Splenic marginal zone lymphoma (SMZL) is a small B-cell lymphoma, which has been recognized as a distinct pathological entity since the WHO 2008 classification. It classically presents an indolent evolution, but a third of patients progress rapidly and require aggressive treatments, such as immuno-chemotherapy or splenectomy, with all associated side effects. In recent years, advances in the comprehension of SMZL physiopathology have multiplied, thanks to the arrival of new devices in the panel of available molecular biology techniques, allowing the discovery of new molecular findings. In the era of targeted therapies, an update of current knowledge is needed to guide future researches, such as those on epigenetic modifications or the microenvironment of these lymphomas.

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Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities. From 2004 to 2020, a retrospective multicentric study was performed, including 9 composite and 13 sequential lymphomas. Clinical data were retrospectively collected. Fluorescent in situ hybridization of BCL2 and BCL6 rearrangements, polymerase chain reaction of IGH and IGK rearrangements, next-generation sequencing of IGK rearrangement, and targeted next-generation sequencing (TNGS) on a panel of genes frequently mutated in lymphomas were performed on each contingent of composite and sequential lymphomas. For TNGS, each contingent was isolated by laser capture microdissection. Clinical presentation and evolution were more aggressive in sequential than composite lymphomas. By fluorescent in situ hybridization, common rearrangements of BCL6 and BCL2 were identified between both contingents. Similarly, a common clonal relationship was established by evaluating IGH and IGK rearrangement by polymerase chain reaction or next-generation sequencing. By TNGS, the same pathogenic variants were identified in both contingents in the following genes: CREBBP, KMT2D, BCL2, EP300, SF3B1, SOCS1, ARID1A, and BCOR. Specific pathogenic variants for each contingent were also identified: XPO1 for Hodgkin lymphoma contingent and FOXO1, TNFRSF14 for follicular lymphoma contingent. This study reinforces the hypothesis of a transdifferentiation process between Hodgkin and follicular contingent of sequential/composite lymphomas.

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The co-occurrence of several lymphomas in a patient defines composite/synchronous lymphoma. A common cellular origin has been reported for both contingents of such entities. In the present review, we aimed to gather the available data on composite lymphomas associating a classical Hodgkin lymphoma (cHL) with another lymphoma, to better understand the plasticity of mature B and T-cells. This review highlights that >70% of patients with a composite lymphoma are ≥55 years old, with a male predominance. The most reported associations are cHL with follicular lymphoma or diffuse large B-cell lymphoma, with over 130 cases reported. The cHL contingent is often of mixed cellularity type, with a more frequent focal/weak CD20 expression (30% to 55.6%) compared to de novo cHL, suggesting a particular pathophysiology. Moreover, Hodgkin cells may express specific markers of the associated lymphoma (e.g., BCL2/BCL6 for follicular lymphoma and Cyclin D1 for mantle cell lymphoma), sometimes combined with common BCL2/BCL6 or CCND1 rearrangements, respectively. In addition, both contingents may share similar IgH/IgK rearrangements and identical pathogenic variants, reinforcing the hypothesis of a common clonal origin. Finally, cHL appears to be endowed with a greater plasticity than previously thought, supporting a common clonal origin and a transdifferentiation process during lymphomagenesis of composite lymphomas.