Since its initial recognition in the mid-1970s, this distinct entity has been described with various diagnostic terms, ie, lymphocytic lymphoma of intermediate differentiation by Berard (Berard CW, Dorfman RF. Histopathology of malignant lymphomas. Clin Hematol. 1974;3:39) centrocytic lymphoma by Lennert (Lennert K, Feller AC. Histology of Non-Hodgkin's Lymphomas (Based on the Updated Kiel Classification). Berlin: Springer-Verlag; 1990), and mantle zone lymphoma by Weisenburgerref. This history reflects the process of identifying the relatively divergent histologic patterns (diffuse, nodular, and mantle zone patterns) of this entity, which may sometimes create diagnostic pitfalls even for expert pathologists. In 1992, Banks et alref showed that these differently named lymphomas fell within the same entity and named it mantle cell lymphoma.

Table of contents :

  • Epidemiology
  • Aetiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Differential diagnosis
  • Therapy 
  • Prognosis
  • Web resources

  • Epidemiology : 5-10% of all NHLs; mainly affects people over 50 years of age (median age of over 60 years), male predominance
    Aetiology : ?
    Pathogenesis :

    In MCL, the postulated cell of origin is a B cell deriving from the mantle zone of a lymphoid follicle that has not entered the GC and, therefore, lacks SHMref. This fact has been questioned because MCL patients with mutated VH genes have been reported by our group and othersref1, ref2, ref3, ref4. Recently, we investigated 51 MCL patients and showed that approximately 16%ref-20%ref-27%ref-29%ref of them displayed hypermutated VH genes but with no evidence of ongoing somatic hypermutations, indicating that this subset of clonal B cells in MCL patients with mutated VH genes are not under prolonged antigenic stimulation in the GC and probably derive from a post-GC B cellref.
    This 2% sequence deviation from the corresponding germline gene cut-off level, which has been empirically derived for B-CLLref to avoid counting Taq polymerase errors and polymorphisms as hypermutationsref, may, however, not be appropriate for defining a mutated case in MCL. There is a large difference in the percentage of mutated cases in each disease (approximately 40%-50% in CLL vs 16% in MCLref1, ref2, ref3, ref4, ref5), and the mean mutation percentage of the mutated group is lower in MCL than in CLL (3ref-3.7%ref vs approximately 6-6.1%). In addition to the 18 patients with mutated VH genes, another 17 patients had VH genes with a mutation rate of 1% to 2%, which may also represent mutated MCL. Therefore, we performed survival analysis using other percentage cut-off levels for defining a mutated case (1%-5%), but similar results were obtained using different borders. Hence, in our cohort of MCL patients, VH gene mutation status was not prognostically useful. Interestingly, patients with nonnodal MCL (patients without clinical lymphadenopathy, who are usually rare) have mutations more frequently (19 of 34 patients) than patients with nodal engagement (5 of 31 patients) : survival did not differ significantly between mutated and unmutated MCL but that there was a tendency toward improved survival in the mutated subset and patients with nonnodal MCL had a less aggressive disease than nodal patients (Garand R, Orchard J, Davis Z, et al. A subset of mantle cell lymphoma exhibits stable disease and correlates with mutated VH genes and low CD38 expression [abstract]. Blood. 2001;98:724a).
    So, while most MCLs derive from pre-GC B cells residing in the follicular mantle, for a small subset of MCL there is either a GC phase or an extra-germinal centre IgH hypermutation processref. Recently, it was reported that patients with X-linked hyper IgM syndrome, which is characterized by a mutation in the CD40L gene and the inability to form GCs, can still have a subset of B cells (CD27+IgM+IgD+) with mutated VH genesref. This is suggestive of the existence of a second diversification pathway to acquire hypermutations without the classical interaction between B and T cells. The rate of somatic hypermutations in these CD27+IgM+IgD+ B cells was generally low (approximately 1%-2%) in patients with hyper IgM syndrome. However, little is known about this separate route, and it remains to be investigated whether different B-cell subsets, such as MCL precursors, acquire hypermutations by this process.
    In terms of prognosis, while B-CLL cases with mutated IgH genes have a significantly better prognosis than unmutated onesref1, ref2, ref3, mutated MCL cases, however, do not differ in outcome from IgH unmutated cases, an observation confirmed by other recent reportsref1, ref2, ref3, ref4.
    MCL cases show a biased usage of individual VH genes, with VH3-21 being the most common followed by VH3-23 and VH4-34ref1, ref2, ref3; VH3-21 is usually combined with a L chain containing the Vl3-19ref. VH3-21+ MCL cases are usually unmutated, and are associated with a better prognosis. This is in contrast to CLL. Indeed, VH3-21+ CLL cases are mutated and have a worse prognosis.
    The nodal architecture in patients with MCL usually consists of atypical small lymphoid cells that generally display a nodular or diffuse pattern of growth, sometimes with elements of each. Focal areas of nodularity are evident in about 30% of cases on initial presentation.
    Histologic progression from a nodular pattern to a diffuse pattern may be evident in repeat biopsy specimens obtained from the same patient, as may progression from the predominantly small lymphocytic forms of MCL to blastic cytology. Some reports suggest that histologic transformation to blastic cytology on re-biopsy can occur in up to 17% of cases, and may be as high as 70% at autopsy. Histologic transformation of MCL to DLBCL, like that seen in patients with FL or B-CLL, is considered a rare eventref. Distinguishing features of MCL compared to 3 NHL subtypes :
    Differential diagnosis :
    FL small cleaved cell Grade 1 CD5, CD23±, CD10+, CD43
    mixed small cleaved and large cell Grade 2
    large cell Grade 3
    small lymphocytic lymphoma with plasmacytoid differentiation (SSL-pl)
    B-CLL CD5+, CD23+, CD43+, CD11a+, FMC7–, IgLdim
    MCL CD5+, CD23– (rarely + ref), CD10±, CD43+, cyclinD1+, FMC7+, IgLbright
    marginal zone lymphoma (MZL) MALT CD5, CD23, CD10, CD43±
    splenic lymphoma with villous lymphocytes (SLVL) CD5, CD11c±, FMC7+, CD22+, CD24+
    hairy cell leukemia (HCL) CD5, CD10, CD25+, CD11c+, CD103+, B-ly-7+
    The clinical separation of MCL from the other subtypes of diseases with which it is often lumped was first clarified in a landmark paper reported by Fisherref, based upon an analysis of patient tissue obtained from three sequential randomized clinical trials conducted by the SWOG between 1972 and 1983. These data re-evaluated the tissue diagnosis from over 376 patients with Working Formulation diagnoses encompassing categories A through E. They reported that 6 of 70 patients with small lymphocytic/diffuse well-differentiated lymphoma (category A) in fact had MCL, while 9 of 171 patients with follicular small cleaved/nodular poorly differentiated lymphoma (category B) had MCL, and 21 of 66 patients with diffuse small cleaved/diffuse lymphoma poorly differentiated lymphoma (category E) had MCL. They also demonstrated that the failure-free survival (FFS) and OS of patients with MCL was significantly worse than that of patients with Working Formulation (WF) diagnoses from categories A and E (P = 0.0001 and 0.0001, respectively). In fact, the OS at 10 years for patients with MCL was only 8% compared to 35% for the WF categories A through E. In addition, separating the different histologic variants of MCL into the nodular, diffuse and blastic variants, the SWOG report demonstrated that the overall survival at 10 years for these MCL subtypes was 14%, 10% and 0% respectively. Clinically, MCL has an approximately 2:1 male to female predominance, with a median age of occurrence of about 58 years. It presents with generalized adenopathy in 71–90% of cases, and with bone marrow positivity in 53%–90% of cases. Involvement of the gastrointestinal tract is thought to be nearly universal at the time of diagnosis. Today we know that the median survival of patients with MCL is only about 3 years, and that the median FFS from up-front conventional CHOP based treatment is only 15 to 18 months. These points are poignantly underscored in the very last sentence from the 1995 SWOG analysisref, where it was emphasized that "...patients with MCL do not have an indolent lymphoma and are candidates for innovative therapy." A recommendation that has been heeded over the past decade with some promising developments. Consensus pathology review of Southest Oncology Group (SWOG) lymphoma cases (1972–1983)ref
    International Working Formulation (IWF) diagnosis
    total (N)
    A 70 6
    B 171 9
    C 40 0
    D 29 0
    E 66 21
    total reviewed 376 36 (10%)
    Despite our ability to distinguish MCL from the other forms of small lymphocytic lymphoma, it is clear that even this new entity of disease represents a spectrum of diseases, a spectrum of biology that is now being reorganized based on recent advancements in molecular analysis and gene expression array technologies. While a detailed analysis of the defining molecular events seen in MCL is beyond the scope of this presentation, it is clear that there are a number of molecular derangements beyond the t(11:14)(q13;q32) translocation that characterize the disease. Derangements in p27 and p53 for example appear to interact almost synergistically to yield a subtype of MCL with a particularly poor prognosisref1, ref2. In addition, Rosenwald et alref reported on the use of gene expression profiling to establish a molecular basis for stratifying different subtypes of MCL. Such techniques are focused on developing a quantitative approach to elucidate the underlying pathogenesis and risk stratification of all patients. These investigators showed that the measurement of tumor cell proliferation determined by the identification of a set of "proliferation signature genes" was able to risk-stratify patients, based to a large extent on the differences in cyclin D1 mRNA abundance and the presence or absence of the cdk inhibitor INK4a/ARFref. Collectively, these data have begun to reveal potential targets in these different subsets of MCL that may be appropriate substrates for novel drug discovery. At the least, this genetic based risk stratification could lead to the tailoring of innovative new treatments based on the particular subtype of MCL.
    Symptoms & signs (despite being previously considered a low-grade and indolent lymphoma, MCL appears to have the worst characteristics of both low- and high-grade lymphomas : incurable and aggressive) : Laboratory examinations : Therapyref1, ref2 : current therapies for MCL are unsatisfactory and there is no standard treatment. Patients with localized disease might be treated with combination chemotherapy followed by radiotherapy; however, these patients are exceedingly rare. For the usual presentation with disseminated disease, treatments have been unsatisfactory, with the minority of patients achieving complete remission. Aggressive combination chemotherapy regimens followed by autologous or allogeneic bone marrow transplantation are frequently offered to younger patients. For the occasional elderly, asymptomatic patient, observation followed by single-agent chemotherapy might be the most practical approach. An intensive combination chemotherapy regimen originally used in the treatment of acute lymphoblastic leukemia (ALL), HyperC-VAD + rituximab seems to be associated with better response rates—particularly in younger patients. CHOP plus rituximab has shown better response rates than CHOP alone, but long-term follow-up is lacking. Prognosis : the 5-year OS for all patients with MCL is 25%. MCL median TTP and OS (3 years)) are the shortest among all lymphoma subtypes Web resources :
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