Elsevier

Human Pathology

Volume 33, Issue 1, January 2002, Pages 7-20
Human Pathology

Current Topics
From centrocytic to mantle cell lymphoma: A clinicopathologic and molecular review of 3 decades*,**

https://doi.org/10.1053/hupa.2002.30221Get rights and content

Abstract

Mantle cell lymphoma (MCL), described almost 3 decades ago as centrocytic lymphoma and by a variety of other names, was initially recognized morphologically. MCL is a classic illustration of how the field of hematopathology and our basic understanding of neoplasia have evolved. The advent of immunophenotypic and increasingly sophisticated genotypic and cytogenetic studies, together with clinical investigations, have led to a better practical and biologic understanding of MCL and have broader implications as well. MCL is now recognized as an aggressive, difficult to treat, B-cell lymphoma with a broader morphologic spectrum than was initially appreciated and a characteristic phenotype (CD5+, CD10−, CD23−, FMC7+). Virtually all MCLs carry the translocation t(11;14)(q13;q32) with overexpression of the involved CCND1 (cyclin D1) gene. Additional cytogenetic and molecular abnormalities have been identified, including some that are early events (such as ATM gene deletion and mutation) and others that appear to be late events (such as deletions and mutations in the negative cell cycle regulatory elements p53, p16, and p18). The latter are often associated with a blastoid morphology and more aggressive clinical course. Ongoing clinical and basic investigations including microarray analysis will undoubtedly provide additional insights into MCL and perhaps more effective and specific therapeutic modalities. HUM PATHOL 33:7-20. Copyright © 2002 by W.B. Saunders Company

Section snippets

Centrocytic lymphoma

CCL was described by Lennert et al as “diffuse germinocytoma” in a symposium on non-Hodgkin lymphoma in London, England, in 1973 (Lennert, personal communication). In the 1975 publication of this work, diffuse germinocytoma was described as a tumor that “looks very much like CLL” but lacks proliferation centers.1 It is composed of lymphocytes slightly larger than CLL cells with nuclei that are “very irregular in shape (not round) and often cleaved” with “very fine” chromatin and very small to

Mantle cell lymphoma

In 1992, the International Lymphoma Study Group proposed that the term mantle cell lymphoma replace CCL as well as other terms that were being used for this and other closely related entities.17 Banks et al noted that “the data indicate that the small cleaved cells of centrocytic lymphoma [lymphocytic lymphoma of intermediate differentiation/intermediate lymphocytic lymphoma, and mantle zone lymphoma] may be the neoplastic counterpart of cells normally residing in the follicle mantle. We

Identification of cyclin D1

The t(11;14)(q13;q32) was first identified in the 1970s as an apparently rare cytogenetic event in B-cell non-Hodgkin lymphoma and lymphocytic leukemia, and the translocation breakpoint was first cloned in 1984 by Tsujimoto et al.27 As in most B-cell neoplasms, the break involved the immunoglobulin heavy chain gene locus, as well as a site at 11q13 designated bcl-1 (B-cell leukemia/lymphoma 1) for the oncogene postulated to exist at that locus. The gene remained elusive until its identification

Cell cycle–regulatory pathways and the development of MCL

Cell cycle regulation is central to the control of cellular proliferation and differentiation programs. One of the primary regulatory checkpoints occurs at the “restriction point” in late G1 phase, where active cyclin/cyclin-dependent kinase (CDK) complexes form that are essential for progression into S phase (Fig 7).

. Schematic of the cell cycle G1/S restriction point showing positive (cyclin D1, CDK4, CDK6) and negative (p53, CDKI p15, p16, p18, p19) regulatory elements. Progression beyond the

Clinical approaches

MCL has one of the poorest overall prognoses of the non-Hodgkin lymphomas.127 However, there may be considerable heterogeneity in both therapeutic response and overall survival as described above. Response to any standard chemotherapy regimen is generally short-lived, and consolidation therapy with autologous stem cell transplantation has had little success.128 However, recent reports of the induction chemotherapy regimen HyperCVAD followed by autologous or allogeneic stem cell transplantation

Acknowledgements

The technical assistance of Margaret Whitefield and Patricia Ennis is gratefully acknowledged. The authors thank Benjamin Williams for assistance with manuscript preparation.

References (134)

  • LJ Medeiros et al.

    Association of bcl-1 rearrangements with lymphocytic lymphoma of intermediate differentiation

    Blood

    (1990)
  • ME Williams et al.

    Rearrangement of the chromosome 11 bcl-1 locus in centrocytic lymphoma: Analysis with multiple breakpoint probes

    Blood

    (1991)
  • RJ Molot et al.

    Antigen expression and polymerase chain reaction amplification of mantle cell lymphomas

    Blood

    (1994)
  • SH Swerdlow et al.

    Expression of cyclin D1 protein in centrocytic/mantle cell lymphomas with and without rearrangement of the BCL1/cyclin D1 gene

    Hum Pathol

    (1995)
  • ME Williams et al.

    In situ hybridization detection of cyclin D1 mRNA in centrocytic/mantle cell lymphoma

    Ann Oncol

    (1995)
  • Y Yatabe et al.

    Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: A clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma

    Blood

    (2000)
  • JW Vaandrager et al.

    Direct visualization of dispersed 11q13 chromosomal translocations in mantle cell lymphoma by multicolor DNA fiber fluorescence in situ hybridization

    Blood

    (1996)
  • LJ Coignet et al.

    Detection of 11q13 rearrangements in hematologic neoplasias by double-color fluorescence in situ hybridization

    Blood

    (1996)
  • JY Li et al.

    Detection of translocation t(11;14)(q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization

    Am J Pathol

    (1999)
  • JL Lai et al.

    Cytogenetics in multiple myeloma: a multicenter study of 24 patients with t(11;14)(q13;q32) or its variant

    Cancer Genet Cytogenet

    (1998)
  • PH Rao et al.

    Multicolor spectral karyotyping identifies new recurring breakpoints and translocations in multiple myeloma

    Blood

    (1998)
  • M Chesi et al.

    Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines

    Blood

    (1996)
  • M Hallek et al.

    Multiple myeloma: Increasing evidence for a multistep transformation process

    Blood

    (1998)
  • DS Viswanatha et al.

    Blastic mantle cell leukemia: An unusual presentation of blastic mantle cell lymphoma

    Mod Pathol

    (2000)
  • T Hunter et al.

    Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age

    Cell

    (1994)
  • T Hirama et al.

    Role of the cyclin-dependent kinase inhibitors in the development of cancer

    Blood

    (1995)
  • GJ Vanasse et al.

    Regulated genomic instability and neoplasia in the lymphoid lineage

    Blood

    (1999)
  • CJ Sherr

    G1 phase progression: Cycling on cue

    Cell

    (1994)
  • S Stilgenbauer et al.

    Molecular characterization of 11q deletions points to a pathogenic role of the ATM gene in mantle cell lymphoma

    Blood

    (1999)
  • C Schaffner et al.

    Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia

    Blood

    (1999)
  • J Imamura et al.

    p53 in hematologic malignancies

    Blood

    (1994)
  • CA Sander et al.

    p53 mutation is associated with progression in follicular lymphomas

    Blood

    (1993)
  • M Shiohara et al.

    Absence of WAF1 mutations in a variety of human malignancies

    Blood

    (1994)
  • H Ohnishi et al.

    Homozygous deletions of p16/MTS1 gene are frequent but mutations are infrequent in childhood T-cell acute lymphoblastic leukemia

    Blood

    (1995)
  • MA Haidar et al.

    p16INK4A and p15INK4B gene deletions in primary leukemias

    Blood

    (1995)
  • G Stranks et al.

    Deletions and rearrangement of CDKN2 in lymphoid malignancy

    Blood

    (1995)
  • PR Koduru et al.

    Deletion of cyclin-dependent kinase 4 inhibitor genes P15 and P16 in non-Hodgkin's lymphoma

    Blood

    (1995)
  • AF Gombart et al.

    Deletions of the cyclin-dependent kinase inhibitor genes p16INK4A and p15INK4B in non-Hodgkin's lymphomas

    Blood

    (1995)
  • JM Cayuela et al.

    Homozygous MTS1 (p16INK4A) deletion in primary tumor cells of 163 leukemic patients

    Blood

    (1995)
  • T Uchida et al.

    Mutational analysis of the CDKN2 (MTS1/p16ink4A) gene in primary B-cell lymphomas

    Blood

    (1995)
  • S Ogawa et al.

    Loss of the cyclin-dependent kinase 4-inhibitor (p16; MTS1) gene is frequent in and highly specific to lymphoid tumors in primary human hematopoietic malignancies

    Blood

    (1995)
  • K Lennert et al.

    Cytological and functional criteria for the classification of malignant lymphomata

    Br J Cancer

    (1975)
  • E Campo et al.

    Mantle-cell lymphoma

    Semin Hematol

    (1999)
  • SH Swerdlow et al.

    Centrocytic lymphoma: A distinct clinicopathologic, immunophenotypic, and genotypic entity

    Pathol Annu

    (1993)
  • P Lardelli et al.

    Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunophenotypic spectrum and clinical correlations

    Am J Surg Pathol

    (1990)
  • DD Weisenburger et al.

    Malignant lymphoma, intermediate lymphocytic type: A clinicopathologic study of 42 cases

    Cancer

    (1981)
  • DD Weisenburger et al.

    Mantle-zone lymphoma: A follicular variant of intermediate lymphocytic lymphoma

    Cancer

    (1982)
  • R Gerard-Marchant et al.

    Classification of non-Hodgkin's lymphomas

    Lancet

    (1974)
  • G Tolksdorf et al.

    Morphological and immunological definition of a malignant lymphoma derived from germinal-centre cells with cleaved nuclei (centrocytes)

    Br J Cancer

    (1980)
  • K Lennert

    Histopathology of Non-Hodgkin's Lymphomas (Based on the Kiel Classification)

    (1981)
  • Cited by (0)

    *

    Based in part on a lecture (by S.H.S.) at Jefferson Medical College, Philadelphia, PA, February 24, 1999.

    **

    Address correspondence and reprint requests to Steven H. Swerdlow, MD, Division of Hematopathology, UPMC-Presbyterian, Room PUH C606, 200 Lothrop St, Pittsburgh, PA 15213.

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