Mantle Cell Lymphoma

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Primary Author(s)*

  • Mahsa Khanlari, MD
  • Zhenya Tang, MD, PhD

The University Of Texas MD Anderson Cancer Center, Department of Hematopathology, Houston, Texas

Cancer Category/Type

Cancer Sub-Classification / Subtype

Definition / Description of Disease

  • Clinically aggressive, mature B cell lymphoma
  • Small to medium sized lymphoid cells (monomorphic, except in pleomorphic variant)
  • Associated with t(11;14)(q13;q32) and cyclin D1 overexpression in over 95% of cases

Synonyms / Terminology

Obsolete names:

  • Centrocytic malignant lymphoma (obsolete) [1]
  • Lymphocytic lymphoma of intermediate differentiation [2]
  • Mantle zone lymphoma [3]
  • Malignant lymphomatous polyposis
  • in situ mantle cell lymphoma (for in situ mantle cell neoplasia)

Epidemiology / Prevalence

  • ~ 7% of B cell lymphomas [4]
  • 2.5%-10% of non-Hodgkin lymphomas [5]
  • Age adjusted incidence: 0.7/100,000 person years in white population in USA [6]
  • Median age: 60 years[7]
  • M:F = 3:1 (range, 1.6-6.8 :1)[8]

Clinical Features[9]

  • Approximately 70% with stage IV disease at presentation
    • Generalized lymphadenopathy, hepatosplenomegaly and bone marrow involvement
    • 40-50% with B symptoms
    • Two subtypes based on clinical presentation:
      • More aggressive, with SOX11 overexpression (SOX11+disease), nodal presentation (the most common subtype)
      • More indolent, without SOX11 expression (SOX11-disease), leukemic presentation, and non-nodal disease
  • Peripheral blood:
    • Atypical lymphoid cells: present virtually in all cases by flow cytometry [10]
      • Atypical lymphoid cells can be detected in the peripheral blood in the absence of lymphocytosis
      • Leukemic involvement: 20 - 70% of patients at diagnosis
      • Leukemic involvement is usually a the sign of disease progression
    • Blastoid morphology of the circulating lymphoma cells may mimic acute leukemia
    • A leukemic phase with no or minimal lymph node involvement is possible, Leukemic Non-Nodal Mantle Cell Lymphoma
      • Asymptomatic for long period
      • Splenomegaly
    • Anemia and thrombocytopenia (10%- 40%)
  • Multiple intestinal polyps (lymphomatous polyposis)
  • Progress to blastoid / pleomorphic variant
    • At the time of relapse (~22%)

Sites of Involvement

  • Lymph node
  • Bone marrow involvement independent of peripheral blood (50 - 90%), peripheral blood (20 - 70%), spleen (~50%), liver (~20%) [11][12][13]
  • Frequent extranodal site involvement : gastrointestinal tract, Waldeyer ring, lungs, pleura, skin, CNS
    • CNS involvement may occur mostly at the time of relapse[14]
  • Extranodal involvement without lymphadenopathies: 4 - 15%

Morphologic Features

  • Architectural pattern: Diffuse > nodular > mantle zone growth patterns
    • Nodal (> 50% nodular), diffuse growth pattern (< 50% nodular)
  • Cytologic variants: Classic, blastoid, pleomorphic, small cell, marginal zone-like
  • Blastoid and pleomorphic cytologic variants are known as aggressive variants of MCL
  • Classic variant:
    • Small to medium monomorphic lymphoid neoplasm
    • Irregular nuclear border, clumped chromatin and inconspicuous nucleoli
    • No proliferation centers
    • No centroblasts, immunoblasts or paraimmunoblasts
    • Hyalinized vessels
    • Epithelioid histiocytes
    • Follicular dendritic cell (FDC) meshwork
      • Nodular pattern
        • Primary follicle-like pattern
        • Germinal center-like pattern
      • Diffuse pattern
  • Aggressive variants
    • Blastoid: lymphoblast-like in appearance, monomorphic
      • >20 - 30 mitoses per 10 high power fields
      • Resemble lymphoblastic lymphoma
    • Pleomorphic: large cells with irregular nuclear border, cerebriform nuclei, multinucleation, lack of monomorphism
      • Prominent nucleoli and abundant pale cytoplasm
      • Resemble DLBCL
  • Other variants
    • Small cell: small round lymphocytes with more clumped chromatin
      • Resemble CLL
    • Marginal zone-like: abundant pale cytoplasm
      • Resembling marginal zone or monocytoid B cells
    • Lymphoplasmacytic differentiation, some cases [15]
  • Bone marrow
    • Nodular, interstitial or paratrabecular or combination
  • Peripheral blood (see below)
    • Similar spectrum seen in tissue sample
    • Nucleoli are sometimes more prominent
  • Spleen
    • White pulp nodules involved (enlarged)
    • Variable involvement of the red pulp
    • Residual naked germinal centers
    • Tumor cells: similar monotonous morphology
    • Some cases may show a marginal zone-like area [16]
  • Gastrointestinal
    • May mimic lymphoepithelial lesions in marginal zone lymphoma [17]
  • Relapse
    • Loss of a mantle zone growth pattern
    • Increase in nuclear size
    • Pleomorphism and chromatin dispersal
    • Increase in mitotic activity and Ki67
    • Cases that are blastoid at diagnosis may relapse with classic morphology [18]

Immunophenotype

Finding Marker
Positive (>95%) cyclin D1
Positive (>90%) Sox-11
Positive (100%) B-cell associated markers (CD19, CD20, CD22, CD79a/b)
Positive (>95%) CD5
Positive CD43
Positive IgM+/- IgD
Positive BCL-2
Positive (flow cytometry) FMC-7
Positive (50% in small subset of cells) MUM1 / IRF4
Positive (subset) MYC
Positive (subset) p53
Positive/ Negative CD10
Positive/ Negative BCL-6
Negative T-cell associated markers (except CD5)
Negative CD200
Negative LEF-1
  • Ki67 count [19]
    • Five independent high power fields count
    • Avoidance of residual germinal centers, hot spots and proliferating T cells
    • Note: Ki67 index is not sufficient to classify as blastoid or pleomorphic subtype
    • Classical mantle cell lymphoma might also show high cell proliferation[20]
  • p53 in subset; intense expression correlates with TP53 gene mutation
    • Note: no protein expression; on the other hand, cannot predict the homozygous deletions of the locus [21]
  • MYC in subset
    • High expression correlates with MYC translocation [22]
  • CD10+ MCL more associated with diffuse growth pattern, blastoid/pleomorphic morphology, and BCL6 expression[23]
  • CD23: small subset of cases [24]
  • CD200: May be positive in a subset of SOX11 negative mantle cell lymphomas[25] Leukemic Non-Nodal Mantle Cell Lymphoma
  • LEF-1: positive in 4 - 9% of mantle cell lymphomas [26][27]
  • Cyclin D1-negative MCL
    • Morphology, phenotype, gene expression, clinical presentation and evolution similar to cyclin D1-positive MCL [28]
    • Positive for Sox-11
    • Frequently express cyclin D2 or cyclin D3 (IG-mediated translocations) [29]
    • cyclin E in cases with negative expression of cyclin D and aggressive behavior [30]

Chromosomal Rearrangements (Gene Fusions)[31]

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(11;14)(q13;q32) IGH/CCND1 der(11) and der(14) >90%
t(2;12)(p12;p13) IGK/CCND1 der(2) and der(12) NA
t(12;22)(p13;q11) IGL/CCND2 der(12) and der(22) NA
t(12;14)(p13;q32) IGH/CCND2 der(12) and der(14) NA
t(6;14)(p21;q32) IGH/CCND3 der(6) and der(14) NA

Characteristic Chromosomal Aberrations / Patterns

  • CCND1 rearrangement; t(11;14)(q13;q32)
    • FISH is convenient because it can be performed on fixed tissue sections
    • Conventional cytogenetics if fresh material available
    • Most PCR assays usually detect 1 major breakpoint region in mantle cell lymphoma
  • Cyclin D2 (CCND2) rearrangements by FISH in 55%-70% of cyclin D1-negative cases
  • Almost all cyclin D1-negative mantle cell lymphomas carry CCND2/CCND3 rearrangements with immunoglobulin genes (including a novel IGK/L enhancer hijacking mechanism)
  • A broad spectrum of secondary chromosomal aberrations have been reported, especially in MCL with bone marrow and peripheral blood involvement[32].
  • Tetraploidy is more frequent in pleomorphic (80%) and blastoid (36%) variants than in classic MCLs (8%) [33]
  • t(8;14)(q24;q32)/MYC-IGH in small subset of cases [34][35]
Parameter n %
CCND2 translocation
IGH-CCND2 3/40 8
IGK-CCND2 10/40 25
IGL-CCND2 5/40 13
CCND2-break 2/40 5
CCDND2-? 2/40 5
Negative 18/40 45

Genomic Gain/Loss/LOH

Secondary chromosomal aberrations[36]

Chromosome Number Gain/Loss/Amp/LOH Region Possible target gene/s Frequency Functional process
3 Gain q26 ? 31 - 50% ?
7 Gain p21 ? 16 - 34% ?
8 Gain q24 MYC 16 - 36% Cell growth, proliferation, apoptosis
11 Gain q13.3-q21 CCND1 4-14% Cell cycle
12 Gain q14 CDK4, MDM2 3-7% Cell cycle, DNA damage response, apoptosis
13 Gain q31 MIR17HG 24% Cell cycle, apoptosis
18 Gain q21.33 BCL2 18-55% Apoptosis
1 Loss p32.3-p33 CDKN2C, FAF1 18-52% Cell cycle, apoptosis
2 Loss q13 BCL2L11 3-17% Apoptosis
2 Loss q37.1 SP100-SP140 15-33% DNA damage response
6 Loss q23.3 TNFAIP3 19-36% NF-κB inhibitor
6 Loss q25 LATS1 19-36% Hippo signaling pathway
8 Loss p21.3 MCPH1 17-34% DNA damage response
9 Loss p21.2 MOBKL2B 10-36% Hippo signaling pathway
9 Loss p21.3 CDKN2A, ARF1 10-36% Cell cycle, DNA damage response
9 Loss q22.2-q22.31 CDC14B, FANCC, GAS1 17-31% ?
10 Loss p14-p13 ? 18-28% ?
11 Loss q22.3 ATM 11-57% DNA damage response
13 Loss q13.3-q34 DLEU1, DLEU2, RB1 25-70% Cell cycle, apoptosis
13 Loss q34 CUL4A, ING1 16-54% DNA damage response
17 Loss p13 TP53 21-45% DNA damage response
19 Loss P13.3 MOBKL2A 10-24% Hippo signaling pathway

Gene Mutations (SNV/INDEL)[37]

Gene Oncogene/Tumor Suppressor/Other Prevalence (COSMIC/TCGA/Other)
BIRC3 Apoptosis regulator/ NF-KB pathway 8.6-16.2%
MYC Apoptosis regulator 11.2-20.8%
CARD11 B-cell receptor signaling 8.5-16.3%
TRAF2 B-cell receptor signaling 4.5-15.7%
BTK B-cell receptor signaling 5.5-17.1%
MAP3K14 B-cell receptor signaling 2.4-14.2%
CCND1 CDK kinase regulator 20.2-27.7%
CDKN2A CDK kinase regulator 23.9-29.5%
SMARCA4 Chromatin modification 14.9-18.7%
ARID2 Chromatin modification 6.8-16.3%
ARID1B Chromatin modification 17.2-18.3%
CHD2 Chromatin modification 4.0-14.1%
ATM DNA damage response 43.5-57.6%
KMT2D Histone modification 18.4-21.8%
NSD2 Histone modification 15.0-22.8%
KMT2C Histone modification 17.6-19.1%
KMT2A Histone modification 8.9-21.4%
BCOR Histone modification 13.6-14.2%
IGH Immune response 21.5-38.4%
MEF2B Immune response 9.3-13.8%
SP140 Immune response 8.4-14.3%
TLR2 Immune response 4.3-14.3%
S1PR1 Immune response 8.6-13.9%
TET2 Myelopoiesis 5.6-14.1%
NOTCH1 NOTCH signaling pathway 10.8-14.8%
NOTCH2 NOTCH signaling pathway 5.8-14.3%
UBR5 Protein ligases 17.8%
TP53 Tumor suppressor 26.8-43.0%
RB1 Tumor suppressor 24.5%

Genes and Main Pathways Involved

Please refer to Gene Mutations (SNV/INDEL)

Diagnostic Testing Methods

  • Tissue biopsy (lymph node / extranodal sites): monomorphic proliferation of small to intermediate sized B cells with overexpression of cyclin D1 or SOX11
  • t(11;14)(q13;q32) IGH/CCND1
  • MRD is defined as the minimal traceable persistence of lymphoma cells after a successful treatment.
  • Many methods to monitor MRD have been published
  • The most sensitive and the most commonly used and best standardized approach in MCL: allele-specific oligonucleotide (ASO) quantitative polymerase chain reaction (qPCR) method [38]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Median survival: 5 - 7 years
    • Mantle cell lymphoma international prognostic index (clinical), MIPI [39]
    • Age, performance status, lactate dehydrogenase, leukocyte count
    • 3 morphologic groups with significantly different prognoses
  • Adverse outcome (histopathology / molecular)
    • High mitotic rate (> 50/mm2) [40]
    • Ki67 or MIB1 IHC stains (> 30%) [41]
    • Blastoid and pleomorphic variants [42]
    • MYC rearrangement [43][34]
    • TP53 mutation / overexpression / loss (17p) [44]
    • Either TP53 mutations or deletions or both associates with poor prognosis[45]
      • Elevated Ki-67
      • Higher MIPI-c classes
      • Blastoid morphology
      • Impact on survival independent of these risk factors
      • Higher levels of MRD positivity after allo-stem cell transplant
    • CDKN2A deletion (9p) [44]
    • Gains in 3q, deletions of 9q [46]
    • Patients with KMT2D mutation [45]
      • Chemo-immunotherapy failure
      • High-risk patients based on MIPI-C

Familial Forms

  • Family history of leukemia may elevate risks particularly among men with mantle-cell lymphomas (OR = 3.1, 95% CI = 1.6-6.2)[47]

Other Information

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Links

Leukemic Non-Nodal Mantle Cell Lymphoma

In Situ Mantle Cell Neoplasia

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References

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EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

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