Editorial Comment Acta Haematol 2015;133:212–213 DOI: 10.1159/000365878
Received: June 11, 2014 Accepted: June 28, 2014 Published online: November 4, 2014
Transformed Nodal Marginal Zone Lymphoma versus Diffuse Large B Cell Lymphoma: The MicroRNA Aspect Maria K. Angelopoulou Department of Hematology and Bone Marrow Transplantation, National and Kapodistrian University of Athens, Athens, Greece
Nodal marginal zone lymphoma (NMZL) is a very rare lymphoma subtype comprising less than 2% of all nonHodgkin lymphomas. It is one of the three well-recognized entities within the broad category of marginal zone lymphomas (MZL), together with splenic marginal zone (SMZL) and mucosa-associated lymphoid tissue (MALT) lymphomas [1]. There are several aspects of interest and unresolved issues regarding this relatively new entity. The first point of interest in NMZL is its diagnostic difficulty. Although NMZL is a separate entity, its recognition is rather challenging, at least at the histopathological level due to a lack of specific markers. Thus, the diagnosis of NMZL relies on clinical presentation in conjunction with a compatible histology/immunophenotype and requires lymph node involvement with concurrent absence of splenic and extranodal disease. Still, there are cases that are difficult to classify with certainty, such as disseminated disease at the time of diagnosis, cases with extranodal involvement and nonregional lymph nodes, or cases with prominent splenomegaly as the major finding combined with extensive abdominal or widespread lymphadenopathy and/or MALT-site involvement. A second point of interest focuses on the biologic similarity of NMZL to the other two entities of MZL. The question of whether NMZL truly represents a distinct en© 2014 S. Karger AG, Basel 0001–5792/14/1332–0212$39.50/0 E-Mail [email protected] www.karger.com/aha
tity still remains unanswered. All three entities share a common immunophenotype and some cytogenetic abnormalities, such as whole or partial gains of chromosomes 3, 12 and 18. However, certain differences indicate that NMZL differs biologically from SMZL and MALT lymphomas: the MALT-specific translocations and the SMZL-associated deletion of 7q are characteristically absent. Regarding the cell of origin, the normal counterpart of NMZL is considered an antigen-experienced, postgerminal center memory B cell that has not necessarily undergone germinal center transit. Findings from gene expression profiling studies point to a genetic similarity between NMZL and MALT lymphomas. However, nuclear factor-κB activation is less frequently encountered compared to MALT lymphomas [1, 2]. A third issue of interest is the invariable presence of scattered large cells (immuno- or centroblasts) which may comprise >20% of the neoplastic cell population in up to half of all cases, in contrast to other low-grade B cell lymphomas. The importance of large cells has been a major debate between pathologists that has not been completely resolved even today. A threshold of >20 or >50% of large cells has been used as a cut-off for defining ‘transformed lymphoma’. Recently, in 2011, a consensus was reached to use the term ‘transformed NMZL’ only if Maria K. Angelopoulou, MD, PhD Department of Hematology and Bone Marrow Transplantation National and Kapodistrian University of Athens 17 Agiou Thoma Street, GR–11527 Athens (Greece) E-Mail mkangelop @ gmail.com
sheets of blasts are present [2]. However, the presence of large cells often renders clinicians uncomfortable and prompts them to treat such cases as transformed lowgrade lymphomas with more aggressive therapy similarly to diffuse large B cell lymphoma (DLBCL). Modern biotechnology such as comparative genomic hybridization and gene expression profiling has brought new insights into the pathogenesis of NMZL. To this matter, the role of microRNAs (miRNAs) as posttranscriptional modulators of gene expression is the new hot topic in lymphomagenesis [3]. miRNAs are small endogenous RNA molecules that regulate gene expression through their sequence complementation with target mRNAs. Alterations of miRNA levels may lead to aberrant gene expression, acting either as tumor suppressors or oncogenes. miRNAs add new information regarding deregulated pathways in lymphomas, but they may also serve as valuable diagnostic and prognostic markers. It appears that different patterns of over- or underexpression of various miRNAs are associated with specific histologic subtypes [3]. In this issue of Acta Haematologica, Gebauer et al. [4] investigate the controversial issue of large cells in
NMZL. They studied the miRNA profile of low-grade versus transformed NMZL in comparison to DLBCL. They elegantly show that the pattern of miRNA expression between low-grade and transformed NMZL is very similar, while it differs from the one observed in DLBCL [4]. These findings offer important information regarding the biology of NMZL and indicate that the increased presence of large cells might be a disease-specific characteristic that does not necessarily mean transformation to a more aggressive entity. Moreover, this study highlights that DLBCL and NMZL are two biologically distinct diseases. To date, there are only two studies evaluating the miRNA signature of NMZL [3, 5]. Both are in agreement with Gebauer et al. [4] regarding the fact that very few miRNAs are aberrantly expressed in NMZL compared to normal lymph nodes. Hopefully, miRNA expression patterns will elucidate the biologic similarities and differences between NMZL and the two other entities of MZL. Apart from highlighting the pathogenetic pathways, these new exciting data of miRNA signatures could prove a valuable diagnostic tool, given the rarity and the diagnostic difficulties of NMZL.
References 1 Angelopoulou MK, Kalpadakis C, Pangalis GA, Kyrtsonis MC, Vassilakopoulos TP: Nodal marginal zone lymphoma. Leuk Lymphoma 2014;55:1240–1250. 2 van den Brand M, van Krieken JHJM: Recognizing nodal marginal zone lymphoma: recent advances and pitfalls – a systematic review. Haematologica 2013;98:1003–1013.
Transformed NMZL vs. DLBCL: The Micro RNA Aspect
3 Di Lisio L, Sanchez-Beato M, Gomez-Lopez G, Rodriguez ME, Montes-Moreno S, Mollejo M, Menarguez J, Martinez MA, Alves FJ, Pisano DG, Piris MA, Martinez N: MicroRNA signatures in B-cell lymphomas. Blood Cancer J 2012;2:e57. 4 Gebauer N, Thorns C, Bernard V, Senft A, Schillert A, Merz H, Feller AC, Bernd H-W: MicroRNA profiling of low-grade and transformed nodal marginal zone lymphoma reveals a similar signature pattern distinct from diffuse large B cell lymphoma. Acta Haematol 2015;133:214–200.
5 Arribas AJ, Campos-Martin Y, Gomez-Abad C, Algara P, Sanchez-Beato M, RodriguezPinilla MS, Montes-Moreno S, Martinez N, Alves-Ferreira J, Piris MA, Mollejo M: Nodal marginal zone lymphoma: gene expression and miRNA profiling identify diagnostic markers and potential therapeutic targets. Blood 2012;119:e9–e21.
Acta Haematol 2015;133:212–213 DOI: 10.1159/000365878
213
Copyright: S. Karger AG, Basel 2015. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: June 11, 2014 Accepted: June 28, 2014 Published online: November 4, 2014
Transformed Nodal Marginal Zone Lymphoma versus Diffuse Large B Cell Lymphoma: The MicroRNA Aspect Maria K. Angelopoulou Department of Hematology and Bone Marrow Transplantation, National and Kapodistrian University of Athens, Athens, Greece
Nodal marginal zone lymphoma (NMZL) is a very rare lymphoma subtype comprising less than 2% of all nonHodgkin lymphomas. It is one of the three well-recognized entities within the broad category of marginal zone lymphomas (MZL), together with splenic marginal zone (SMZL) and mucosa-associated lymphoid tissue (MALT) lymphomas [1]. There are several aspects of interest and unresolved issues regarding this relatively new entity. The first point of interest in NMZL is its diagnostic difficulty. Although NMZL is a separate entity, its recognition is rather challenging, at least at the histopathological level due to a lack of specific markers. Thus, the diagnosis of NMZL relies on clinical presentation in conjunction with a compatible histology/immunophenotype and requires lymph node involvement with concurrent absence of splenic and extranodal disease. Still, there are cases that are difficult to classify with certainty, such as disseminated disease at the time of diagnosis, cases with extranodal involvement and nonregional lymph nodes, or cases with prominent splenomegaly as the major finding combined with extensive abdominal or widespread lymphadenopathy and/or MALT-site involvement. A second point of interest focuses on the biologic similarity of NMZL to the other two entities of MZL. The question of whether NMZL truly represents a distinct en© 2014 S. Karger AG, Basel 0001–5792/14/1332–0212$39.50/0 E-Mail [email protected] www.karger.com/aha
tity still remains unanswered. All three entities share a common immunophenotype and some cytogenetic abnormalities, such as whole or partial gains of chromosomes 3, 12 and 18. However, certain differences indicate that NMZL differs biologically from SMZL and MALT lymphomas: the MALT-specific translocations and the SMZL-associated deletion of 7q are characteristically absent. Regarding the cell of origin, the normal counterpart of NMZL is considered an antigen-experienced, postgerminal center memory B cell that has not necessarily undergone germinal center transit. Findings from gene expression profiling studies point to a genetic similarity between NMZL and MALT lymphomas. However, nuclear factor-κB activation is less frequently encountered compared to MALT lymphomas [1, 2]. A third issue of interest is the invariable presence of scattered large cells (immuno- or centroblasts) which may comprise >20% of the neoplastic cell population in up to half of all cases, in contrast to other low-grade B cell lymphomas. The importance of large cells has been a major debate between pathologists that has not been completely resolved even today. A threshold of >20 or >50% of large cells has been used as a cut-off for defining ‘transformed lymphoma’. Recently, in 2011, a consensus was reached to use the term ‘transformed NMZL’ only if Maria K. Angelopoulou, MD, PhD Department of Hematology and Bone Marrow Transplantation National and Kapodistrian University of Athens 17 Agiou Thoma Street, GR–11527 Athens (Greece) E-Mail mkangelop @ gmail.com
sheets of blasts are present [2]. However, the presence of large cells often renders clinicians uncomfortable and prompts them to treat such cases as transformed lowgrade lymphomas with more aggressive therapy similarly to diffuse large B cell lymphoma (DLBCL). Modern biotechnology such as comparative genomic hybridization and gene expression profiling has brought new insights into the pathogenesis of NMZL. To this matter, the role of microRNAs (miRNAs) as posttranscriptional modulators of gene expression is the new hot topic in lymphomagenesis [3]. miRNAs are small endogenous RNA molecules that regulate gene expression through their sequence complementation with target mRNAs. Alterations of miRNA levels may lead to aberrant gene expression, acting either as tumor suppressors or oncogenes. miRNAs add new information regarding deregulated pathways in lymphomas, but they may also serve as valuable diagnostic and prognostic markers. It appears that different patterns of over- or underexpression of various miRNAs are associated with specific histologic subtypes [3]. In this issue of Acta Haematologica, Gebauer et al. [4] investigate the controversial issue of large cells in
NMZL. They studied the miRNA profile of low-grade versus transformed NMZL in comparison to DLBCL. They elegantly show that the pattern of miRNA expression between low-grade and transformed NMZL is very similar, while it differs from the one observed in DLBCL [4]. These findings offer important information regarding the biology of NMZL and indicate that the increased presence of large cells might be a disease-specific characteristic that does not necessarily mean transformation to a more aggressive entity. Moreover, this study highlights that DLBCL and NMZL are two biologically distinct diseases. To date, there are only two studies evaluating the miRNA signature of NMZL [3, 5]. Both are in agreement with Gebauer et al. [4] regarding the fact that very few miRNAs are aberrantly expressed in NMZL compared to normal lymph nodes. Hopefully, miRNA expression patterns will elucidate the biologic similarities and differences between NMZL and the two other entities of MZL. Apart from highlighting the pathogenetic pathways, these new exciting data of miRNA signatures could prove a valuable diagnostic tool, given the rarity and the diagnostic difficulties of NMZL.
References 1 Angelopoulou MK, Kalpadakis C, Pangalis GA, Kyrtsonis MC, Vassilakopoulos TP: Nodal marginal zone lymphoma. Leuk Lymphoma 2014;55:1240–1250. 2 van den Brand M, van Krieken JHJM: Recognizing nodal marginal zone lymphoma: recent advances and pitfalls – a systematic review. Haematologica 2013;98:1003–1013.
Transformed NMZL vs. DLBCL: The Micro RNA Aspect
3 Di Lisio L, Sanchez-Beato M, Gomez-Lopez G, Rodriguez ME, Montes-Moreno S, Mollejo M, Menarguez J, Martinez MA, Alves FJ, Pisano DG, Piris MA, Martinez N: MicroRNA signatures in B-cell lymphomas. Blood Cancer J 2012;2:e57. 4 Gebauer N, Thorns C, Bernard V, Senft A, Schillert A, Merz H, Feller AC, Bernd H-W: MicroRNA profiling of low-grade and transformed nodal marginal zone lymphoma reveals a similar signature pattern distinct from diffuse large B cell lymphoma. Acta Haematol 2015;133:214–200.
5 Arribas AJ, Campos-Martin Y, Gomez-Abad C, Algara P, Sanchez-Beato M, RodriguezPinilla MS, Montes-Moreno S, Martinez N, Alves-Ferreira J, Piris MA, Mollejo M: Nodal marginal zone lymphoma: gene expression and miRNA profiling identify diagnostic markers and potential therapeutic targets. Blood 2012;119:e9–e21.
Acta Haematol 2015;133:212–213 DOI: 10.1159/000365878
213
Copyright: S. Karger AG, Basel 2015. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
