Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by profound immune dysregulation, frequently precipitated by malignancy. Among adults, lymphoma represents the most common neoplastic trigger—a condition termed lymphoma-associated HLH (LA-HLH). Published cohorts consistently report T-cell and B-cell non-Hodgkin lymphomas (NHL) as the primary drivers, with Hodgkin lymphoma (HL) accounting for fewer than 10% of cases. This retrospective, multicenter study aimed to characterize the features of LA-HLH in a predominantly Hispanic patient population and to investigate associations between ethnicity, lymphoma subtype, and clinical outcomes.

Methods: We retrospectively identified all adult patients (age ≥ 18 years) diagnosed with HLH between January 1, 2000, and January 31, 2024, at two urban academic medical centers (Harris Health Ben Taub Hospital and Mount Sinai Medical Center, Miami Beach), yielding 78 cases. Medical records were reviewed to confirm HLH diagnoses according to HLH-2004 diagnostic criteria. Cases were then classified as infection-associated, autoimmune-associated, malignancy-associated, or idiopathic based on clinical, laboratory, and pathological data. Of the 78 initial cases, 31 (39.7%) were classified as malignancy-associated HLH (M-HLH). Patients with non-lymphoid malignancies (n = 11) were excluded, resulting in a final cohort of 20 patients with a diagnosis of LA-HLH.

Results: Our cohort of 20 patients with LA-HLH had a median age of 45.5 years, a male predominance (80%, n = 16), and a Hispanic majority (70%, n = 14). In sharp contrast to published cohorts, the most common underlying malignancy was Hodgkin lymphoma (HL; 60%, n = 12), representing a significant overrepresentation compared to prior reports of LA-HLH, in which T-cell and B-cell lymphomas predominate (60% vs. <10% HL; p < 0.001). Among patients with Hodgkin lymphoma–associated HLH (HL-HLH), 58% (7/12) were Hispanic, compared to 88% (7/8) of those with non-HL subtypes. Other associated subtypes included T-cell lymphoma (20%, n = 4), diffuse large B-cell lymphoma (10%, n = 2), marginal zone lymphoma (5%, n = 1), and primary central nervous system lymphoma (5%, n = 1). The LA-HLH cohort had a markedly higher rate of HIV positivity compared to HLH populations across all etiologies (35% vs. ~3.4%; p = 0.0002), while rates of EBV viremia were similar.

Stratification by HIV status revealed two distinct clinicopathological entities. The HIV-negative group (n = 13) was younger (median age 34.5 vs. 52 years; p = 0.03) and almost exclusively driven by HL; 85% (11/13) of these patients had HL-HLH. In contrast, the HIV-positive group (n = 7) was older, presented with markedly greater hyperferritinemia (median 10,000 ng/mL vs. 2,750 ng/mL; p = 0.02), and was predominantly driven by NHL; 71% (5/7) of these patients had NHL-associated HLH (p = 0.03 for association between HIV status and HL vs. NHL). Outcome data were available for 19 of 20 patients. The overall mortality rate for the cohort was 58% (11/19), consistent with the historically poor prognosis of LA-HLH.

Conclusion: In a predominantly Hispanic population, we identify a novel clinical entity within LA-HLH characterized by a high prevalence of Hodgkin lymphoma. Stratified analysis revealed that HIV status was a major determinant of both the inflammatory phenotype and lymphoma subtype, suggesting the existence of two distinct pathobiological drivers. The first is a “classic” secondary HLH pathway in HIV-positive individuals, associated with aggressive NHL and a profound systemic inflammatory response. The second reflects a distinct pathway in HIV-negative, predominantly Hispanic patients, in which HLH appears directly driven by Hodgkin lymphoma.

We hypothesize that this novel association may be driven by ethnicity-specific immunogenetics interacting with the unique inflammatory tumor microenvironment of HL. These findings support prioritizing Hodgkin lymphoma in the differential diagnosis of HLH, particularly in HIV-negative Hispanic individuals.

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2025
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