PRECURSOR LYMHPOID NEOPLASMS. B lymphoblastic leukaemia/lymphoma T lymphoblastic leukaemia/lymphoma
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1 PRECURSOR LYMHPOID NEOPLASMS B lymphoblastic leukaemia/lymphoma T lymphoblastic leukaemia/lymphoma
2 B lymphoblastic leukaemia/lymphoma Definition: B lymphoblastic leukaemia/lymphoma is a neoplasm of precursor cells (lymphoblasts) committed to B-cell lineage lymphoma (LBL) : process confined to a mass lesion with no or minimal evidence of peripheral blood and bone marrow involvement (<25%) leukaemia (ALL) : extensive peripheral blood and bone marrow involvement (distinction arbitrary, in patients with mass and lymphoblasts in bone marrow) Epidemiology: primarily a disease of children (75% of ALL < 6 years) > 80 of ALL in childhood > 75% of ALL in adults 10% of LBL Sites of involvement: bone marrow peripheral blood extramedullary involvement (skin, lymph node, liver, spleen, CNS, testis) mediastinal masses infrequent
3 relatively uniform round oval chromatin finely dispersed nucleoli inconspicuos to prominent nuclei ndented or convoluted
4 lymph node GC starry sky extramedullary involvement
5 skin extramedullary involvement testis
6 M5? CD79a MORFOLOGIA ASPECIFICA
7 MCL blastoid variant BCL1
8 B-LYMPHOCYTES MATURATION BONE MARROW pre-bcr BCR IgM IgM BCR IgD HSC lymphoid stem cell pre-pro-b pro-b pre-b immature-b mature naïve-b CD117 CD34 surface markers CD10 CD19 CD22 CD20 cytoplasmic markers CD79a nuclear markers PAX5 IG genes DJ H VDJ H VDJ H VDJ H VJ k/λ VDJ H VJ k/λ
9 CD34 CD10
10 B-LYMPHOCYTES MATURATION BONE MARROW pre-bcr BCR IgM IgM BCR IgD HSC lymphoid stem cell pre-pro-b pro-b pre-b immature-b mature naïve-b CD117 CD34 surface markers CD10 CD19 CD22 CD20 cytoplasmic markers CD79a nuclear markers PAX5 IG genes DJ H VDJ H VDJ H VDJ H VJ k/λ VDJ H VJ k/λ
11 PAX5 (BSAP) is a member of the highly conserved paired box (PAX)-domain family of transcription factors PAX5 It is encoded by the homologous PAX5 gene and: favours V H to D H J H rearrangements activates the expression of B-cell specific genes (CD79a, CD19, RAG) represses of non-b lymphoid genes Expression in pro-b, pre-b, mature B cells Most sensitive and specific marker for B-ALL/LBL but Pax5 is expressed in t(8;21)-aml (together with CD79a and CD19) Giemsa MPO PAX5 Tiacci et al Cancer Res 2004, Valbuena et al Am J Clin Pathol 2006
12 CD79a T-ALL/LBL CD3 CD79a
13 CD3 CD45 -/+ T-cell markers negative myeloid markers negative CD13 and CD33 may be expressed CD20 MPO CD68PGM1
14 B-LYMPHOCYTES MATURATION BONE MARROW pre-bcr BCR IgM IgM BCR IgD HSC lymphoid stem cell pre-pro-b pro-b pre-b immature-b mature naïve-b CD117 CD34 surface markers CD10 CD19 CD22 CD20 cytoplasmic markers CD79a nuclear markers PAX5 IG genes DJ H VDJ H VDJ H VDJ H VJ k/λ VDJ H VJ k/λ
15 Locus β chain T-cell receptor gene rearrangements may be seen (up to 70%) J Van Dongen et al Leukaemia 2000 β2 Sànchez-Garcia et al Leukaemia 2000 Van der Velden et al Leukaemia 2004 V β V βn D β1 J β1 C β1 D β C β2 Locus αδchains V α V αn J α (70) C β2 V δ1 V δ2 V δ3 D δ1 D δ2 D δ3 J δ1 J δ2 J δ3 C δ V δ4 Locus γ chain Vγ1 Vγ8 Vγ9 Vγ10 Vγ11 Jγ1 Cγ1 Jγ2 Cγ2
16 pro-b CD CD10 + CD20 - CD34 CD20 CD79A cd79 B-ALL/B-LBL pre-b CD34 +/- +/- CD10 + CD20 -(-/+) Cμ + SIgM - CD10 CD20 PAX5 Immature B CD CD10 + CD20 -/+ Cμ - SIgM (-/+) CD34 CD20
17 lymph node in adult Bone marrow from patient 3 yrs old caspasi deficit HHV7 chronic infection CD79a Onciu et al Am J Clin Pathol 2002 increased number of immature lymphoid cells (haematogones)resembling lymphoblast are sometimes seen in children and, rarely in adolescent and adults, can be observed after CHT for ALL after bone marror transplantation in infections in non-haematopoietic tumours They are polymorphic and express CD79a, CD34,, CD10 CD34
18 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4 Edition B lymphoblastic leukaemia/lymphoma, not otherwise specified B-ALL/LBL B lymphoblastic luekaemia/lymphoma, with recurrent genetic abnormalities with t(v;11q23); MLL rearranged with t(9;22)(q34;11.2);bcr-abl1 with hypodiploidy t(5;14)(q31;q32); IL3-IGH with t(1;19)(q23;p13.3);e2a-pbx1 with hyperdiploidy with t(12;21)(q13;p22);tel-aml1 (ETV6-RUNX1)
19 Who 2008 chapter 9 B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged translocation in utero most common ALL < 1 yrs leukaemia with high WBC >100x10 9 /L >CNS at diagnosis fusion partner AF4 pro-b CD10 -, CD15 +, NG2 + prognosis: poor (particularly <6 months) B lymphoblastic leukaemia/lymphoma with t(9;22)(q34;11.2);bcr-abl1 most common in adults (25% ALL) leukaemia CD10 +, CD25 +, often CD13 +, CD33 + prognosis: worst prognosis among ALL B lymphoblastic leukaemia/lymphoma with hypodiploidy loss of one or more chromosomes (from 45 to near haploid) children and adults structural abnormality uncommon prognosis: poor (depends on the number of chromosomes) Who 2008 chapter 4 B lymphoblastic leukaemia/lymphoma with t(5;14)(q31;q32); IL3-IGH <1% children and adults symptomatic eosinophilia (rwactive) with few blasts in PB prognosis: few case to be certain Who 2008 chapter 9
20 B lymphoblastic leukaemia/lymphoma with t(1;19)(q23;p13.3);e2a-pbx1 6% of B-ALL in children pre-b CD9 +, CD34 - prognosis: was associated with poor prognosis but this is readily overcome with modern intensive therapy Who 2008 chapter 9 B lymphoblastic leukaemia/lymphoma with hyperdiploidy increased number of chromosomes without structural abnormality (usually >50 <66) 25% children prognosis: favourable (cures in >90%) B lymphoblastic leukaemia/lymphoma with t(12;21)(q13;p22);tel-aml1 (ETV6-RUNX1) 25% children translocation is an early event (in utero?), but no sufficient for the development of leukaemia; late relapse could derive from preleukaemic clones prognosis: favourable (cures in >90%) especially if others favourable factors are presents Who 2008 chapter 9
21 T lymphoblastic leukaemia/lymphoma Definition: B lymphoblastic leukaemia/lymphoma is a neoplasm of precursor cells (lymphoblasts) committed to T-cell lineage lymphoma (LBL) : process confined to a mass lesion with no or minimal evidence of peripheral blood and bone marrow involvement (<25%) leukaemia (ALL) : extensive peripheral blood and bone marrow involvement (distinction arbitrary, in patients with mass and lymphoblasts in bone marrow) Epidemiology: 15% of ALL in childhood more common in adolescents 25 % of ALL in adults 90 % of LBL Sites of involvement: bone marrow peripheral blood extramedullary involvement (skin, lymph node, liver, spleen, CNS, testis) frequent mediastinal masses (thymic)
22 MO LN B B Stem cells +, CD34 + T Thymus T perpheral organs T T B spleen
23 T-cell ontogenesis thymus medulla periphery bone marrow ?? 3ε 3ε 7 3ε lymphoid stem cell pro-t 7 cortex 1a 2 4 3ε 5 TCR α,β a 2 3ε TCR γ,δ 5 pre-t TCR α,β TCR α,β TCR γ,δ Mature-T 3 5 7
24 KWS thymus GC lymph node
25 CD99 CD34 CD1a
26 pro-t CD3c + + CD34 + CD1a- CD4 - / CD8 - CD34 CD4 CD8 T-ALL/B-LBL pre-t CD3c + + CD34 + CD1a- CD2 + CD4 - / CD8 - CD34 CD8 CD3a cyt CD3 CD7 + and CD2 + CD13 + and CD33 + in 20% cortical-t medullary-t CD3c + + CD34 - CD1a + CD2 + CD4 + / CD8 + CD3c + /CD3s + - CD34 - CD1a -. CD2 + CD4 + or CD8 + CD34 CD3 CD4 CD8 CD8
27 T-cell ontogenesis thymus medulla periphery bone marrow ?? 3ε 3ε 7 3ε lymphoid stem cell pro-t 7 cortex 1a 2 4 3ε 5 TCR α,β a 2 3ε TCR γ,δ 5 pre-t TCR α,β TCR α,β TCR γ,δ Mature-T 3 5 7
28 CD3 CD79a PAX5 Hashimoto et al.2002 CD79a in 50% of T-ALL/LBL normal thymus ly in thymomas
29 pro-t CD3c + + CD34 + CD1a- CD4 - / CD8 - CD34 CD4 CD8 T-ALL/B-LBL pre-t CD3c + + CD34 + CD1a- CD2 + CD4 - / CD8 - CD34 CD8 CD3a cyt CD3 CD7 + and CD2 + CD13 + and CD33 + in 20% cortical-t medullary-t CD3c + + CD34 - CD1a + CD2 + CD4 + / CD8 + CD3c + /CD3s + - CD34 - CD1a -. CD2 + CD4 + or CD8 + CD34 CD3 CD4 CD8 CD8
30 T-cell Prolymphocitic Leukaemia CD34-,, -,, CD1a- CD3 debolmente + CD2+, CD5+, CD7+ CD4+/CD8- (60%) CD4-/CD8+ (15%) CD4+/CD8+ (25%) TCL1+ CD52+ CD3 CD8 CD4
31 Locus β chain B-cell receptor gene rearrangements may be seen (up to 70%) V β V βn D β1 J β1 C β1 D β2 J β2 C β Locus αδchains V α V αn J α (70) C β2 V δ1 V δ2 V δ3 D δ1 D δ2 D δ3 J δ1 J δ2 J δ3 C δ V δ4 Locus γ chain Vγ1 Vγ8 Vγ9 Vγ10 Vγ11 Jγ1 Cγ1 Jγ2 Cγ2
32 CD1a GC GC 2004: tonsillectomy male 48 yrs hyperplasia with expansion of interfollicular area +, CD3 +, CD1a +, CD10 + CD10
33 CD1a 2008: tonsillectomy glosso-epiglottic swelling CD99 +, +, CD1a +, CD3 +, CD10 +,CD4 +,CD8 + Indolent T-lymphoblastic proliferation James et al Am J Surg Pathol 2001 Velankar et al Am J Surg Pathol 1999 CD10 TCR not rearranged
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