Compendium of Cancer Genome Aberrations

HAEM4: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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Leukemic Non-Nodal Mantle Cell Lymphoma

In Situ Mantle Cell Neoplasia

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References

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  1. ↑ K, Lennert; et al. (1975). "Cytological and functional criteria for the classification of malignant lymphomata". PMC 2149614. PMID 52366.CS1 maint: PMC format (link)
  2. ↑ H, Kim; et al. (1982). "Pathology Panel for Lymphoma Clinical Studies: a comprehensive analysis of cases accumulated since its inception". PMID 6948126.
  3. ↑ Dd, Weisenburger; et al. (1982). "Mantle-zone lymphoma: a follicular variant of intermediate lymphocytic lymphoma". PMID 6895860.
  4. ↑ "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project". 1997. PMID 9166827.
  5. ↑ Ke, Smedby; et al. (2011). "Epidemiology and etiology of mantle cell lymphoma and other non-Hodgkin lymphoma subtypes". PMID 21945518.
  6. ↑ B, Aschebrook-Kilfoy; et al. (2013). "An upward trend in the age-specific incidence patterns for mantle cell lymphoma in the USA". PMID 23350889.
  7. ↑ Lh, Argatoff; et al. (1997). "Mantle cell lymphoma: a clinicopathologic study of 80 cases". PMID 9058729.
  8. ↑ P, Lardelli; et al. (1990). "Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunophenotypic spectrum and clinical correlations". PMID 2198813.
  9. ↑ Arber, D.A., et al., Hematopathology. 2017, Philadelphia, PA: Elsevier.
  10. ↑ A, Ferrer; et al. (2007). "Leukemic involvement is a common feature in mantle cell lymphoma". PMID 17477385.
  11. ↑ J, Wasman; et al. (1996). "Mantle cell lymphoma. Morphologic findings in bone marrow involvement". PMID 8712173.
  12. ↑ Ma, Vasef; et al. (1997). "Cyclin D1 immunohistochemical staining is useful in distinguishing mantle cell lymphoma from other low-grade B-cell neoplasms in bone marrow". PMID 9291459.
  13. ↑ H, Samaha; et al. (1998). "Mantle cell lymphoma: a retrospective study of 121 cases". PMID 9697885.
  14. ↑ Cy, Cheah; et al. (2013). "Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network". PMID 23616279.
  15. ↑ Kh, Young; et al. (2006). "Mantle cell lymphoma with plasma cell differentiation". PMID 16861965.
  16. ↑ Ma, Piris; et al. (1998). "A marginal zone pattern may be found in different varieties of non-Hodgkin's lymphoma: the morphology and immunohistology of splenic involvement by B-cell lymphomas simulating splenic marginal zone lymphoma". PMID 9777389.
  17. ↑ M, Fraga; et al. (1995). "Mucosal mantle cell (centrocytic) lymphomas". PMID 7657310.
  18. ↑ N, Vogt; et al. (2013). "Variability in morphology and cell proliferation in sequential biopsies of mantle cell lymphoma at diagnosis and relapse: clinical correlation and insights into disease progression". PMID 23240716.
  19. ↑ W, Klapper; et al. (2009). "Ki-67 as a prognostic marker in mantle cell lymphoma-consensus guidelines of the pathology panel of the European MCL Network". doi:10.1007/s12308-009-0036-x. PMC 2725281. PMID 19669190.CS1 maint: PMC format (link)
  20. ↑ O, Determann; et al. (2008). "Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group". PMID 18077791.
  21. ↑ L, Hernandez; et al. (1996). "p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas". PMID 8605352.
  22. ↑ Jy, Choe; et al. (2016). "MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma". PMID 26100211.
  23. ↑ J, Xu; et al. (2017). "CD10-positive mantle cell lymphoma: clinicopathologic and prognostic study of 30 cases". doi:10.18632/oncotarget.23571. PMC 5837746. PMID 29545910.CS1 maint: PMC format (link)
  24. ↑ S, Kumar; et al. (1996). "Use of CD23 (BU38) on paraffin sections in the diagnosis of small lymphocytic lymphoma and mantle cell lymphoma". PMID 8878025.
  25. ↑ B, Espinet; et al. (2014). "Distinction between asymptomatic monoclonal B-cell lymphocytosis with cyclin D1 overexpression and mantle cell lymphoma: from molecular profiling to flow cytometry". doi:10.1158/1078-0432.CCR-13-1077. PMC 4488901. PMID 24352646.CS1 maint: PMC format (link)
  26. ↑ Dp, O'Malley; et al. (2017). "Expression of LEF1 in mantle cell lymphoma". PMID 28038713.
  27. ↑ B, Sander; et al. (2016). "Mantle cell lymphoma--a spectrum from indolent to aggressive disease". PMID 26298543.
  28. ↑ K, Fu; et al. (2005). "Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling". doi:10.1182/blood-2005-04-1753. PMC 1895253. PMID 16123218.CS1 maint: PMC format (link)
  29. ↑ I, Wlodarska; et al. (2008). "Translocations targeting CCND2, CCND3, and MYCN do occur in t(11;14)-negative mantle cell lymphomas". PMID 18391076.
  30. ↑ D, Martín-Garcia; et al. (2019). "CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1 - mantle cell lymphoma". doi:10.1182/blood-2018-07-862151. PMC 6396173. PMID 30538135.CS1 maint: PMC format (link)
  31. ↑ Martín-Garcia, David; et al. (02 28, 2019). "CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1- mantle cell lymphoma". Blood. 133 (9): 940–951. doi:10.1182/blood-2018-07-862151. ISSN 1528-0020. PMC 6396173. PMID 30538135. Check date values in: |date= (help)
  32. ↑ Royo, Cristina; et al. (2011-11). "The complex landscape of genetic alterations in mantle cell lymphoma". Seminars in Cancer Biology. 21 (5): 322–334. doi:10.1016/j.semcancer.2011.09.007. ISSN 1096-3650. PMID 21945515. Check date values in: |date= (help)
  33. ↑ G, Ott; et al. (1997). "Blastoid variants of mantle cell lymphoma: frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones". PMID 9028966.
  34. ↑ 34.0 34.1 L, Wang; et al. (2020). "MYC rearrangement but not extra MYC copies is an independent prognostic factor in patients with mantle cell lymphoma". PMID 32273477 Check |pmid= value (help).
  35. ↑ Un, Vaishampayan; et al. (2001). "Blastic mantle cell lymphoma associated with Burkitt-type translocation and hypodiploidy". PMID 11722412.
  36. ↑ C, Royo; et al. (2011). "The complex landscape of genetic alterations in mantle cell lymphoma". PMID 21945515.
  37. ↑ Rosenquist, R.; et al. (11 2017). "Genetic landscape and deregulated pathways in B-cell lymphoid malignancies". Journal of Internal Medicine. 282 (5): 371–394. doi:10.1111/joim.12633. ISSN 1365-2796. PMID 28631441. Check date values in: |date= (help)
  38. ↑ Ferrero, Simone; et al. (07 2017). "Minimal residual disease in mantle cell lymphoma: are we ready for a personalized treatment approach?". Haematologica. 102 (7): 1133–1136. doi:10.3324/haematol.2017.167627. ISSN 1592-8721. PMC 5566011. PMID 28655809. Check date values in: |date= (help)
  39. ↑ E, Hoster; et al. (2008). "A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma". PMID 17962512.
  40. ↑ M, Tiemann; et al. (2005). "Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network". PMID 16173960.
  41. ↑ N, Vogt; et al. (2013). "Variability in morphology and cell proliferation in sequential biopsies of mantle cell lymphoma at diagnosis and relapse: clinical correlation and insights into disease progression". PMID 23240716.
  42. ↑ E, Hoster; et al. (2016). "Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network". PMID 26926679.
  43. ↑ Z, Hu; et al. (2017). "Mantle Cell Lymphoma With MYC Rearrangement: A Report of 17 Patients". PMID 27776009.
  44. ↑ 44.0 44.1 Mh, Delfau-Larue; et al. (2015). "High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma". PMID 26022239.
  45. ↑ 45.0 45.1 S, Ferrero; et al. (2020). "KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study". doi:10.3324/haematol.2018.214056. PMC PMC7271566 Check |pmc= value (help). PMID 31537689.CS1 maint: PMC format (link)
  46. ↑ I, Salaverria; et al. (2007). "Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature". doi:10.1200/JCO.2006.08.4251. PMC 2366164. PMID 17296973.CS1 maint: PMC format (link)
  47. ↑ Ss, Wang; et al. (2007). "Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph)". doi:10.1182/blood-2006-06-031948. PMC 1852242. PMID 17185468.CS1 maint: PMC format (link)

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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