasts on the myelogram

43. Refractory cytopenia with multilineage dysplasia 9985/3 Thrombocytopenia, neutropenia with or without anemia No sign of positive diagnosis  Myelogram: dysplasias not always very specific  Normal karyotype in 50% of cases  Culture of progenitor cells: normal in 50% of cases Diagnosis of elimination

44. Refractory anaemia with excess blasts 9983/3 Aregenerative Anemia, bicytopenia or tricytopenia Myelogram: presence of blast cells between 5 and 19%

45. MDS associated with isolated del(5q) Aregenerative anemia, normochromic mormocytic isolated Karyotype: positive diagnosis  Myelogram: some specific abnormalities of neutrophils or megakaryocytes  Karyotype: isolated loss of the long arm of chromosome 5 9986/3

46. Myelodysplastic/myeloproliferative neoplasms Intermediate forms difficult to classify in one or other of the above categories

47. Myelodysplastic/myeloproliferative neoplasms Chronic myelomonocytic leukaemia9945/3 Atypical chronic myeloid leukaemia BCR-ABL1 negative9876/3 Juvenile myelomonocytic leukaemia9946/3 Myelodysplasic/myeloproliferative neoplasm, unclassifiable9975/3 Refractory anaemia with ring sideroblasts associated with marked thrombocytosis 9982/3 (RAS)

48. Chronic myelomonocytic leukaemia 9945/3 Blood monocytes > 10 3 /mm 3 persistent Cytopenia or leukocytosis Myelogram : Dysplasia of one or more lines Abundant monocytes Less than 20% blasts Karyotype: no t(9;22) The same thing with a child under 15 years Juvenile myelomonocytic leukaemia9946/3

49. Atypical chronic myeloid leukaemia 9876/3 Very similar to chronic myeloid leukemia but  Karyotype : no t(9;22), sometimes +8, del(20q),…  Molecular biology: no BCR/ABL rearrangement

50. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 Myeloid and lymphoid neoplasms with PDGFRA rearrangement9965/3 Myeloid neoplasms with PDGFRB rearrangement9966/3 Myeloid and lymphoid neoplasms with FGFR1 abnormalities9967/3 New category Codes proposed for ICD-0-4

51. Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis9898/1 Myeloid leukemia associated with Down syndrome9898/3

52. specificities MDS secondary to treatment : added to AML secondary to treatment : 9920/3 (Therapy-related myeloid neoplasms) AML following MDS : AML with multilineage dysplasia AML following a known previous MDS or MPN : not an incident cases AML is occuring in the natural history of MDS, MPN, and MDS/MPN : they are not multiple primaries RA can evolves in RAEB PV, ET and PMF can be found in the evolution in the same patient

54. Entities ICD-O- 3 codes n%Incidence RateSex ratioMean Age RHEMCO 1980-2004 /100,000 inhabitants /year MenWomenallMenWomen Refractory Anemia998069200.30.20.31.3*7973 Refractory Anemia with Ringed Sideroblasts9982121350.60.30.41.8**7679 Refractory Anemia with Excess of Blasts9983131380.80.30.52.5***7276 Refractory Cytopenia with Multilineage Dysplasia9985510.00 -74 - MDS associated with isolated del (5q)99861030.00.10.00,28473 MDS, unclassifiable (nos)9989930.10.0 4.35771 All Myelodysplastic Syndromes3451001.91.01.32***7476 Chronic Myelogenous Leukaemia9863, 9875141241.10.70.91.5*56 Polycythaemia vera9950116200.70.6 1.36566 Essential thrombocythaemia9962229391.11.2 0,965 Primary myelofibrosis996175130.60.20.42.9***6773 Others9963, 996400 - - - - - - Myeloproliferative neoplasm unclassifiable9960, 99752340.20.00.14.5**7080 All Myeloproliferative Neoplasms5841003.72.73.21.4***6364 Chronic Myelomonocytic Leukemia9945146960.80.30.53.3***7682 Juvenile Chronic Myelomonocytic Leukemia99461100.0 - -1 Atypical Chronic Myeloid Leukemia9876530.100.0 -59 - Myelodysplastic/Myeloproliferative N.1521000.90.30.63***7680

55. WPS Incidence rate of AML in Côte d’or, 1980-2004

56. WPS Incidence rate of MDS and MPN in Côte d’or, 1980-2004

57. PeriodAMLMDSMPNMDS/MPN MWMWMWMW 1980-19842.62.51.00.83.82.10.70.2 1985-19891.82.72.10.83.12.91.10.1 1990-19943.01.61.81.34.42.80.60.3 1995-19993.92.61.90.74.02.81.20.4 2000-20043.11.82.31.233.31.10.5 Annual rate 1.3% - 1.1%2.0 % * 2.9 % * -0.6 %2.3% ** 1.7 %3.8 % Evolution of WPS Incidence rate in Côte d’or, 1980-2004

58. WPS Incidence rate of AML in Côte d’or, 1980-2004

59. 5 –year Relative Survival, by age in 22 European countries MM - Toledo - GRELL 2010 MDS/MPN18.7 % MPN62.7 % MDS30.7 % AML17.0 %

60. 5 –year Relative Survival, by age MM - Toledo - GRELL 2010 MDS/MPN18.7 % MPN62.7 % MDS30.7 % AML17.0 %

61. AML : Period RS estimates 2000-2002 by follow up time MM - Toledo - GRELL 2010 AML Multilineage dysplasia Cytogenetic abnormalities Others with Myelofibrosis

62. Myelodysplysplastic syndrome : Period RS estimates 2000-2002 by follow up time MM - Toledo - GRELL 2010 MDS MDS, NOS RAEB RA RARS

63. Myeloproliferative neoplasm : Period RS estimates 2000-2002 by follow up time MM - Toledo - GRELL 2010 MPN PV, TE,.. MPN, NOS CML

64. Relative Survival of AML in Côte d’or, 1980-2004

65. Relative Survival of MDS in Côte d’or, 1980-2004

66. Epidemiology AMLMDSMPNMDS/MPN Incidence (WSP)2.51.33.20.6 Sex ratio1.3***2***1.4***3*** Mean age62766480 % of evolution of incidence / y +1+2.5*+2.3** ( W)+2.5 5-y Relative Survival (%) 173062.718.7 20-y Relative Survival (%) 13634-