Gene expression profiling and other molecular technologies have led us to discriminate the developmental stage of the cell of origin of B-cell lymphoma subtypes.23
Since B-cell lymphomas originate from distinct steps of differentiation of normal B-cells, we would expect that some entities would be more prone to differentiate into PCs than others. Indeed, many marginal zone lymphomas and virtually all lymphoplasmacytic lymphomas have a clonal PC component.7,8,21
Others, like diffuse large B-cell lymphomas,27,35
and follicular lymphoma16,20
may show plasmacytic differentiation, while little is known about MCL.29,46
With the current study we provide strong evidence that clonal PCs differentiation can also occur in certain cases of MCL, clearly demonstrating that the PCs and MCL cells can derive from the same B-cell clone.
In the present study, we investigated seven new cases of otherwise typical MCL that showed significant PC populations within the tumor tissue. In order to achieve robust conclusions regarding the relationships between the two neoplastic populations, we used PCR for the IGH with capillary gel electrophoresis, FICTION and RFLP/IgH assay for each microdissected MCL and PCs. The molecular analysis for the immunoglobulin heavy chain rearrangement revealed an identical clonal origin of the MCL and PC populations in five of the seven samples, indicating that these cases represent an interesting morphologic type of MCL. Results of capillary gel electrophoresis of PCR products were concordant with RFLP/IgH analysis, independently confirming our findings. As shown in , Case 1 and Case 5 had instead no clonal relationship between PCs and MCL, and represented a concomitant plasma cell neoplasm or a nodal marginal zone lymphoma and MCL in the same patient. Composite lymphoma consisting of MCL and a clonally unrelated plasmacytoma or plasma cell myeloma have occasionally been reported.2,40,45
The distinction between MCL with a concomitant plasma cell neoplasm and a unique variant of MCL has relevant clinical significance, since prognosis and treatment of the two forms of disease would be expected to be different. A multidisciplinary approaches including detailed morphologic evaluation and a panel of immunostains, along with cytogenetic analysis for the t(11;14)(q13;q32) are needed to rule out other subtypes of B-cell lymphoid neoplasms with more frequent plasmacytic differentiation, especially when the tumor presents in unusual sites.
The present report follows two previously published cases46
describing for the first time the presence of clusters of monotypic kappa light chain expressing PCs in the center of MCL nodules and within the reactive GCs. In the previous study, the presence of the t(11;14)(q13;q32) both in the MCL cells and clonal PCs was considered compatible with a common origin from the same B-cell clone. However, the demonstration of the translocation itself in the two clones is insufficient to discriminate between MCL with plasmacytic differentiation and MCL with concurrent plasma cell neoplasm, as the t(11;14)(q13;q32) is commonly observed in nonhyperdiploid plasma cell myeloma.11
More recently, another case of MCL with evidence of clonal plasmacytic differentiation has been reported by Naushad et al.,29
using multi-parameter flow cytometry to demonstrate a close relationship between the two clones.
Monoclonal paraproteins, mostly of the IgM type, can be demonstrated in the serum of B-cell lymphoma, mostly in CLL/SLL and marginal zone lymphoma, usually at lower levels than in lymphoplasmacytic lymphoma.24
Using a sensitive serum immunoassay, monoclonal IgM and IgG were previously reported in 18% and 5% of patients with MCL, respectively.32
These findings suggest that clonal PCs can be part of MCL tumor microenvironment, and the frequency of clonal PCs in MCL may be more common than previously thought. Among our cases a monoclonal paraprotein was present in 3 of 7 (43%) patients with clonal PC population.
During normal immune response, when naïve B-cells meet an antigen with adequate affinity, they are selected and induced to proliferate either entering the GC or extra-follicular areas, where they divide further before differentiating into short-lived PCs. Therefore, plasmacytic differentiation could develop via two different pathways: GC (activated B-cells) and non-GC (naïve B-cells).30
The underlying mechanisms are better understood for the GC pathway in which environmental stimuli may induce the GC B-cell to become a PC. As GC B-cells begin to differentiate into PC, they up-regulate the transcription factor interferon regulatory factor 4 (IRF4), which initiates plasmacytic differentiation by increasing the expression of B lymphocyte-induced maturation protein 1 (BLIMP1)
and extinguishes the GC B-cell program by repressing BCL6.38
In this scenario, growth factors (IL-6), and cell-cell interactions (CD40L) play regulatory roles in mediating transcription factor expression and lead to somatic hypermutation of their rearranged IgH genes and finally to PC differentiation.3,12,19
It is generally accepted that most biologically long-lived PCs derive from B-cells in the GCs or post-GC marginal zones. Alternatively, PCs can also arise from memory B-cells derived from GC centrocytes and can quickly differentiate into PCs through the GC-pathway upon secondary encounter with minute amounts of antigen.
In contrast, little is known regarding plasmacytic differentiation via the non-GC pathway. A proportion of naïve B-cells can undergo IgH-gene mutations outside the GCs without T-cell help and express IgG, but most of them are not switched and express IgM,37,44
as observed in CLL/SLL.6 In-vitro
studies have confirmed that PCs can differentiate from naïve B-cells, but they are usually short-lived with low quantity production.30
Somatic hypermutation and class switch recombination are critical to PC differentiation through the GC, and require the presence of activation-induced cytidine deaminase (AID), which is virtually absent on naïve primary follicle, mantle zone, and extra-follicular B-cells. However, a fraction of naive B-cells can harbor mutated IgH-gene and express AID, suggesting that these cells may be able to enter the GC and differentiate into PCs.22
It is likely that MCL cells under some circumstances can enter the GC and differentiate into PCs, as outlined in two cases of MCL with clusters of clonal PCs within reactive GCs46
and as suggested by recent reports of IgH-gene mutations in a considerable subset of MCL.4
In this regard, it would be of interest to explore the correlation of IgH gene mutational status in groups of MCL cases with and without PC component, which may in part address the question of GC versus non-GC mediated PC differentiation. Further study of similar cases will be needed to better understand these processes.
In conclusion, our study clearly demonstrated the existence of MCL with related plasmacytic component. Our comprehensive analysis shows that in most MCL with clonal plasma cells, the two components are clonally related (5/7, 71%), indicating that clonal PC differentiation may occur in most of MCL in which PC component is present. However, in some cases the two clones are unrelated likely a reflection of a composite tumor, while the presence of polyclonal PCs within MCL as previously thought seems rather unusual. A molecular approach to analyse the clonal relationship between the two populations is needed to exclude a composite lymphoma and allow for appropriate treatment.