1. Biology and Pathology of
Mantle Cell Lymphoma
Elias Campo
Hospital Clinic, University of Barcelona

2. Mantle Cell Lymphoma
1.0
0.8
Probability
0.6
Cyclin D1 0.4
0.2
0.0
0 2 4 6 8
Years
Complete Response 25% (6-50%)
14 der(14) 11 der(11) Duration of CR 1.5 yrs (0.5-2.5 yrs)
Median Survival 3-4 years
IGH/CCND1

3. Improvement in Survival of Patients
with non-blastoid MCL
1996 to 2004
1975 to 1986
• New diagnostic tools and management measures
• Application of new therapeutic regimens
Herrmann, A. et al. J Clin Oncol; 27:511-518 2009

4. MCL Pathogenesis
• Cell Cycle Dysregulation
• Dysruption of DNA damage
response pathway
• Cell survival pathways

5. Mantle Cell Lymphoma: Cytological Variants
Classical Small cell
Blastic Pleomorphic

6. MCL Phenotype
CD20 CD3
Cyclin D1 CD5

7. Prognostic Value of Proliferation in MCL
Ki-67 Ki-67
MIPI-b
Katzenberger, T. et al. Blood 2006;107:3407 Hoster, E. et al. Blood 2008;111:558-565

8. Cell Cycle Regulatory Pathways
Amplified (10%) BMI-1
Deleted (30%) ARF-INK4a Locus
9
p14/p19arf p16ink4a
Amplified (10%)
MDM2 CDK4 / Cyclin D
Mutated (30%) p53 Rb
Deleted (<5%)
G1 S G2 M APOPTOSIS G1 S
17

9. Genetic Stability DNA Damage Response Pathways
DNA damage
Replication
stress
ATM
11
1.0
FS564stop R3008H
R23stop
0.8 FS1349stop D2725V
FS32stop
No gain (n=8)
PROBABILITY
M1L K2717M
0.6
1 to 4 gains (n=28) ATM
0.4
protein
p53 b-adaptin c-Abl Rad-3 PI3-kinase
binding binding binding homology domain
0.2 >4 gains (n=6)
P=0.02
0.0
0 2 4 6 8 10 Truncated protein Conserved residue
YEARS substitution

10. Activated pathways in MCL without
apparent genetic alterations
Wnt Pathway
PI3K, AKT, mTOR
Pathway
NFkB Pathway
Navarro et al Sem Hematol 2011

11. Nucleus stromal cells
nurse-like cells
AbaDR4 folicullar dentritic cells
AbaDR5 macrophages
AbaCD38
TRAIL
IL10 TNFa IL6
SDFa1
ImiDS VEGF CD31
CD40L
TRAIL-R BCR
AbaCD20
CD38
VEGF-R CD40
T Lymph
SrcK CXCR4 ImiDS
CD20
IL-4
PK Inh PI3K
Akt BAFF
CD40L NF-KB Inh
mTOR
BAFF-R
NF-KB
CD40 PI3K/Akt/mTOR APRIL
Axis Inh TACI
Proteasome Inh
BCL-2 Inh
BCMA
HSP90
Inhibitors
IAPs Mitochondria
HSP-90
DNMT/HDAC
Inhibitors IAPs
Antagonists
Nucleoside
Analogs
Nucleus
B cell neoplasm
Saborit-Villarroya et al, Curr Drug Targets. 2010;11:769-80.

12. Molecular Pathogenesis in MCL
Early Classical Blastoid
Naive B
MCL MCL MCL
lymphocyte
t(11;14) ATM p16/CDK4/Rb Bcl-2/other
ARF/MdM2/p53
Cyclin D1 CHK2
Increased High Cell
Rb p27 Genomic Proliferation Survival
Instability
Jares P et al Nat Rev Cancer 2007

13. IGH Somatic Hypermutations in 807 MCL
 Highly mutated 111 (13%)
 Minimally/borderline mutated 458 (57%)
 Truly Unmutated 238 (30%)
Hadzidimitriou A et al Blood 2011

14. MCL: From Naive to an Antigen Selected Cell ?
UnMutated-MCL
T Cell-Independent Response
Naïve Boderline Mutated-MCL
V D J cμ cγ
Antigen Selection
Ig Somatic Mutations
Class Switch
HyperMutated-MCL

15. CD20
CD5 CD3

16. Cyclin D1 p27

17. Cyclin D1 Negative MCL Variant
Cyclin D1
Cyclin D3 Cyclin D2
Fu et al, Blood 2005

18. SOX11 mRNA Expression in non-HL
is Highly Specific of MCL
MCL
CCND1-
MCL, n=89 n=6
SOX11
CCND1
BL, n=33 DLBCL, n=46 PMBL, n=20 FL, n=44
SOX11
CCND1
Mozos et al Haematologica 2009

19. Sox11 Protein Expression in MCL
MCL Cyclin D1 (SP4) Sox11
CyclinD1 negative MCL
Mozos et al Haematologica 2009

20. SOX11 Expression is Highly Specific of MCL
and Recognizes Cyclin D1 Negative tumors
Lymphoma Sox11 + Lymphoma Sox11 +
MCL CCND1- 39/41 cHL 1/36
MCL 97/112 NLPHL 0/5
DLBCL 0/63 PTCL NOS 0/15
SMZL 0/9 AILT 0/5
MZL 0/11 Hepatosplenic 0/3
FL 0/22 ALK+ 0/3
CLL 0/12 ALK- 0/3
BL 2/8 (3)* T-PLL 2/3
B/T LBL 8/8 T/NK Nasal type 0/3
Mozos A et al Haematologica 2009, updated * weak

21. Classical MCL
Cyclin D1
SOX11

22. CCND1
p27
SOX11 SOX1

23. MCL with Indolent Clinical Behavior
OS from diagnosis OS from treatment
Martin P et al JCO 2009

24. Conventional vs Indolent MCL
Clinical Characteristics
Clinical data Conventional Indolent
MCL (15) MCL (12)
Chemotherapy 15 0
Median Follow-up 15 m (0.5 - 79) 70 m (25-121)
5-year Overall Survival 49% 100%*
ECOG≥2 70% 0+
Intermediate/High MIPI 46% 0+
Lymphadenopathy (>1cm) 15/15 2/12+
Lymphocytosis (≥5x109/L) 9/11 4/9
+ p <0.05
* p=0.002 Fernandez V et al Cancer Res 2010

25. iMCL and cMCL Have a Distinct Gene Expression Signature
Supervised analysis
Indolent and
conventional MCL
LGALS3BP
CSNK1E
SOX11
KIAA1909
FARP1
PON2
CNN3
DBN1
HDGFRP3
CDK2AP1
HMGB3
SETMAR
CNR1
RNGTT
Fernandez V et al Cancer Res 2010

26. SOX11 Protein Expression in MCL
Cyclin D1 SOX11
Indolent MCL
Conventional
MCL

27. Can SOX11 expression recognize a subtype of MCL with
different clinicopathological features and outcome?
Clinical data SOX11 - SOX11 +
(n = 15) (n = 97)
High MIPI 33% 46%
Lymphn nodes (>1cm) 53% 99% *
Splenomegaly 92% 48%*
WBC ≥ 10x109/L 57% 18%*
Lymphocytosis (≥5x109/L) 83% 24% *
Ki67 high >50% 20% 28%
Adriamycin-Regimens 67% 72%
Complete Response 40% 54%
5-year OS (%) 78% 36%*
+ p <0.01 Fernandez V et al Cancer Res 2010

28. Overall Survival in MCL patients according to SOX11 Expression
1
SOX11 negative (N=15; dead: 4)
.8
.6
Sox11 -
.4
PROBABILITY
SOX11 positive (N=97; dead: 68)
.2 Sox11 +
0
0 2 4 6 8 10 12 14 16
YEARS
P< 0.001
Fernandez V et al Cancer Res 2010

29. Cyclin D1

30. Cyclin D1 SOX11
Cyclin D1 SOX11

31. “In situ” MCL (17 cases )
• Location at diagnosis
– Solitary LN 10
– LN several sites 2
– Extranodal 5
– Bone Marrow, Peripheral blood 3/7
• SOX11+ 7/16 (44%)
• Follow-up
– 9 W&W
• 2 Progression to overt MCL (4 years)
• 4 Alive with stable (2) or no disease (2) (med 8 yr; range 1-
19)
• 1 Dead, unrelated cause (1.4 y, 84 year-old)
– 4 Chemotherapy Alive No Disease 4 yr
– 2 Rx Alive no Disease > 2 yr
• 1 incidental finding 3 yr after overt MCL in complete remission
Carvajal-Cuenca et al Haematologica 2011

32. Genetically Stable
Hypermutated IG
Leukemic/ non-nodal type MCL
(del)17p
“In situ” MCL
SOX11-
t(11;14)
SOX11+
Classical MCL Blastoid MCL
Genomic Instability
Unmutated Ig

33. Conclusions
- MCL pathogenesis integrates alterations in cell cycle, DNA damage
response and survival pathways that may be targeted by new
therapies
- Antigen selection may play a role in the pathogenesis of at least a
subgroup of MCL
- Cyclin D1 negative MCL can be recognized by SOX11 expression
and seem to have similar clinical and genetic characteristics to
conventional MCL.
- Some MCL have an indolent clinical course and may benefit of a
more conservative clinical management. A subset of them seems to
correspond to a different biological subtype.
- We may recognize early steps in MCL lymphomagenesis that
should be managed with caution.

34. Acknowledgments
Hospital Clínic-University National Institute of Health
of Barcelona Bethesda
Adrian Wiestner
Silvia Bea Wyndham Wilson
Cristina Royo Elaine Jaffe
Alba Navarro
Guillem Clot
Alejandra Martinez Institute of Pathology-Würzburg
Eva Giné Elena Hartmann
Gonzalo Gutierrez Andreas Rosenwald
Verònica Fernàndez
Dolors Colomer
Abteilung für Klinische-Pathologie-
Neus Villamor
Stuttgart
Pedro Jares
German Ott
Armando Lopez-Guillermo
University Hospital
Schleswig-Holstein-Kiel
Chistiane Pott Addenbrooke’s Hospital-Cambridge
Itziar Salverria Nicola Trim
Reiner Siebert
Wendy Erber
University Hospital Munich-
Grosshadern-Munich S. Orsola-Malpighi Hospital-Bologna
Martin Dreyling Claudio Agostinelli
Stefano A Pileri