Hemophagocytic Lymphohistiocytosis (HLH)

Description: A life-threatening syndrome of severe, uncontrolled immune activation resulting in a massive cytokine storm and widespread tissue damage. It is characterized by the accumulation of activated macrophages and lymphocytes in the reticuloendothelial system.

• Classification:

  • Familial (Primary) HLH: Inherited disorder most commonly presenting during infancy.

  • Secondary (Acquired) HLH: Triggered by an underlying condition in patients of any age.

Diagnostic Criteria: Diagnosis requires either an established molecular/genetic defect OR meeting at least 5 of the following 8 criteria:

1. Fever

2. Splenomegaly

3. Cytopenias involving 2 or 3 lineages

4. Hypertriglyceridemia and/or hypofibrinogenemia

5. Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver

6. Low or absent natural killer (NK) cell activity

7. Ferritin >500 µg/L

8. Elevated soluble CD25 (soluble IL-2 receptor)

Clinical Pearl: Prompt initiation of immunochemotherapy is vital for survival, but treatment is often complicated by a dynamic clinical course, treatment-related morbidity, and high recurrence risk.

Genetic/Acquired Defect → Impaired cytotoxic function of NK cells and cytotoxic T-lymphocytes (CTLs) → Inability to clear infected cells/antigens → Persistent antigen stimulation → Uncontrolled proliferation of activated T-cells and macrophages → Massive release of pro-inflammatory cytokines (cytokine storm) → Systemic inflammation, cytopenias, and multiorgan failure.

Familial HLH: Follows an autosomal recessive pattern of inheritance. It is driven by mutations in genes involved in the NK/T-cell cytotoxic pathway, most classically the perforin gene (PRF1).

Secondary HLH: Provoked by an intense immune challenge. Triggers include viral infections (Epstein-Barr virus [EBV] is the most common; others include cytomegalovirus [CMV] and herpes viruses), opportunistic infections due to immunosuppression (e.g., Histoplasma capsulatum), vaccinations, autoimmune disorders, and malignancies.

Architecture: Normal architecture of the bone marrow, lymph node, spleen, or liver may be distorted by an infiltrate of morphologically benign, non-neoplastic histiocytes (macrophages) and lymphocytes.

Key Feature: Hemophagocytosis, which is the active engulfment of erythrocytes, leukocytes, platelets, or their precursors by morphologically bland macrophages.

Bone Marrow: Often hypercellular in the early stages with reactive changes, but can become markedly hypocellular, necrotic, or fibrotic as the disease and cytokine storm progress.

Board Pearls & Pitfalls:

• Hemophagocytosis is simply a marker of profound histiocytic activation. It is neither pathognomonic nor required for the diagnosis of HLH.

• Hemophagocytosis may be absent early in the disease course, so its absence does not rule out HLH if clinical criteria are met.

• Rosai-Dorfman Disease:

Distinction: Features emperipolesis (intact, viable lymphocytes passing through the cytoplasm of large histiocytes) rather than destructive hemophagocytosis. The lesional histiocytes are S100 positive and CD1a negative.

• Langerhans Cell Histiocytosis (LCH):

Distinction: Characterized by grooved, "coffee-bean" nuclei in an eosinophil-rich background. LCH cells are strongly positive for CD1a, S100, and Langerin (CD207).

• Macrophage Activation Syndrome (MAS):

Distinction: MAS is essentially secondary HLH occurring in the setting of a rheumatologic or autoimmune disease (e.g., systemic juvenile idiopathic arthritis). It is morphologically indistinguishable from other forms of HLH and relies entirely on clinical history for distinction.

• EBV-positive T-cell/NK-cell Lymphoproliferative Disorders:

Distinction: These malignancies can trigger secondary HLH but feature cytologically atypical, clonal lymphoid infiltrates. T-cell receptor (TCR) clonality studies and careful cytologic evaluation are required to distinguish the reactive lymphocytes of primary HLH from an underlying lymphoma.

Key Immunohistochemistry (≤5 markers):

• CD163 and CD68 (+): Highlights the increased number of histiocytes and helps visualize hemophagocytosis.

• CD3 and CD8 (+): Demonstrates the reactive, proliferating cytotoxic T-cell population.

• EBER ISH (+/-): Essential to evaluate for EBV infection, which is the most frequent trigger of secondary HLH.

• Molecular Alterations: Genetic testing is paramount for familial cases. Pathogenic variants are most often found in PRF1 (perforin), UNC13D, STX11, or STXBP2.

• H&E Diagnostic Status: H&E morphology alone is never diagnostic. HLH is a strict clinicopathologic diagnosis requiring the integration of microscopic findings, laboratory values, and clinical symptoms.

Bone marrow, posterior iliac crest, aspirate and core biopsy:

• Hypercellular marrow with a prominent histiocytic infiltrate and frequent hemophagocytosis, findings supportive of hemophagocytic lymphohistiocytosis (HLH) in the appropriate clinical and laboratory context.