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
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
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
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
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