Non-Hodgkins Lymphoma Mantle Cell Lymphoma

Administrative Office
St. Joseph's Hospital Site, L301-10
50 Charlton Avenue East
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Issue No. 74
April 2004
Non-Hodgkins Lymphoma
Mantle Cell Lymphoma
Introduction: Mantle cell lymphoma is a form of non-Hodgkin’s lymphoma and is a distinct clinical-pathologic
entity only recently recognized by the Revised European-American Lymphoma (REAL) and World Health
Organization (WHO) classification schemas. The disease is a relatively aggressive form of lymphoma and is
characterized by a cytogenetic abnormality, t(11; 14) (q13;q32) that results in over expression of the cell cycle
regulating factor cyclin D1. Mantle cell lymphoma accounts for 8% of all cases of lymphoma and typically
presents in older patients.. Similar to other types of lymphoma, patients may present with generalized
lymphadenopathy, fatigue that may be associated with anemia or a high disease burden, and B symptoms
(fevers, nights sweats, weight loss). Mantle cell lymphoma frequently presents with extra-nodal involvement,
with 70% of patients having stage IV disease; potential sites of extra-nodal disease include gastrointestinal,
pulmonary and central nervous system involvement. Although several therapeutic options exist, no curative
strategy has been established and overall median survivals remain poor (approximately 3 years) with only 10%
of patients demonstrating long-term survival. Given aspects of prognosis and with the potential associated with
newer cyclin-targeted therapies, it is important to clearly identify patients with this specific form of lymphoma.
The diagnosis of mantle cell lymphoma involves a systematic and collaborative approach; within the Hamilton
Regional Laboratory Medicine Program, this includes participation of Anatomic Pathology for evaluation of
morphology and immunohistochemistry, Hematology including the Malignant Cell Diagnostics Laboratory for
evaluation of flow cytometry and Molecular Hematology for molecular evaluation using polymerase chain
reaction, and Molecular Genetics for evaluation of cytogenetics or testing using fluorescence in situ
hybridization. (FISH).
Pathophysiology: Mantle cell lymphoma is characterized by a genetic translocation that involves
chromosomes 11 (bcl-1) and 14 (immunoglobulin heavy chain IgH) resulting in the over expression of bcl1/cyclin D1 (See Figure 1); t(11;14) is not specific to mantle cell lymphoma and may be seen in some cases of
diffuse large cell lymphoma, chronic lymphocytic leukemia and multiple myeloma. Cyclin D1 forms a complex
with cyclin dependent kinases (cdk4/cdk6). Cyclin d1-cylin dependent kinase-4 complex phosphorylates the
retinoblastoma (RB) protein, which removes its growth suppressive effects and propels cells from G1 to S in the
cell cycle. The MDR1 gene (tumor resistance to doxorubicin and vincristine) also on chromosome 11 may also
be translocated and other molecular events in MCL include 13q abnormalities, p53 mutations and loss of the
tumour suppressor gene ATM.
Diagnosis: Mantle cell lymphoma can be diagnosed from samples of lymph node or extra-nodal tissue, bone
marrow, and in some cases peripheral blood. Most cases will be diagnosed by lymph node biopsy and it is
essential that surgical node biopsy samples be submitted for evaluation using a specific protocol to evaluate
tissues for lymphoma diagnosis and classification. This process allows for performing special studies, such as
flow cytometry and molecular evaluation, prior to formalin-based fixation. The histologic features of mantle cell
lymphoma are of small to medium sized cells with relatively open chromatin and nuclear contour irregularities.
The pattern of infiltration may be nodular, diffuse or a mantle zone proliferation. These cells are derived from a
subset of naïve pre-germinal center cells localized in the primary follicles or in the mantle region of secondary
follicles. The characteristic immunophenotype observed with immunohistochemical and flow cytometric
assessment is the finding of cells that are CD5+ and CD23-, which distinguishes mantle cell lymphoma from
chronic lymphocytic leukemia, which is CD5+ and CD23+. Other cell markers include FMC7, CD19, CD20,
CD22, surface IgM and IgD. As opposed to other primitive lymphoid malignancies, mantle cell lymphoma is
typically negative for CD10. A panel of immunophenotypic markers can be assessed by flow cytometry
(Henderson site) and/or immunohistochemistry (AP Labs). Immunohistochemical analysis also includes staining
for cyclin D1 protein. Further confirmation can be made by molecular analysis that demonstrates the presence
of the t(11:14) translocation. This can be accomplished through evaluation by FISH, cytogenetics, or PCR. The
use of FISH involves the detection of highly specific DNA probes that have been hybridized to either interphase
or metaphase chromosomes using fluorescence microscopy and has a high rate of sensitivity (1/250 cells) and
specificity. Sensitivity appears to be greater by FISH as primers in the major translocation cluster/JH region are
positive in only 30-40% of cases.
Figure 1 The genetic translocation of chromosomes 11:14 results in the overexpression of cyclinD1. CyclinD1
plays an important role along with other cyclin dependent kinases in regulating the cell cycle and malignant
phenotype. New therapies targeting cyclinD1 are being developed. The unique translocation is also used as a
diagnostic tool.
Treatment: Therapy for patients with mantle cell lymphoma includes strategies that are similar to those used in
treating most forms of lymphoma. The mainstay of treatment includes combination chemotherapy that may be
supplemented by using radiation therapy. Biologic therapies, such as use of the anti – CD20 monoclonal
antibody, rituximab, are evolving. At the Juravinski Cancer Centre, there is an active clinical research program
with patients eligible to enter clinical trials testing new agents such as flavopiridol and bortezomib (proteosome
Summary: Although relatively uncommon, MCL is a unique form of NHL now recognized as a distinct
clinicopathological entity. Accurate diagnosis requires specific collaborative skills from Antatomic Pathology and
Hematology/Molecular laboratories. As new improved targeted therapies emerge, such as MCL, accurate
diagnosis will be essential in determining the presence of specific molecular targets.
Lenz G, Dreyling M, Hiddemann W. Mantle cell lymphoma: established therapeutic options and future
directions. Ann Hematol. 2004 Feb; 83(2): 71-7
Frater JL, Hsi ED. Properties of the mantle cell and mantle cell lymphoma. Curr Opin Hematol. 2002 Jan;
9(1): 56-62.
Dr. S. R. Foley
Discipline of Special Hematology
Hamilton Regional Laboratory Medicine Program
Henderson General Hospital Site