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LINFOMA MANTELLARE : DALLA PATOGENESI MOLECOLARE AGLI ASPETTI ISTOPATOLOGICI

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LINFOMA MANTELLARE : DALLA PATOGENESI MOLECOLARE AGLI ASPETTI ISTOPATOLOGICI

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    1. LINFOMA MANTELLARE : DALLA PATOGENESI MOLECOLARE AGLI ASPETTI ISTOPATOLOGICI Edoardo Pescarmona Dipartimento di Medicina Sperimentale Universitŕ degli Studi di Roma “La Sapienza” Mediterranean School of Oncology “DiAGNOSTIC AND THERAPEUTIC BURNING QUESTIONS ON LYMPHOPROLIFERATIVE DISEASES” Rieti, 27-29 Ottobre 2006

    4. t(11;14) AND HAEMATOLOGICAL NEOPLASIAS T-cell acute lymphoid leukemia (a few cases) Myeloma (20-30% of cases) Mantle cell lymphoma (virtually all cases)

    5. t(11;14) AND HAEMATOLOGICAL NEOPLASIAS T-cell acute lymphoid leukemia ? t(11;14)(p13;q11) Myeloma ? t(11;14)(q13;q32) Mantle cell lymphoma ? t(11;14)(q13;q32)

    6. t(11;14) AND HAEMATOLOGICAL NEOPLASIAS T-cell acute lymphoid leukemia ? t(11;14)(p13;q11) ? TCR delta (14q11) Myeloma ? t(11;14)(q13;q32) ? PRAD1/CCND1 (11q13) rearrangement Mantle cell lymphoma ? t(11;14)(q13;q32) ? PRAD1/CCND1 (11q13) rearrangement

    7. t(11;14) AND HAEMATOLOGICAL NEOPLASIAS T-cell acute lymphoid leukemia ? t(11;14)(p13;q11) ? TCR delta (14q11) Myeloma ? t(11;14)(q13;q32) ? PRAD1/CCND1 (11q13) rearrangement ? cyclin D1 deregulation / over-expression Mantle cell lymphoma ? t(11;14)(q13;q32) ? PRAD1/CCND1 (11q13) rearrangement ? cyclin D1 deregulation / over-expression

    11. CYCLIN D1 FUNCTION Key role in : A) Shortening of G1 phase and B) Progression to S phase of cell cycle Retinoblastoma (Rb) protein binding Cyclin-dependant Kinases (CDKs) binding ? CDK4 and CDK6

    13. CYCLIN D1 DEREGULATION / OVEREXPRESSION Key role in :A) Shortening of G1 phase and B) Progression to S phase of cell cycle Retinoblastoma (Rb) protein binding Cyclin-dependant Kinases binding ? CDK4 and CDK6 Role of alterations of CDK inhibitors ? INK4 family (p15, p16, p18, p19) and p21/p27 family IS t(11;14)(q13;q32) AND CYCLIN D1 DEREGULATION / OVER-EXPRESSION ONCOGENIC BY ITSELF ? (cMYC, p53….?)

    15. MANTLE CELL LYMPHOMA HISTORICAL OVERVIEW Intermediate differentiated lymphocytic lymphoma (Berard, 1974) Centrocytic lymphoma (Lennert, 1975) Mantle zone lymphoma (Weisenburger, 1982) Mantle cell lymphoma (REAL-1994, WHO-2001)

    16. MANTLE CELL LYMPHOMA CLINICAL FEATURES 3-10% of all lymphoma cases Mean age at presentation : 60 years M:F = 3:1 Main involved sites : lymph nodes, bone marrow, spleen, liver, GI tract, peripheral blood Stage III-IV at presentation (70-80% of cases) Poor prognosis : 5 years OS : 30% What treatment ?

    17. MANTLE CELL LYMPHOMA IMMUNOLOGICAL PHENOTYPE B-cell antigens: CD19, CD20, CD22, CD79, sIg (IgM/IgD, Lambda > Kappa) T-cell associated antigens: CD5, CD43 CD23, CD10, BCL6 negative

    18. MANTLE CELL LYMPHOMA MOLECULAR-GENETICS Immunoglobulin (H and L chains) clonal rearrangement IgVH unmutated (70-80% of cases) ? origin from a subset of (CD5+) “naive” (pre-germinal centre) B lymphocytes t(11;14)(q13;q32) Conventional cytogenetics : often complex caryotype; del 6q, del 11q22, del 13q14… CGH : chromosomal gains (3q26-27,…); and losses (13,Y,…)

    19. MANTLE CELL LYMPHOMA MAIN INVOLVED SITES Lymph nodes > 90% Bone marrow 70-80% Spleen 60% Liver 30% G.I. tract 20-30% ( “lymphomatous polyposis”) Peripheral blood (lymphocytosis) 20-30%

    20. MANTLE CELL LYMPHOMA DIAGNOSTIC TOOLS (1) Flow cytometry Routine histopathology Immunohistochemistry FISH Conventional cytogenetics PCR

    21. MANTLE CELL LYMPHOMA DIAGNOSTIC TOOLS (2) Flow cytometry ? Immunophenotype (CD5+ / CD23- …) Routine histopathology ? Morphology Immunohistochemistry ? Immunophenotype; cyclin D1 over-expression FISH, conventional cytogenetics, PCR ? t(11;14)(q13;q32)

    23. MANTLE CELL LYMPHOMA DIAGNOSTIC TOOLS (2) Flow cytometry ? Immunophenotype (CD5+ / CD23- …) Routine histopathology ? Morphology (H&E, Giemsa) Immunohistochemistry ? Immunophenotype; cyclin D1 over-expression ( IgG rabbit MoAb, clone SP4) FISH, conventional cytogenetics, PCR ? t(11;14)(q13;q32)

    25. MANTLE CELL LYMPHOMA DIAGNOSTIC TOOLS (2) Flow cytometry ? Immunophenotype (CD5+ / CD23- …) Routine histopathology ? Morphology (H&E, Giemsa) Immunohistochemistry ? Immunophenotype; cyclin D1 over-expression FISH, conventional cytogenetics, PCR ? t(11;14)(q13;q32)

    29. MANTLE CELL LYMPHOMA MAIN INVOLVED SITES Lymph nodes > 90% Bone marrow 70-80% Spleen 60% Liver 30% G.I. tract: 20-30% ( “lymphomatous polyposis”) Peripheral blood (lymphocytosis) 20-25%

    30. MANTLE CELL LYMPHOMA HISTOPATHOLOGY : GROWTH PATTERNS Nodular (pseudo-follicular) Mantle zone Diffuse

    35. MANTLE CELL LYMPHOMA HISTOPATHOLOGY : CYTOLOGICAL FEATURES Small cell (small lymphocyte-like; intermediate lymphocyte) 80% of cases “Blastoid” (classical/monomorphic; pleomorphic) 20% of cases

    40. MANTLE CELL LYMPHOMA DIFFERENTIAL DIAGNOSIS (1) SLL/CLL : CD5/CD23+ ; cyclin D1 - Follicular lymphoma : CD10/Bcl6 + ; CD5/cyclin D1 - Marginal zone lymphoma (including MALT lymphomas) : CD5 /CD10/Bcl6 /cyclin D1 -

    41. MANTLE CELL LYMPHOMA DIFFERENTIAL DIAGNOSIS (2) “BLASTOID” VARIANT B-cell lymphoblastic lymphoma : TdT + ; CD10/CD34 +/- ; CD 20 -/+ ; cyclin D1 - Diffuse large B-cell lymphoma : CD10/Bcl6/Bcl2 +/- ; CD5 –(+) ; cyclin D1 -

    43. MANTLE CELL LYMPHOMA MAIN INVOLVED SITES Lymph nodes > 90% Bone marrow 70-80% (d.d. with SLL/CLL, follicular lymphoma, marginal zone lymphoma) Spleen 60% Liver 30% G.I. tract: 20-30% Peripheral blood: 20-30%

    46. MANTLE CELL LYMPHOMA MAIN INVOLVED SITES Lymph nodes > 90% Bone marrow 70-80% Spleen 60% Liver 30% G.I. tract 20-30% (“lymphomatous polyposis” ; d.d. with MALT lymphoma) Peripheral blood 20-30%

    51. MANTLE CELL LYMPHOMA MAIN INVOLVED SITES Lymph nodes > 90% Bone marrow 70-80% Spleen 60% Liver 30% G.I. tract: 20-30% Peripheral blood (lymphocytosis): 20-30% (d.d. with CLL)

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