Characteristics and outcome of composite lymphomas: A synthetic cohort approach

Abstract

Abstract The coexistence of two distinct lymphoma subtypes within a single patient, either in the same anatomical site (composite lymphoma, CL) or at different sites (discordant lymphoma, DL), are rare entities and therefore difficult to characterize. Furthermore, both terms are often used synonymously, leading to confusion in clinical practice. To evaluate the relevance of distinguishing CL from DL as well as the clinical characteristics of affected patients, we conducted a systematic literature review of case reports and series under strict inclusion criteria: only reports describing two lymphomas diagnosed synchronously or within 6 months without evidence of transformation were included. Cases of indolent or incurable aggressive lymphomas (e.g. multiple myeloma, MM) were included if a sequential lymphoma occurred. Sequential lymphomas with latency > 6 months, cases involving Richter or other transformations, poorly classified cases, and non-English or inaccessible publications were excluded. Cases not classifiable by the WHO lymphoma classification were also omitted. The search, conducted via PubMed and Web of Science through March 2023, used terms including “composite lymphoma”, “discordant lymphoma”, and “synchronous lymphoma”. Two independent researchers screened cases, with a third resolving disagreements to ensure robust and transparent selection. Our cohort included 1,183 cases (758 males, 425 females). CL occurred more frequently in older patients than DL (mean age 62.4 vs 60.3 years), in line with recent reports (Cerhan et al., Am J Hematol 2024). Frequent sites included lymph nodes (n = 166), bone marrow (n = 107), peripheral blood (n = 47), and skin (n = 15). Survival did not significantly differ between CL and DL (median overall survival (mOS) 48.0 months for both), but sequential lymphomas had significantly poorer prognosis than synchronous ones (mOS 25 vs 60 months). CL/DL cases composed exclusively of indolent subtypes showed excellent survival (mOS 168 months), whereas those with two aggressive or one indolent and one aggressive lymphoma showed mOS of 36 and 28 months, respectively. However, there was no significant difference between aggressive and mixed groups. The most common histological combinations included chronic lymphocytic leukemia (CLL) and MM (94 patients, 7.4%), angioimmunoblastic T-cell lymphoma (AITL) and diffuse large B-cell lymphoma (DLBCL; 82 patients, 6.43%), follicular lymphoma (FL) and Hodgkin lymphoma (HL; 81 patients, 6.35%), as well as DLBCL and HL (78 patients, 6.12%). High frequency of combined DLBCL and FL aligns with SEER database findings (Cerhan et al., 2024). Due to the high frequency of CLL cases, we conducted a sub-analysis of mOS of CLL-associated CL/DL, revealing marked heterogeneity by subtype: anaplastic large cell lymphoma (36 months), AITL (24 months), acute lymphocytic leukemia (ALL; 8.5 months), biclonal CLL (undefined), cutaneous T-cell lymphoma (CTCL; 88.6 months), DLBCL (10 months), FL (168 months), hairy cell leukemia (HCL; undefined), mantle cell lymhoma (undefined), MM (27 months), and peripheral T-cell lymphoma (4 months). While CLL+DLBCL (Broseus et al., Nat Commun 2023), HL (Stephens et al., Haematologica 2021), and CTCL (Chang et al., Int J Dermatol 2018) are well-documented, synchronous or sequential occurrence of ALL and MM remains rare. Limitations of our analysis include the major challenge of distinguishing transformation from a de novo secondary lymphoma, an ongoing discussion, e. g. in Richter's transformation (Broseus et al., Nat Comm 2024), which requires sequencing for confirmation. Given the rarity of some lymphomas (e.g., HCL), a secondary de novo origin is highly unlikely and may instead reflect disease-inherent plasticity or patient-specific risk factors as for example previous chemotherapy or exposition to radiation. Additionally, use of case reports rather than patient cohorts introduces bias and may over- or underrepresent certain histologic combinations. In summary, our study suggests the distinction between CL and DL lacks prognostic relevance, whereas synchronous versus sequential presentation is more impactful, with sequential cases showing worse outcomes. High disease heterogeneity highlights the need for further refined analyses.