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LINFOMA MANTELLARE : DALLA PATOGENESI MOLECOLARE AGLI ASPETTI ISTOPATOLOGICI

LINFOMA MANTELLARE : DALLA PATOGENESI MOLECOLARE AGLI ASPETTI ISTOPATOLOGICI. Edoardo Pescarmona Dipartimento di Medicina Sperimentale Università degli Studi di Roma “La Sapienza” Mediterranean School of Oncology “DiAGNOSTIC AND THERAPEUTIC BURNING QUESTIONS ON LYMPHOPROLIFERATIVE DISEASES”

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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 Università degli Studi di Roma “La Sapienza” Mediterranean School of Oncology “DiAGNOSTIC AND THERAPEUTIC BURNING QUESTIONS ON LYMPHOPROLIFERATIVE DISEASES” Rieti, 27-29 Ottobre 2006

  2. CHROMOSOMAL TRANSLOCATION t(11;14) AND HAEMATOLOGICAL NEOPLASIAS

  3. FISH for t(11;14)

  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

  8. 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

  9. 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….?)

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

  11. MANTLE CELL LYMPHOMACLINICAL 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 ?

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

  13. MANTLE CELL LYMPHOMAMOLECULAR-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,…)

  14. MANTLE CELL LYMPHOMAMAIN 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%

  15. MANTLE CELL LYMPHOMADIAGNOSTIC TOOLS (1) • Flow cytometry • Routine histopathology • Immunohistochemistry • FISH • Conventional cytogenetics • PCR

  16. MANTLE CELL LYMPHOMADIAGNOSTIC 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)

  17. MANTLE CELL LYMPHOMA : CD19/CD5 CO-EXPRESSION

  18. MANTLE CELL LYMPHOMADIAGNOSTIC 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)

  19. MANTLE CELL LYMPHOMADIAGNOSTIC 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)

  20. MANTLE CELL LYMPHOMA : FISH for t(11;14)

  21. FISH IMMUNOHISTOLOGY HISTOLOGY

  22. MANTLE CELL LYMPHOMAMAIN 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%

  23. MANTLE CELL LYMPHOMAHISTOPATHOLOGY : GROWTH PATTERNS • Nodular (pseudo-follicular) • Mantle zone • Diffuse

  24. MANTLE CELL LYMPHOMA : MANTLE ZONE PATTERN

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

  26. MANTLE CELL LYMPHOMA : “BLASTOID” VARIANT

  27. MANTLE CELL LYMPHOMADIFFERENTIAL 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 -

  28. MANTLE CELL LYMPHOMADIFFERENTIAL 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 -

  29. MANTLE CELL LYMPHOMAMAIN 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%

  30. MANTLE CELL LYMPHOMA : BONE MARROW INVOLVEMENT (H&E)

  31. MANTLE CELL LYMPHOMA : BONE MARROW INVOLVEMENT (CYCLIN D1)

  32. MANTLE CELL LYMPHOMAMAIN 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%

  33. MANTLE CELL LYMPHOMA : G.I. TRACT INVOLVEMENT

  34. MANTLE CELL LYMPHOMA : G.I. TRACT INVOLVEMENT

  35. MANTLE CELL LYMPHOMA : G.I. TRACT INVOLVEMENT (CD20)

  36. MANTLE CELL LYMPHOMA : G.I. TRACT INVOLVEMENT (CYCLIN D1)

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