LINFOMA MANTELLARE : DALLA PATOGENESI MOLECOLARE AGLI ASPETTI ISTOPATOLOGICI

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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

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CHROMOSOMAL TRANSLOCATION t(1114) AND
HAEMATOLOGICAL NEOPLASIAS
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FISH for t(1114)
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t(1114) AND HAEMATOLOGICAL NEOPLASIAS

• T-cell acute lymphoid leukemia (a few cases)
• Myeloma (20-30 of cases)
• Mantle cell lymphoma (virtually all cases)

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t(1114) AND HAEMATOLOGICAL NEOPLASIAS

• T-cell acute lymphoid leukemia ?
  t(1114)(p13q11)
• Myeloma ? t(1114)(q13q32)
• Mantle cell lymphoma ? t(1114)(q13q32)

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t(1114) AND HAEMATOLOGICAL NEOPLASIAS

• T-cell acute lymphoid leukemia ?
  t(1114)(p13q11) ? TCR delta (14q11)
• Myeloma ? t(1114)(q13q32) ? PRAD1/CCND1 (11q13)
  rearrangement
• Mantle cell lymphoma ? t(1114)(q13q32) ?
  PRAD1/CCND1 (11q13) rearrangement

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t(1114) AND HAEMATOLOGICAL NEOPLASIAS

• T-cell acute lymphoid leukemia ?
  t(1114)(p13q11) ? TCR delta (14q11)
• Myeloma ? t(1114)(q13q32) ? PRAD1/CCND1 (11q13)
  rearrangement ? cyclin D1 deregulation /
  over-expression
• Mantle cell lymphoma ? t(1114)(q13q32) ?
  PRAD1/CCND1 (11q13) rearrangement ? cyclin D1
  deregulation / over-expression

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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

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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(1114)(q13q32) AND CYCLIN D1 DEREGULATION /
  OVER-EXPRESSION ONCOGENIC BY ITSELF ? (cMYC,
  p53.?)

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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)

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MANTLE CELL LYMPHOMACLINICAL FEATURES

• 3-10 of all lymphoma cases
• Mean age at presentation 60 years
• MF 31
• 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 ?

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MANTLE CELL LYMPHOMAIMMUNOLOGICAL PHENOTYPE

• B-cell antigens CD19, CD20, CD22, CD79, sIg
  (IgM/IgD, Lambda gt Kappa)
• T-cell associated antigens CD5, CD43
• CD23, CD10, BCL6 negative

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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(1114)(q13q32)
• Conventional cytogenetics often complex
  caryotype del 6q, del 11q22, del 13q14
• CGH chromosomal gains (3q26-27,) and losses
  (13,Y,)

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MANTLE CELL LYMPHOMAMAIN INVOLVED SITES

• Lymph nodes gt 90
• Bone marrow 70-80
• Spleen 60
• Liver 30
• G.I. tract 20-30 ( lymphomatous polyposis)
• Peripheral blood (lymphocytosis) 20-30

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MANTLE CELL LYMPHOMADIAGNOSTIC TOOLS (1)

• Flow cytometry
• Routine histopathology
• Immunohistochemistry
• FISH
• Conventional cytogenetics
• PCR

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MANTLE CELL LYMPHOMADIAGNOSTIC TOOLS (2)

• Flow cytometry ? Immunophenotype (CD5 / CD23- )
• Routine histopathology ? Morphology
• Immunohistochemistry ? Immunophenotype cyclin
  D1 over-expression
• FISH, conventional cytogenetics, PCR ?
  t(1114)(q13q32)

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MANTLE CELL LYMPHOMA CD19/CD5 CO-EXPRESSION
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MANTLE CELL LYMPHOMADIAGNOSTIC TOOLS (2)

• Flow cytometry ? Immunophenotype (CD5 / CD23- )
• Routine histopathology ? Morphology (HE, Giemsa)
• Immunohistochemistry ? Immunophenotype cyclin
  D1 over-expression ( IgG rabbit MoAb, clone SP4)
• FISH, conventional cytogenetics, PCR ?
  t(1114)(q13q32)

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MANTLE CELL LYMPHOMADIAGNOSTIC TOOLS (2)

• Flow cytometry ? Immunophenotype (CD5 / CD23- )
• Routine histopathology ? Morphology (HE, Giemsa)
• Immunohistochemistry ? Immunophenotype cyclin
  D1 over-expression
• FISH, conventional cytogenetics, PCR ?
  t(1114)(q13q32)

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MANTLE CELL LYMPHOMA
FISH for t(1114)
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FISH
IMMUNOHISTOLOGY
HISTOLOGY
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MANTLE CELL LYMPHOMAMAIN INVOLVED SITES

• Lymph nodes gt 90
• Bone marrow 70-80
• Spleen 60
• Liver 30
• G.I. tract 20-30 ( lymphomatous polyposis)
• Peripheral blood (lymphocytosis) 20-25

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MANTLE CELL LYMPHOMAHISTOPATHOLOGY GROWTH
PATTERNS

• Nodular (pseudo-follicular)
• Mantle zone
• Diffuse

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MANTLE CELL LYMPHOMA MANTLE ZONE PATTERN
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MANTLE CELL LYMPHOMAHISTOPATHOLOGY CYTOLOGICAL
FEATURES

• Small cell (small lymphocyte-like intermediate
  lymphocyte) 80 of cases
• Blastoid (classical/monomorphic pleomorphic)
  20 of cases

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MANTLE CELL LYMPHOMA BLASTOID VARIANT
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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 -

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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 -

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MANTLE CELL LYMPHOMAMAIN INVOLVED SITES

• Lymph nodes gt 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

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MANTLE CELL LYMPHOMA BONE MARROW
INVOLVEMENT (HE)
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MANTLE CELL LYMPHOMA BONE MARROW
INVOLVEMENT (CYCLIN D1)
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MANTLE CELL LYMPHOMAMAIN INVOLVED SITES

• Lymph nodes gt 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

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MANTLE CELL LYMPHOMA G.I.
TRACT INVOLVEMENT
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MANTLE CELL LYMPHOMA G.I.
TRACT INVOLVEMENT
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MANTLE CELL LYMPHOMA G.I. TRACT INVOLVEMENT
(CD20)
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MANTLE CELL LYMPHOMA G.I. TRACT INVOLVEMENT
(CYCLIN D1)
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MANTLE CELL LYMPHOMAMAIN INVOLVED SITES

• Lymph nodes gt 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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MANTLE CELL LYMPHOMA
PERIPHERAL BLOOD SMEAR
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MANTLE CELL LYMPHOMA THERAPEUTIC PERSPECTIVES