Mantle Cell Lymphoma

(Centrocytic Lymphoma or Intermediate Lymphocytic Lymphoma)

Epidemiology:

• Middle aged to older adults (median 60y)
• Male predominance (at least 2:1)

Common sites:

• Lymph nodes
• Spleen
• early bone marrow involvement
• GI tract (up to almost 30%)
• May be multiple (most cases of multiple lymphomatous polyposis are mantle)
• Peripheral blood (at least 25%)

Gross features:

•  Hepatosplenomegaly
• massive splenomegaly frequently

Histologic features:

• follicular architecture (often)
• may be confused with follicular lymphoma
• residual “naked” germinal centres may be decreased in size, funny shapes
• monomorphic population of small to medium-sized cells
• centrocyte-like features
• irregularly angular nuclear borders
• scant pale cytoplasm
• inconspicuous nucleoli
• scattered single epithelioid histiocytes giving starry sky appearance (many cases)
• plasma cells may be present (non-neoplastic)
• ABSENCE of:
• Neoplastic transformed cells (centroblasts, immunoblasts, paraimmunoblasts, pseudofollicles)
• Hyalinized small vessels commonly
• may see:
• loss of mantle zone growth pattern
• increase in nuclear size
• pleomorphism
• chromatin dispersal
• increase in mitotic activity
• some of these fall into “blastoid variant”
• blastoid variants:
• usual:
• cells resemble lymphoblasts
1. dispersed chromatin
• high mitotic rate (>10/10 HPF, usually 20-30 / 10HPF)
• pleomorphic:
• heterogeneous cells
• large cleaved to oval nuclei
• pale cytoplasm on Giemsa (or MGP) stain
• nucleoli may be prominent
• other variants:
• small round lymphocytes with more clumped chromatin mimicking SLL
• prominent foci of monocytoid cells resembling marginal zone or pseudofollicular proliferation zones

Immunophenotype:

Marker:	Sensitivity:	Specificity:
sIg (M, +/- D)
Light chain: lambda > kappa
Cyclin D1	Virtually all
CD5	80%
FMC-7
CD43	Usually
CD23 / CD21 (neg)	Some are weakly positive for CD23. Often identify ill-defiined loose or expanded follicular dendritic cell meshworks (80%)
CD10 (follicular AND interfollicular)	-/+
Bcl-2	All	Any small lymphocyte is positive
Bcl-6 (neg)
Pan B (CD19, 20, 22, 79a)
CD10 (neg)	Usually
Alpha-4-beta-7 homing receptor (cases with GI involvement)
CD11c (neg)
CD25 (neg)

• CD21 or CD35 – loose meshworks of follicular dendritic cells

Molecular features:

• Rearrangement of immunoglobulin heavy (IgH) and light chain genes (IgL)
• Variable region genes unmutated usually (pre-germinal centre B cell)
• Somatic hypermutation in IG genes (15-40%)
• t(11;14) (q13;q32) (virtually all cases by FISH)
• considered primary genetic event
• CCND1/PRAD1/BCL1 translocated to immunoglobulin heavy chain gene
• overexpression of cyclin D1 / bcl-1 / PRAD-1 gene
• overexpression of CYCLIN D1 mRNA
• encodes for cyclin D1 protein
• NOTE : not pathognomonic of mantle cell lymphoma
• Multiple myeloma
• “some few cases of true CLL”
• “…and splenic lymphoma with villous lymphocytes (SLVL)”
• Variant translocations have been reported
• CCND1-IGL
• CCND1-IGK
• t(2;12)(p12;p13) (CCND2-IGK)
• CCND1 negative
• Non-random secondary chromosomal aberrations:
• Gains:
• 3q26 (31-50%) (poor prognosis)
• 7p21 (16-34%)
• 8q24 (MYC) (16-36%)
• Losses:
• 1p13-p31 (29-52%) (more frequent in blastoid / pleomorphic variants)
• 6q23-q27 (23-38%)
• 9p21 (18-31%)
• 9q (poor prognosis)
• 11q22-q23 (21-59%)
• 13q11-q13 (22-55%)
• 13q14-q34 (43-51%)
• 17p13-pter (21-45%) (poor prognosis) (more frequent in blastoid / pleomorphic variants)
• Trisomy 12 (total or partial) (25%)
• Tetraploid (80% of pleomorphic) (36% of blastoid) (8% typical morphology)
• t(8;14)(q24;q32) (IGH-MYC) (rare) (aggressive clinical course)
• BCL6 (3q27) translocations (uncommon)
• Mutations:
• Inactivating point mutations of ATM (ataxia telangiectasia mutated) gene (40-75%)
• some may be germline mutations
• TP53 mutations
• Deletions:
• INK4a/ARF
• CDK inhibitor p18INK4c
• RB1 (microdeletions)
• Amplifications:
• BMI1 polycomb
• CDK4
• many other cytogenetic abnormalities

Other features:

• poor prognosis:
• median survival 3-5y
• most patients present with stage III or IV disease
• slow but progressive mortality rate despite treatment
• vast majority are not cured
• does not transform to typical large cell lymphoma
• CD5 negative cases may be more indolent
• High mitotic rate is most significant adverse prognostic parameter
• >10-37.5/15 HPF
• >50/mm2
• MIB1 > 40-60%
• Proliferation signature by gene expression
• Other adverse prognostic features reported:
• Blastoid / pleomorphic morphology
• variety of clinical parameters including overt PB involvement
• Cytogenetic changes (not well established, especially with modern treatments)
• Trisomy 12
• 3q gains
• 9q22 deletions
• 13q14 deletion by FISH (one recent study)
• Karyotypic complexity
• TP53 mutation/overexpression/loss
• Peripheral blood involvement is adverse prognostic

References:

• Dr. Fernandes
• DakoCytomation Lymphoma Classification (2000)
• WHO blue book (2001, 2008)
• Heim & Mitelman. Cancer Cytogenetics, 3^rd ed. (2009)
• GENES, CHROMOSOMES & CANCER 49:439–451 (2010)