Adult Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: Clinical Features, Diagnostic Challenges, and Treatment Outcomes—A 24-Year Multi-Center Analysis

Background/Objectives: Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) is a fatal hyperinflammatory syndrome. Non-Hodgkin lymphoma (NHL) is the established primary trigger, while Hodgkin lymphoma (HL) is considered a rare cause. This exploratory study aimed to characterize the features of LA-HLH in a predominantly Hispanic patient population to generate novel pathophysiological hypotheses. Methods: We conducted a retrospective, multicenter analysis of adult patients diagnosed with HLH between 2000 and 2024. Using HLH-2004 criteria, we identified a final cohort of 20 patients with LA-HLH for analysis. Results: In our cohort (70% Hispanic, reflecting the catchment populations of the partic-ipating centers), the most common underlying malignancy was HL (60%), contradicting established literature. Stratification by HIV status suggested two distinct profiles: the HIV-negative group (n=13) was younger and driven almost exclusively by HL (85%), whereas the HIV-positive group (n=7) was older, driven by NHL (86%), and presented with more extreme hyperferritinemia and higher soluble IL-2 receptor (sIL-2R) levels. The overall mortality rate was 57.9%. Conclusions: The unexpected predominance of HL-driven HLH in this cohort suggests a need to re-evaluate the differential diagnosis in specific demographic contexts. Our findings are hypothesis-generating and suggest differing clinicopathological patterns by HIV status and lymphoma subtype; further studies are required to determine whether distinct biological pathways underlie these patterns. Given the retrospective nature and limited sample size, further multicenter studies with uniform laboratory testing and molecular profiling are required to clarify potential biological heterogeneity among LA-HLH presentations.