Myeloid cell nuclear differentiation antigen is expressed in a subset of marginal zone lymphomas and is useful in the differential diagnosis with follicular lymphoma

    MNDA is expressed in a subset of marginal zone lymphomas and is useful in the differential diagnosis with follicular lymphoma Ryan A. Metcalf, Ahmad Monabati, Monika Vyas, Giovanna Roncador, Gabriela Gualco, Carlos E. Bacchi, Sheren F. Younes, Yasodha Natkunam, Aharon G. Freud PII: DOI: Reference:

S0046-8177(14)00157-9 doi: 10.1016/j.humpath.2014.04.004 YHUPA 3290

To appear in:

Human Pathology

Received date: Revised date: Accepted date:

3 June 2013 9 April 2014 11 April 2014

Please cite this article as: Metcalf Ryan A., Monabati Ahmad, Vyas Monika, Roncador Giovanna, Gualco Gabriela, Bacchi Carlos E., Younes Sheren F., Natkunam Yasodha, Freud Aharon G., MNDA is expressed in a subset of marginal zone lymphomas and is useful in the differential diagnosis with follicular lymphoma, Human Pathology (2014), doi: 10.1016/j.humpath.2014.04.004

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ACCEPTED MANUSCRIPT MNDA expression in marginal zone lymphomas

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Metcalf et al.

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MNDA is expressed in a subset of marginal zone lymphomas and is

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useful in the differential diagnosis with follicular lymphoma

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Ryan A. Metcalf1, Ahmad Monabati1, Monika Vyas1, Giovanna Roncador2, Gabriela

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Gualco3, Carlos E. Bacchi3, Sheren F. Younes4, Yasodha Natkunam1, Aharon G. Freud1

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Department of Pathology, Stanford University School of Medicine, Stanford, CA USA

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Biotechnology Program, Spanish National Cancer Research Centre, Madrid, Spain

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Consultoria em Patologia, Botucatu, São Paulo, Brazil

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Department of Pathology, University of Menoufiya, Menoufiya, Egypt

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Running title: MNDA expression in marginal zone lymphomas

Correspondence should be addressed to: Yasodha Natkunam, MD, PhD Department of Pathology, L235 Stanford University School of Medicine 300 Pasteur Drive, Stanford, CA 94305-5324 Tel: (650) 725-9354; FAX: (650) 725-7409 E-mail: [email protected]

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MNDA expression in marginal zone lymphomas

Abstract The diagnosis of marginal zone lymphomas is challenged by the lack of specific markers that

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distinguish them from other low-grade non-Hodgkin B cell lymphomas. Myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein that labels myelomonocytic cells as well as B-lymphocytes that localize to the marginal zone areas of splenic white pulp. We evaluated

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MNDA expression in a large series of B cell lymphomas to assess the sensitivity and specificity

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of this antigen for the characterization of marginal zone lymphoma. A total of 440 tissue sections containing extramedullary B cell lymphomas and 216 bone marrow biopsies containing atypical

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or neoplastic lymphoid infiltrates were stained for MNDA by immunohistochemistry. Among the extramedullary lymphoma cases, approximately 67% of nodal marginal zone lymphoma, 61% of

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extranodal marginal zone lymphoma, and 24% of splenic marginal zone lymphoma expressed MNDA. MNDA was also infrequently expressed in other B cell neoplasms including mantle cell

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lymphoma (6%), chronic lymphocytic leukemia/small lymphocytic lymphoma (13%), follicular

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lymphoma (4%), lymphoplasmacytic lymphoma (25%), and diffuse large B cell lymphoma (3%). In contrast, MNDA was only expressed in 2.3% of all bone marrow biopsies involved by

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lymphoid infiltrates, including two cases of follicular lymphoma and one case of marginal zone lymphoma. Collectively, these data support the inclusion of MNDA in the diagnostic evaluation of extramedullary B cell lymphomas, particularly those in which the differential diagnosis is between low-grade follicular lymphoma and marginal zone lymphoma.

Key words: MNDA, lymphoma, B cell, lymphoid neoplasia, marginal zone lymphoma, follicular lymphoma, non-Hodgkin lymphoma

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Introduction Non-Hodgkin lymphomas that derive from mature B cells comprise a diverse group of

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malignancies that retain many features of their non-neoplastic counterparts.1 As such,

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immunophenotypic evaluation of antigenic markers that distinguish normal B cell subsets is highly utilized for the appropriate diagnosis and classification of B cell malignancies. For

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example, follicular lymphomas (FL) are thought to derive from germinal center B cells, and germinal center-associated antigens, B cell lymphoma 6 (BCL6), CD10, human germinal center-

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associated lymphoma (HGAL), and LIM domain only 2 (LMO2), are useful as diagnostic

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markers of FL in the appropriate clinicopathological context.2 Likewise, marginal zone lymphomas (MZL), of which three distinct entities are described in the recent 2008 World Health Organization (WHO) classification (nodal, extranodal, and splenic), likely share a common

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derivation from normal marginal zone and/or memory B cells that localize to marginal zone-like

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areas of spleen, peripheral lymph nodes, and tertiary lymphoid tissues.1,3,4 To date there are no known specific markers of marginal zone cells or of MZL. Moreover, MZL typically lack CD5 and

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CD10 with variable plasmacytic differentiation and therefore their separation from other lowgrade B cell lymphomas (LGBCL) that may show similar, non-specific immunophenotypic and/or

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cytomorphological features is challenging.3 Continued investigation to identify new markers that can distinguish MZL from other neoplastic lymphoid proliferations is therefore warranted. Myeloid cell nuclear differentiation antigen (MNDA) is a regulatory protein involved in cell differentiation and apoptosis and is normally expressed at high levels in the myeloid and monocytic lineages.5,6 It is encoded by the MNDA gene, which is located on human chromosome 1q22 and is a member of the interferon-regulated 200 family of genes (HIN-200).7 In addition to its expression by myelomonocytic cells, MNDA is also expressed by B cells that colocalize to the marginal zones of splenic white pulp as well as less frequently to the marginal zone-like and mantle zone areas of some lymph nodes.6,8 In light of the normal distribution of this antigen, MNDA protein expression was previously shown to be expressed in a subset of

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myeloid neoplasms as well as in a subset of mature B cell neoplasms.6,8 In particular, MNDA was shown to be frequently expressed in all three 2008 WHO subtypes of MZL as well as in

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chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic

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lymphoma (LPL), and close to half of tested diffuse large B cell lymphoma (DLBCL) with preferential staining of those DLBCL cases that expressed other genes associated with an

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activated B cell type.8 In contrast FL cases were only rarely positive for MNDA. Given the potential utility of this antigen in the diagnostic workup of hematolymphoid neoplasms, we

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sought to investigate the expression patterns of MNDA in a separate large series of lymphoma

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cases including many challenging cases for which the differential diagnosis primarily included FL versus MZL. In agreement with prior data, we find that MNDA is most frequently expressed in nodal and extranodal MZL and that this marker may be most useful in cases where the

Materials and methods

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differential diagnosis primarily includes low-grade FL.

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All studies were approved by the Stanford University institutional review board. Paraffin-embedded tissue samples

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Formalin-fixed, paraffin-embedded (FFPE) tissue specimens were obtained from the Stanford University Department of Pathology tissue archives. Many of the cases were sent to our department in consultation, and a subset of cases was included in a prior study.2 At least 75% of MZL cases included in this study were initial diagnostic specimens. Tissue microarrays (TMA) were constructed from FFPE tissues as previously described.9 Unstained sections from a previously described TMA containing 128 cases of mantle cell lymphoma were also included in the study.10 Diagnoses were made according to criteria from the 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.1

Immunohistochemistry

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FFPE whole tissues and TMAs were sectioned at 0.4 M thickness, deparaffinized in xylene, and hydrated across graded alcohol solutions.

MNDA immunohistochemistry (IHC) was

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performed using a monoclonal mouse anti-human anti-MNDA antibody (clone 253,8 1:50

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dilution) on a Leica Bond-Max (Leica Microsystems, Buffalo Grove, IL; Wetzlar, Germany) automated immunostainer with EDTA-based ER2, pH 9.0 antigen retrieval. CD43 IHC was

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performed using a monoclonal mouse anti-human antibody (clone L60, 1:2000 dilution, BD Biosciences, San Jose, CA) on a Ventana Benchmark XT (Ventana Medical Systems, Inc.,

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Tucson, AZ) automated immunostainer with EDTA retrieval. Slides were counter-stained with

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hematoxylin and then coverslipped using aqueous based mounting medium. Signal localization was interpreted in conjunction with previously stained hematoxyline & eosin and other IHC stains mentioned in the text below and stained as previously reported.2 MNDA expression was

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scored as negative (<15% of lesional cells positive) or positive (≥15% of lesional cells positive).

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Samples were scored by at least two pathologists (A.G.F., R.M., A.M., M.V., and/or Y.N.). Difficult and/or discordant cases were jointly reviewed using a multi-headed microscope and

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subsequently assigned a final interpretation. Digital images of IHC slides were acquired using a

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Nikon Eclipse E1000 microscope (Nikon, Tokyo, Japan) equipped with a SPOT flex mosaic 15.2 digital camera and software (Diagnostic Instruments, Sterling Heights, MI).

Results MNDA expression in extramedullary non-Hodgkin B cell lymphomas In agreement with previously published findings, IHC analysis of peripheral lymph nodes, reactive tonsils, Peyer’s patches, spleen, and bone marrow biopsies revealed that MNDA is normally expressed by myelomonocytic cells as well by a subset of B lineage cells that localize to marginal zones of splenic tissue as well as to the marginal zone-like and mantle zone areas surrounding germinal centers (Figure 1 and data not shown).6 IHC analysis revealed that MNDA labeling was restricted to the nucleus, with relatively darker staining observed in

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myelomonocytic cells compared to lymphoid cells.

Notably, positive nuclear staining in

myelomonocytic cells served as a useful internal positive control in cases that were negative for

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MNDA in the lymphoid cells. Plasma cell labeling was not observed.

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To evaluate for the expression of MNDA in non-Hodgkin B cell lymphomas, we stained a total of 440 mature B cell neoplasms involving extramedullary tissue by IHC. These results are

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presented in Table 1, and examples of MNDA IHC staining are shown in Figures 2 and 3. Among low-grade B cell neoplasms, MNDA preferentially labeled nodal MZL (NMZL) and

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extranodal MZL (EMZL) (66.7% and 61.4%, respectively). A subset of splenic MZL (SMZL) was

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also positive for MNDA (23.8%) (Figure 2 and Table 1). Likewise, minor subsets of chronic CLL/small lymphocytic lymphoma (SLL), MCL, and LPL also showed nuclear labeling for MNDA by IHC (Figure 3 and Table 1). Rare cases of both low- and high-grade FL also expressed

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MNDA, and of the three low-grade FL cases positive for MNDA, the latter was restricted to the

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perifollicular areas showing marginal zone differentiation (Figure 2). In most instances, the staining intensity of the lymphoma cells was relatively weak in comparison to background

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myelomonocytic cells. Labeled cells were small lymphocytes, whereas plasma cells, if present, were negative for MNDA staining (not shown). Moreover, often only subsets (~30-70%) of the

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neoplastic B cell infiltrates stained positive for MNDA, although in some cases there was near uniform nuclear MNDA expression (Figure 2).

MNDA and CD43 expression patterns are partially overlapping and non-mutually exclusive in EMZL and NMZL CD43 is expressed normally by T cells, natural killer cells, histiocytes, and plasma cells, among other cell types, but it is not normally expressed by most mature B cell populations. However, CD43 expression is aberrantly expressed in a variety of mature B cell neoplasms, including subsets of NMZL and EMZL, and anomalous coexpression of CD43 on B-cells may be used as a surrogate marker of B cell neoplasia in some settings. In our series, 39 of 44 EMZL and 18 of

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24 NMZL cases were also stained for CD43, and this analysis demonstrated that CD43 and MNDA expression patterns partially overlap and are non-mutually exclusive (Table 2).

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Consistent with previously published findings, we did not observed CD43 expression in ten

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SMZL cases (Table 2).11

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MNDA expression was rarely detected in trephine bone marrow biopsy samples Given the relatively high expression of MNDA in EMZL and NMZL cases in extramedullary

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tissues, we sought to determine if MNDA might be a useful marker to evaluate lymphoid

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aggregates and infiltrates in trephine bone marrow biopsy specimens. As described above, we observed robust nuclear labeling of internal control myelomonocytic cells in such specimens, indicating that the epitope recognized by the monoclonal anti-MNDA antibody is preserved

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following decalcification and fixation in Bouin’s fixative. However, among 216 total bone marrow

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biopsies involved by lymphoid infiltrates or aggregates, including five cases diagnosed as “atypical” and six cases favored to be “reactive”, only five cases showed MNDA expression by

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the lymphoid cells (Table 3 and data not shown). Of these, two were FL, one was MZL (not further subtyped), one was MCL, and one was a LGBCL, not further classified. These diagnoses

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were based on concurrent morphologic and immunophenotypic findings in the same bone marrow biopsy, diagnostic findings in concurrent extramedullary tissue, or a prior history of disease. As was observed for the MNDA positive extramedullary lymphoma cases described above, these five MNDA positive cases showed relatively weak nuclear MNDA labeling in comparison to background myelomonocytic cells (Figure 3).

Discussion Nodal, extranodal, and splenic marginal zone lymphomas comprise a heterogeneous group of low-grade non-Hodgkin B cell lymphomas that potentially share a derivation from marginal zone/memory B cells.1,4 Typically, these neoplasms lack surface expression of CD5 and CD10,

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and although a significant minority of cases is associated with distinct cytogenetic abnormalities, many MZL are classified based on combined morphologic, immunophenotypic, and clinical

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features (e.g. disease restricted to lymph nodes only for NMZL). However, these features may

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overlap with those of other types of lymphomas derived from small B-cells, including LPL, FL that lacks CD10, or CLL/SLL and MCL that lack CD5.3,12 In particular, distinguishing follicular

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colonization of reactive germinal centers in MZL from marginal zone differentiation of FL represents a particularly challenging diagnostic dilemma.13,14 Our group previously showed that

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the germinal center markers, CD10, BCL6, HGAL and LM02, are useful to help exclude MZL in

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this situation.2 Moreover, we show here that MNDA is highly expressed in MZL but not in most cases of FL. Therefore, MNDA staining appears to be a useful adjunct to the immunophenotypic

between MZL and low-grade FL.

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workup of a lymphoma derived from small B-cells, particularly in the differential diagnosis

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Our data are further supported by earlier studies demonstrating high rates of MNDA expression in all three subtypes of MZL as well as in subsets of CLL/SLL, MCL, LPL, and

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DLBCL.6,8 Overall we observed less frequent positivity of MNDA labeling of these B cell lymphoma types as well as in labeling B cell infiltrates in the bone marrow compared to what observed

by

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was

et

al,

who

used

the

same

anti-MNDA

antibody

for

immunohistochemical analysis; these differences in data may be due to technical variables including time of fixation of tissues and other staining parameters.8 Nonetheless, the overall trend of our data is similar, with high rates of MNDA expression observed in MZL and very few cases of FL showing MNDA positivity. Therefore, MNDA appears to be a useful, albeit nonspecific marker of MZL, and it will be of interest in future studies to determine how diagnostically useful MNDA labeling may be when used in combination with other recently identified markers of MZL.15,16 Given our prior experience together with the current data presented here and in accordance with prior findings by Kanellis et al, our group at Stanford has incorporated MNDA staining into our routine practice in cases where the differential diagnosis primarily includes FL

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and MZL.2,8 In particular, for cases with positive expression of germinal center markers and negative expression of MNDA, especially within follicles, we favor a diagnosis of follicular

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lymphoma. In contrast, in the rare event of positive MNDA expression in the setting of positive

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germinal center markers, especially HGAL which we have observed to be the most sensitive and specific marker of follicular lymphoma,2 we put less weight on the MNDA staining result and

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still favor a diagnosis of follicular lymphoma. We also obtain cytogenetic and/or molecular studies for t(14;18) BCL2-IGH rearrangements in such cases. Cases lacking germinal center

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markers and showing positive expression of MNDA would be most likely diagnosed as marginal

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zone lymphoma.

The clinical significance of MNDA expression in B cell neoplasia is not yet known. Interestingly, although MNDA is expressed in all three types of MZL, the detection of recurring

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cytogenetic abnormalities that are specific to subtypes of MZL, such as those resulting in

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MALT1 and/or BCL10 gene rearrangements in EMZL but not in NMZL and SMZL, strongly suggests that these MZL subtypes are distinct diseases.3,14,17,18 Therefore, the pathophysiologic

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influence of MNDA expression in B cell neoplasms and the possible requirement of MNDA expression as a specific driver of lymphomagenesis in certain malignancies is unclear. Indeed

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MNDA staining was also demonstrable in other lymphomas derived from small B-cells and DLBCL. Joshi et al previously reported an association of MNDA expression in CLL and improved clinical outcome.19 However, as the role(s) of MNDA and the regulation of its expression in normal marginal zone B cells are also not yet known, one can only speculate as to the possible contribution this protein may have in the pathogenesis of MZL. Alternatively, MNDA may be a sensitive marker of marginal zone B cell differentiation that is influenced by the milieu, and this could at least in part account for the observed differences in frequency of MNDA positivity comparing MZL involving bone marrow versus extramedullary tissues. For example, MNDA has been shown to be inducible in monocytic cells as well as in a Burkitt lymphoma cell line in response to interferon-alpha stimulation.20,21 In light of this, it is also interesting that in our

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study MNDA expression was observed in a small fraction of cases of FL with marginal zone differentiation with labeling restricted to the latter. In future studies, it will be of interest to

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investigate what role MNDA might play during lymphomagenesis, the regulation of MNDA

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expression in neoplastic B cells, and whether MNDA expression may correlate with any

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recurring genetic abnormalities or activated signaling pathways.

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Disclosure/Conflict-of-interest: The authors declare that they have no competing interests.

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Acknowledgements

The authors would like to thank Edward Gilbert and Ivy Mangonon from the Stanford

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Immunohistochemistry Laboratory for their valuable assistance with this study.

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separation of lymphomas derived from small B cells in nodal and extranodal sites, including the bone marrow. American journal of clinical pathology 2011;135:697-708. Molina TJ, Lin P, Swerdlow SH, Cook JR. Marginal zone lymphomas with plasmacytic

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differentiation and related disorders. American journal of clinical pathology 2011;136:211-25. Pillai S, Cariappa A, Moran ST. Marginal zone B cells. Annual review of immunology

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Choubey D, Duan X, Dickerson E, et al. Interferon-inducible p200-family proteins as

novel sensors of cytoplasmic DNA: role in inflammation and autoimmunity. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2010;30:371-80. 8.

Kanellis G, Roncador G, Arribas A, et al. Identification of MNDA as a new marker for

nodal marginal zone lymphoma. Leukemia 2009;23:1847-57. 9.

Natkunam Y, Warnke RA, Montgomery K, Falini B, van De Rijn M. Analysis of

MUM1/IRF4 protein expression using tissue microarrays and immunohistochemistry. Modern

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pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2001;14:686-94. Gualco G, Weiss LM, Harrington WJ, Jr., Bacchi CE. BCL6, MUM1, and CD10

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expression in mantle cell lymphoma. Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry 2010;18:103-8. Dogan A, Isaacson PG. Splenic marginal zone lymphoma. Seminars in diagnostic

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pathology 2003;20:121-7.

Lin P, Molina TJ, Cook JR, Swerdlow SH. Lymphoplasmacytic lymphoma and other non-

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marginal zone lymphomas with plasmacytic differentiation. American journal of clinical pathology 2011;136:195-210. 13.

Naresh KN. Nodal marginal zone B-cell lymphoma with prominent follicular colonization -

Salama ME, Lossos IS, Warnke RA, Natkunam Y. Immunoarchitectural patterns in nodal

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difficulties in diagnosis: a study of 15 cases. Histopathology 2008;52:331-9.

2009;132:39-49. 15.

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marginal zone B-cell lymphoma: a study of 51 cases. American journal of clinical pathology

Arribas AJ, Campos-Martin Y, Gomez-Abad C, et al. Nodal marginal zone lymphoma:

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gene expression and miRNA profiling identify diagnostic markers and potential therapeutic targets. Blood 2012;119:e9-e21. 16.

Falini B, Agostinelli C, Bigerna B, et al. IRTA1 is selectively expressed in nodal and

extranodal marginal zone lymphomas. Histopathology 2012;61:930-41. 17.

Kuper-Hommel MJ, van Krieken JH. Molecular pathogenesis and histologic and clinical

features of extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue type. Leukemia & lymphoma 2012;53:1032-45. 18.

Traverse-Glehen A, Baseggio L, Salles G, Felman P, Berger F. Splenic marginal zone

B-cell lymphoma: a distinct clinicopathological and molecular entity. Recent advances in ontogeny and classification. Current opinion in oncology 2011;23:441-8.

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Joshi AD, Hegde GV, Dickinson JD, et al. ATM, CTLA4, MNDA, and HEM1 in high

versus low CD38 expressing B-cell chronic lymphocytic leukemia. Clinical cancer research : an

Briggs R, Dworkin L, Briggs J, et al. Interferon alpha selectively affects expression of the

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official journal of the American Association for Cancer Research 2007;13:5295-304.

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granulocytic lineage. Journal of cellular biochemistry 1994;54:198-206.

Geng Y, Choubey D. Differential induction of the 200-family proteins in Daudi Burkitt's

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2000;14:263-8.

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Diagnosis

Number MNDA positive

Percent MNDA positive

Follicular lymphoma, grade 1-2

3/69*

4.3%

Follicular lymphoma, grade 3

3/41

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Table 1. MNDA expression analysis in extramedullary tissues involved by lymphoma

Diffuse large B cell lymphoma

2/61

Nodal marginal zone lymphoma

16/24

Extranodal marginal zone

27/44

5/21

Splenic diffuse red pulp small B-cell

1/1

Chronic lymphocytic leukemia/small

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lymphocytic lymphoma Mantle cell lymphoma

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lymphoma

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Splenic marginal zone lymphoma

3.3%

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lymphoma

7.3%

61.4%

23.8% 100%

4/31

12.9%

9/140

6.4%

2/8

25%%

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Lymphoplasmacytic lymphoma

66.7%

*In two of the three cases of FL with MNDA expression, the latter was restricted to perifollicular areas demonstrating marginal zone differentiation (Figure 2).

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MNDA+CD43+

MNDA-CD43+

MNDA+CD43-

MNDA-CD43-

EMZL (n=39)

8 (20.5%)

3 (7.7%)

16 (41.0%)

12 (30.8%)

NMZL (n=18)

7 (38.9%)

3 (16.7%)

4 (22.2%)

4 (22.2%)

SMZL (n=10)

0 (0%)

0 (0%)

4 (40.0%)

6 (60.0%)

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Diagnosis

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Table 2. MNDA and CD43 expression analysis in marginal zone lymphomas

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Diagnosis

Number MNDA positive

Percent MNDA positive

Follicular lymphoma

2/87

2.3%

Marginal zone lymphoma

1/16

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Table 3. MNDA expression analysis of bone marrow specimens

Lymphoplasmacytic lymphoma

0/28

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6.3% 0%

Mantle cell lymphoma

1/18

Hairy cell leukemia

0/8

Hairy cell leukemia variant

0/1

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0/15

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lymphocytic lymphoma

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Chronic lymphocytic leukemia/small

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Low grade B cell lymphoma, not further specified

0% 5.6% 0% 0%

1/30

3.3%

0/2

0%

Atypical lymphoid aggregates

0/5

0%

Reactive lymphoid aggregates

0/6

0%

Total

5/216

2.3%

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Large B cell lymphoma

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Titles and legends to figures Figure 1. MNDA expression in normal spleen and bone marrow tissues.

MNDA

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immunohistochemistry performed on histological sections of normal adult spleen (left) and bone

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marrow (BM) (right) shows dark nuclear labeling of myelomonocytic cells, whereas weaker and subset labeling of nuclei is present within the marginal zone (MZ) of the splenic white pulp. RP:

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red pulp. Both panels, original magnification ×200.

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Figure 2. Nuclear MNDA expression in marginal zone lymphomas. Shown are three

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examples of extranodal marginal zone lymphoma (EMZL), one example of nodal marginal zone lymphoma (NMZL), and one example of splenic marginal zone lymphoma (SMZL) with positive nuclear expression of MNDA. MNDA staining intensity of the neoplastic B cells is dimmer than

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that of scattered background neutrophils and monocytes. The lower right panel demonstrates a

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case of low grade follicular lymphoma (FL) with positive nuclear MNDA expression detected

Figure 3.

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only in the areas of marginal zone differentiation. All panels, original magnification ×100.

Examples of MNDA expression in non-marginal zone lymphomas. MNDA

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expression is shown in the indicated lymphomas. The top two panels show lymphomas involving lymph nodes, whereas the bottom two panels show lymphomas involving bone marrows. CLL/SLL: chronic lymphocytic leukemia/small lymphocytic lymphoma; MCL: mantle cell lymphoma; LGBCL: low grade B cell lymphoma; BM: bone marrow; FL: follicular lymphoma. All panels, original magnification ×400.

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