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, 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

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 %
Spleen 60%
Liver 30%
G.I. tract % ( “lymphomatous polyposis”)
Peripheral blood (lymphocytosis) %

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)

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

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)

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

28. FISH
IMMUNOHISTOLOGY
HISTOLOGY

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

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

32. MANTLE CELL LYMPHOMA : MANTLE ZONE PATTERN

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

39. MANTLE CELL LYMPHOMA : “BLASTOID” VARIANT

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%

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

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

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

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

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

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

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

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

52. MANTLE CELL LYMPHOMA : PERIPHERAL BLOOD SMEAR

53. MANTLE CELL LYMPHOMA : THERAPEUTIC PERSPECTIVES