HLH Lymphoma: Manifestations, Diagnostic Criteria, and Prognosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition marked by excessive immune activation, leading to severe inflammation and multi-organ damage. It is often triggered by infections, autoimmune diseases, or malignancies such as lymphoma. Without timely diagnosis and treatment, HLH can progress rapidly, making early recognition critical for improving outcomes.

Relationship to Lymphoma

HLH is closely associated with lymphoma, particularly hematologic malignancies, which are among the most common triggers of secondary HLH. Lymphoma-associated HLH (LA-HLH) occurs when malignant lymphoid cells drive an uncontrolled inflammatory response, leading to widespread tissue damage. T-cell and natural killer (NK)-cell lymphomas, especially extranodal NK/T-cell lymphoma in East Asian populations, have the strongest link to HLH. B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), are also implicated, though less frequently. The aggressive nature of these malignancies exacerbates HLH severity, complicating diagnosis and treatment.

Unlike infection-associated HLH, where immune activation is a response to an external pathogen, lymphoma cells themselves can secrete pro-inflammatory cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). These cytokines contribute to macrophage activation and hemophagocytosis, a hallmark of HLH. Additionally, lymphoma cells may evade immune regulation, amplifying inflammation. This unchecked activation leads to systemic complications, including cytopenias, hepatosplenomegaly, and coagulopathy, which can obscure the underlying malignancy and delay treatment.

LA-HLH often mimics aggressive lymphoma, making differentiation challenging. Patients frequently exhibit persistent fever, profound fatigue, and organ dysfunction, symptoms that may be mistaken for lymphoma progression. In some cases, HLH is the first sign of an undiagnosed lymphoma, necessitating a high index of suspicion. Bone marrow biopsy may reveal hemophagocytosis alongside malignant lymphoid infiltration, providing a crucial clue to the underlying pathology. However, when lymphoma involvement is subtle or masked by extensive immune activation, additional tools such as PET-CT imaging and molecular profiling may be needed to confirm malignancy.

Immune Dysregulation

HLH results from an unrestrained inflammatory response that fails to self-regulate, causing widespread tissue damage. In LA-HLH, malignant lymphoid cells either directly produce inflammatory mediators or disrupt immune homeostasis by interfering with regulatory pathways. Normally, cytotoxic T cells and NK cells eliminate infected or malignant cells through perforin- and granzyme-mediated apoptosis. In HLH, these cytotoxic functions are impaired, allowing persistent macrophage activation and uncontrolled cytokine release.

A defining feature of this dysregulation is the excessive secretion of cytokines, often called a “cytokine storm.” Elevated levels of IFN-γ, IL-6, TNF-α, and IL-18 contribute to macrophage activation and hemophagocytosis. In LA-HLH, malignant lymphoid cells worsen this process by producing these cytokines or inducing bystander immune cells to do so. High IL-18 levels sustain IFN-γ production, fueling immune activation. This cytokine-mediated amplification damages organs such as the liver, spleen, and bone marrow. The persistence of this immune activation distinguishes HLH from transient inflammatory responses seen in infections or autoimmune flare-ups, making therapeutic intervention necessary.

T-cell dysfunction plays a central role in perpetuating immune dysregulation. Normally, activated CD8+ T cells contract after pathogen clearance, restoring immune balance. In HLH, this contraction phase is defective, leading to prolonged T-cell activation and sustained cytokine release. Additionally, regulatory T cells (Tregs), which dampen excessive immune responses, exhibit diminished function, reducing the ability to control inflammation. The failure of immune checkpoints to rein in hyperactivation allows unchecked proliferation of activated T cells, further stimulating macrophages and contributing to hemophagocytosis. In LA-HLH, lymphoma cells may directly interfere with immune checkpoint pathways, worsening immune dysfunction.

Key Clinical Manifestations

Patients with LA-HLH present with symptoms reflecting widespread organ involvement and systemic dysfunction. Persistent high fever, unresponsive to conventional antipyretics, is a hallmark. Unlike fevers seen in routine infections, those in LA-HLH are prolonged and accompanied by profound fatigue, reflecting severe inflammation.

Hepatosplenomegaly is another key feature, often leading to abdominal discomfort and distension. Liver dysfunction frequently accompanies hepatomegaly, with elevated transaminases, hyperbilirubinemia, and coagulopathy being common. In some cases, liver failure ensues, worsening prognosis. Splenomegaly increases the risk of cytopenias by contributing to sequestration and destruction of blood cells.

Cytopenias affecting multiple cell lineages are frequently observed, often manifesting as pancytopenia. Anemia presents with pallor and fatigue, while thrombocytopenia raises the risk of spontaneous bleeding, exacerbated by underlying coagulopathy. Neutropenia heightens susceptibility to infections, complicating management. Unlike cytopenias caused by marrow infiltration in primary hematologic malignancies, those in HLH result from hemophagocytosis and peripheral destruction, making them particularly refractory to supportive measures such as transfusions.

Neurological involvement, though less common, can be severe. Patients may experience altered mental status, seizures, or focal neurological deficits, often indicative of central nervous system (CNS) involvement. Cerebrospinal fluid (CSF) analysis frequently reveals pleocytosis and elevated protein, mimicking infectious or leukemic meningitis. Neurological symptoms can arise abruptly and progress rapidly, necessitating close monitoring and early intervention. In some instances, CNS involvement may be the first indication of HLH, particularly when systemic findings are initially subtle.

Diagnostic Criteria

Diagnosing LA-HLH is challenging due to overlapping features with aggressive lymphomas and severe infections. The HLH-2004 criteria, established by the Histiocyte Society, remain the most widely used framework. A diagnosis of HLH requires at least five of the following eight criteria: fever, splenomegaly, cytopenias affecting at least two blood cell lineages, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissues, low or absent NK cell activity, elevated ferritin levels, and high soluble IL-2 receptor (sCD25) levels. While these criteria provide structure, they were initially designed for primary (genetic) HLH and may not fully capture the complexities of lymphoma-driven HLH.

In LA-HLH, additional diagnostic tools are often necessary. Bone marrow biopsy plays a central role, as it may reveal hemophagocytosis alongside lymphoma infiltration. However, hemophagocytosis is not always present early in the disease, necessitating repeat biopsies if clinical suspicion remains high. Imaging such as PET-CT scans can help identify occult lymphomatous involvement, particularly when HLH symptoms precede a formal lymphoma diagnosis. Elevated ferritin levels above 10,000 ng/mL, while not specific, are strongly associated with HLH and can serve as a valuable diagnostic clue.

Associated Genetic Mutations

While LA-HLH is primarily driven by malignancy-induced immune dysregulation, genetic predisposition can influence disease susceptibility and severity. Germline mutations in genes associated with primary HLH, such as PRF1, UNC13D, and STXBP2, have been identified in some adults with lymphoma who develop HLH. These mutations impair cytotoxic lymphocyte function, reducing the ability to clear activated immune cells and resolve inflammation. Even in a heterozygous state, these genetic alterations may contribute to an inadequate immune response, predisposing individuals to HLH in lymphoma. Identifying these mutations can provide insight into disease pathogenesis and may influence treatment decisions, particularly in refractory cases.

Somatic mutations within malignant lymphoid cells may also play a role in HLH development. Genetic alterations in pathways regulating cytokine production, immune evasion, and apoptosis have been implicated in aggressive lymphomas associated with HLH. For example, mutations in STAT3 and JAK/STAT signaling components can enhance cytokine release, fueling the hyperinflammatory state. Similarly, disruptions in TP53 and BCL2 may contribute to lymphoma cell survival, prolonging immune activation. As genomic sequencing becomes more accessible, integrating genetic insights into HLH management could improve diagnostic accuracy and inform personalized treatment strategies.

Prognosis

The prognosis of LA-HLH is significantly worse than that of HLH triggered by infection or autoimmune disease, largely due to the aggressive nature of the underlying malignancy. Mortality rates remain high, with survival often below 50%. Uncontrolled inflammation, multi-organ failure, and chemotherapy-related complications contribute to poor outcomes. Delays in diagnosis frequently result in irreversible organ damage before treatment can be initiated, further worsening mortality risk.

Prognostic factors include lymphoma type, response to initial treatment, and degree of systemic involvement. T-cell and NK-cell lymphomas, particularly those linked to Epstein-Barr virus (EBV), carry a worse prognosis due to rapid progression and high relapse rates. Patients who fail to achieve remission after first-line therapy have significantly reduced survival. Markers of severe disease, including persistently high ferritin levels, profound cytopenias, and CNS involvement, also correlate with poor outcomes. Ongoing research into novel therapies, such as JAK inhibitors and CAR-T cell therapies, offers hope for improving survival in LA-HLH.