Le neoplasie mieloproliferative

Transcription

1 CORSI DELLA SCUOLA NAZIONALE DI ANATOMIA PATOLOGICA La patologia neoplastica del sistema emolinfopoietico: attualità e prospettive Responsabile del Corso: Prof. Stefano A. Pileri Bologna, Dicembre 2014 Le neoplasie mieloproliferative U. Gianelli Haematopathology Section Pathology Unit IRCCS Ca Granda Maggiore Policlinico Hospital Foundation Milan, Italy [email protected]

2 Le neoplasie mieloproliferative 1. Approccio alla BOM e lesioni elementari delle NMP 2. I criteri diagnostici WHO per le Ph-NMP 3. Le novità della classificazione WHO

3 Parametri morfologici Pattern istologico

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8 Cluster di tipo loose Cluster di tipo dense

9 Haematologica 2005; 90:

10 Requisiti di base di una BOM Biopsia non tangenziale Lunghezza almeno cm 1,5 Spessore ottimale delle sezioni: 3-4 mm (Soprattutto per la valutazione del reticolo!) Dove valutare la fibrosi midollare? La densità delle fibre deve essere valutata nelle aree emopoietiche

11 Vasi -controllo interno della colorazione - non vanno considerati nella valutazione della fibrosi Courtesy of E. Boveri

12 Noduli linfoidi -presentano spesso un addensamento del reticolo - non vanno considerati nella valutazione della fibrosi Courtesy of E. Boveri

13 MF-0 Reticolo lineare sparso, senza intersezioni (cross-overs). Corrisponde al midollo normale Courtesy of E. Boveri

14 MF-1 Network lasso di reticolo con molte intersezioni, specialmente nelle aree perivascolari Courtesy of E. Boveri

15 MF-2 Aumento diffuso e denso del reticolo con estese intersezioni, occasionalmente con focali bande di collagene e/o focale osteosclerosi Courtesy of E. Boveri

16 MF-3 Aumento diffuso e denso del reticolo con estese intersezioni e bande dense di collagene, spesso associato con osteosclerosi Courtesy of E. Boveri

17 Le classificazione delle neoplasie mieloproliferative (WHO 2008)

18 Essential thrombocythaemia ET is a chronic MPN that involves primarily the megakaryocytic lineage. ET incidence: per persons/yr; most cases occur in patients years of age, with no major sex predilection. Clinical features: more than 1/2 of patients are asymptomatic when a markedly elevated platelet count is discovered. The remaining patients present with some manifestation of vascular occlusion or haemorrhage: microvascular occlusion may lead to transient ischaemic attacks, digital ischaemia with paraesthesias, and gangrene. Thrombosis of major arteries and veins may be a cause of splenic or hepatic vein thrombosis as in the Budd-Chiari syndrome. Bleeding occurs most commonly from mucosal surfaces, such as the gastrointestinal tract or upper airway passages. JAK2 V617F mutation is found in about 40 50%.

19 WHO criteria for Essential Thrombocythemia Diagnosis requires meeting all four criteria. (2008)

20 F, 81aa; WBC: 8.75, RBC: 5.28, Hb: 15.1, Htc: 45.2, PTL: 534 JAK2(+); LDH: 201; EPO: 3.55

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24 MF-0

25 M, 33; WBC: 8.1, RBC: 4,7, Hb: 14.9, Htc: 42, PTL: 799 JAK2(+); EPO: 3.6

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30 MF-0

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32 Primary myelofibrosis PMF is a clonal MPN characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow (BM) that in fully developed disease is associated with reactive deposition of fibrous connective tissue and with extra medullary haematopoiesis (EMH). There is a stepwise evolution from an initial prefibrotic (cellular phase) characterized by a hypercellular BM with absent or minimal reticulin fibrosis to a fibrotic phase with marked reticulin or collagen fibrosis in the BM and often osteo sclerosis. This fibrotic stage of PMF is characterized by leukoerythroblastosis in the blood with teardrop-shaped red cells and by hepatomegaly and splenomegaly

33 The overt fibrotic phase is estimated to occur at per person /yr. It occurs most commonly in the 6 th to 7 th decade of life, and both sexes are nearly equally affected. Clinical features: up to 30% of patients are asymptomatic at the time of diagnosis and are discovered by detection of splenomegaly during a routine physical examination or when a routine blood count discloses anaemia, leukocytosis and/or thrombocytosis or increased LDH. Constitutional symptoms may include fatigue, dyspnoea, weight loss, night sweats, low grade fever and bleeding episodes. Splenomegaly of varying degree is detected in up to 90% of patients and may be massive; nearly 50% have hepatomegaly. The JAK2 V617F mutation may be found in ~50-60% of patients

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35 WHO criteria for Primary Myelofibrosis Prefibrotic cellular phase Fibrotic phase Diagnosis requires meeting all 3 major and 2 minor criteria. (2008)

36 F, 72; WBC: 6.88; RBC: 3.28; Hb: 9.9; Htc: 36; PTL: 408; JAK2(-); EPO: 2.29; LDH: 381

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41 MF-1

42 MF-1

43 M, 36 WBC: 7.98, RBC: 4.41, Hb: 13.2 Htc: 36, PTL: 578 JAK2(+); EPO: 57.1; LDH: 509

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48 MF-3

49 MF-3

50 Polycythaemia vera PV is a chronic MPN characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. Virtually all patients carry the somatic gain-of-function mutations of the Janus 2 kinase gene that results in proliferation not only of the erythroid lineage but of the granulocytes and megakaryocytes as well, i.e. panmyelosis. Three phases of PV may be recognized: (1) a prodromal, prepolycythaemic phase characterized by borderline to only mild erythrocytosis; (2) an overt polycythaemic phase, associated with a significantly increased red cell mass; and (3) a spent or postpolycythaemic myelofibrosis phase in which cytopenias, including anaemia, are associated with ineffective haematopoiesis, bone marrow fibrosis, extramedullary haematopoiesis, and hypersplenism.

51 The incidence of PV varies from 0.7 to 2.6 per inhabitants in Europe and North America; slight male predominance, with the M:F ratio ranging from 1 2:1; the median age at diagnosis is 60 years. Clinical features: symptoms are related to hypertension or vascular abnormalities caused by the increased red cell mass. In nearly 20% of patients an episode of venous or arterial thrombosis, such as deep and splanchnic vein thrombosis (Budd-Chiari syndrome), myocardial ischaemia or stroke, is documented in the medical history and may be the first manifestation of PV. Headache, dizziness, visual disturbances and paraesthesias are major complaints, and pruritus, erythromelalgia and gout are also common. In the full-blown polycythaemic stage physical findings usually include plethora and palpable splenomegaly in 70% and hepatomegaly in 40% of patients

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53 WHO criteria for Polycythemia Vera Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria. (2008)

54 M, 75 WBC: 11.78; RBC: 5.78; Hb: 18.3; Htc: 49.8, PTL: 594 JAK2(+); EPO: 1.54

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58 MF-0

59 F, 63aa; WBC: 11.19; RBC: 5.74; Hb: 16.7; Htc: 48, PTL: 495 JAK2(+); EPO: 2.07

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63 Myeloproliferative neoplasm, unclassifiable The designation MPN, U should be applied only to cases that have definite clinical, laboratory and morphological features of an MPN but that fail to meet the criteria for any of the specific MPN entities, or that present with features that overlap two or more of the MPN categories. Most cases of MPN, U, will fall into one of three groups: 1) Early stages of PV, PMF or ET, in which the characteristic features are not yet fully developed; 2) Advanced stage MPN, in which pronounced myelofibrosis, osteo sclerosis, or transformation to more aggressive stage (i.e. increased blasts and/or dysplasia) obscures the underlying disorder ; 3) Patients with convincing evidence of an MPN in whom a co-existing neoplastic or inflammatory disorder obscures some of the diagnostic clinical and/or morphological features.

64 M, 75aa; WBC: 8.93; RBC: 5.55; Hb: 16.8; Htc: 49.6, PTL: 571 JAK2(+); EPO: 1.79

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68 Criteri istologici aggiuntivi, utili per la diagnosi di NMP

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70 113 pts - 98 PMF - 15 MF-post PV (Mayo PSS) Vener et al. Blood :

71 Gianelli U et al. Mod Pathol. 2012; 25: Vs IPSS Risk factors Age > 65 years Constitutional symptoms Hb < 10g / dl WBC count > 25 x 10 9 /L Blood blasts > 1% 196 pts PMF

72 The simultaneous use of both IPSS and E-BMF scoring systems allows for a more precise prediction of survival (*) Hazard Ratio was calculated using both E-BMF=MF-0 and IPSS=0 as references LR = Likelihood Ratio Univariate analysis LR = 19.6 (IPSS) and 29 (E-BMF) Multivariate analysis LR = 42.3

73 The simultaneous use of both scoring systems allows for a more precise prediction of survival.

74 The MVD-HS method revealed statistically significant differences between NC ( ), ET ( ), PV ( ), and CIMF ( ) NCs ET PV Gianelli et al. Am J Clin Pathol, 2007;128: CIMF

75 Questo il presente.e il prossimo futuro?

76 WHO CLINICAL ADVISORY COMMITTEE MEETING, CHICAGO, MARCH 31- APRIL 1, 2014

77 Some points of discussion on Ph-MPNs Integration of CALR mutational status in the diagnostic algorithm for ET and PMF Clinical features and bone marrow pathology of masked PV

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79 Patients with CALR-mutated ET were significantly younger than those with JAK2- mutated ET (P ). Compared with patients with CALR-mutated ET, those with JAK2-mutated ET had higher hemoglobin (Hb) level and white blood cell (WBC) count, and lower platelet (PLT) count and serum erythropoietin (Epo) level. There was no significant difference in myelofibrotic transformation between the 2 subtypes of essential thrombocythemia. Patients with JAK2-mutated essential thrombocythemia and those with polycythemia vera had a similar risk of thrombosis, which was twice that of patients with the CALR mutation.

80 CALR mutations were associated with younger age (P<0.0001), higher platelet count (P<0.0001) and lower DIPSS-plus score (P=0.02). CALR-mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status (P=0.001; HR 3.4 for triple-negative and 2.2 for JAK2- mutated).

81 Tefferi A. et al. Leukemia, 2014; 28:

82 Some points of discussion on Ph-MPNs Integration of CALR mutational status in the diagnostic algorithm for ET and PMF Clinical features and bone marrow pathology of masked PV

83 In this study, we compared the clinico-pathologic and molecular features of 17 patients with e-pv(*) with those of 14 patients with ET and 19 with PV. The results for e-pv were more similar to those for PV than for ET. Patients with e-pv showed a hypercellular marrow due to increased erythropoiesis and granulopoiesis, associated with megakaryocytic hyperplasia, with pleomorphic aggregates (P <.001) (*) Ptl > /L and upper limit or increased Hb levels but lower than necessary for a PV diagnosis; pp-pv developed (median time of evolution, 9 years; range, 2-17 years).

84 140 patients JAK2(+) and a bone marrow morphology conforming with WHO criteria of PV, but a Hb level of <18.5 g/dl in males (range ) and <16.5 g/dl in females (range ). Am J Hematol. 2014;89: This cohort was compared with 257 patients with overt PV and displayed male predominance, a more frequent history of arterial thrombosis and thrombocytosis. In multivariable analysis mpv diagnosis was an independent predictor of poor survival along with age >65 years and leukocyte count >10X10 9 /L

85 European LeukemiaNet study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia Hans Michael Kvasnicka, 1* Attilio Orazi, 2* Juergen Thiele, 3* Giovanni Barosi, 4 Carlos E. Bueso-Ramos, 5 Alessandro M. Vannucchi, 6 Robert P. Hasserjian, 7 Jean-Jacques Kiladjian, 8 Umberto Gianelli, 9 Richard Silver, 12 Tariq I. Mughal, 16 and Tiziano Barbui 1 A total of 98 JAK2-positive cases was selected for the blinded review from two different sources: - the Frankfurt database from which 74 patients were recruited including overt PV (n=25), mpv (n=27), ET (n=10) and other control specimens (n=12) - the New York database from which 24 samples were selected presenting with mpv (n=15), overt PV (n=7), and ET (n=2) Concordance among six panelists concerning PV diagnosis and controls Overall agreement 92.6 % Fleiss Kappa Intraclass correlation (ICC) 0.982

86 Key points to discriminate ET from masked PV ET Cellularity (age-matched) normocellular (< 20% slightly hypercellular) Increased lineage(s) Megakaryocytes no left shift in erythro- /granulopoiesis Morphological characteristics large/giant, mature megakaryocytes with hyperlobulated nuclei Bone marrow stroma minor increase in reticulin fibers <5% normal sinus very rarely lymphoid nodules Molecular features* hypercellular Masked PV (mpv) erythro-/megakaryo- /granulopoiesis (panmyelosis) left shift in erythro- and granulopoiesis Mature megakaryocytes with significant variability in size (pleomorphism) minor increase in reticulin fibers <20% dilated sinus up to 20% reactive lymphoid nodules JAK2: 64%, CALR: 15%, 100% JAK2 / Exon 12

87 Tefferi A. et al. Leukemia, 2014; 28:

88 Grazie!