Multilayer taxonomy of nodal marginal zone lymphoma

The extranodal, splenic, and nodal MZL are the three main malignant disorders derived from marginal zone B-cells. They are recognized as separate entities by current classifications of lymphoid tissue tumors. While the clinicopathologic presentation, genetic characteristics, diagnostic definitions, and therapy of extranodal and splenic MZL are clearly characterized, the specific clinical, pathologic, and genetic aspects of NMZL remain largely undefined. The lack of typical markers makes NMZL diagnosis difficult, time-consuming, and not readily reproducible. The term NMZL currently includes a heterogeneous collection of cytologically distinct tumors, whose pathogenesis and biological features are incompletely understood. Moreover, NMZL are incurable tumors with no available specific clinical management. Their heterogeneity represents a barrier not only to the diagnosis but also to the successful deployment of novel, biologically targeted therapies. Molecular profiling studies have recently proposed new molecular classification systems for some lymphoma entities that are heterogeneous like NMZL. Hence, molecular subtyping is the next step in the precision medicine of lymphomas. Molecular subtypes can be delineated and validated through multilayer molecular profiling of the tumor coupled with machine-learning bioinformatics. They are ultimately defined by the most enriched combinations of genetic alterations and transcriptional subtypes.

The International Extranodal Lymphoma Study Group is a non-profit academic organization aimed at advancing biological studies to improve the treatment outcome of extranodal lymphomas. Investigators from more than 300 sites in Europe, Australia, North America, Latin America, and Asia have joined IELSG studies.

Here, we propose the IELSG52 study. It has a retrospective, observational, multicenter design and aims to recruit at least 500 pathologically confirmed NMZL biopsies and their clinical annotations. The IELSG52 study seeks to resolve the biological heterogeneity of NMZL into more homogeneous and manageable subgroups of tumors that rely on shared oncogenic programs.

The IELSG52 study is expected to produce insightful results that would:

- provide valuable aid in establishing the diagnosis and prognosis of NMZL

- enable the selection of optimal therapy for individual patients

- provide a biology-based framework for the design, conduct, and interpretation of clinical studies on novel targeted agents.