Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis

Sa A. Wang, MD

In a lymph node involved by hemophagocytic lymphohistiocytosis (HLH), the sinus is expanded by numerous mature histiocytes/macrophages, some exhibiting phagocytosis of mostly erythrocytes image.

This patient presented with fever and pancytopenia prompting bone marrow examination. Bone marrow aspirate smear (Wright-Giemsa stain) shows erythrophagocytosis image.



  • Hemophagocytic syndrome

  • Erythrophagocytic lymphohistiocytosis

  • Viral-associated hemophagocytic syndrome


Inherited vs. Secondary/Acquired Defects

  • Inherited genetic defects

    • Result in depressed functional cytotoxicity of natural killer (NK) cells and cytotoxic T cells

      • T cells cannot terminate the stimulatory responses they receive from antigen-presenting cells

      • NK cells and cytotoxic T cells cannot clear infection

    • Perforin (PRF1) mutation

      • Localized at 10q21-22

      • Results in decrease or absence of perforin in NK or CD8(+) T cells

    • Griscelli syndrome (MUNC13-4 defect)

      • Lack of protein rab27a, which controls secretion of lytic granules in NK and cytotoxic T cells

    • Chediak-Higashi syndrome (LYST gene defect)

      • Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is involved

      • Failure to move CTLA-4 from secretory lysozymes to cell membrane

    • Syntaxin gene mutations

      • NK cells fail to degranulate when encountering susceptible targets

    • X-linked lymphoproliferative disease (XLP)

      • SH2D1A gene mutation

      • Defect in T-cell signal transduction

      • T-cell lytic defect against EBV-infected B lymphocytes

      • Trigger vigorous cytotoxic cellular responses

      • a.k.a. Duncan syndrome

    • Defect in apoptosis-caspase 3 leading to accumulation of T cells

  • Acquired/secondary defects

    • It is not clear how NK-cell and T-cell function is impaired

    • Many infectious agents are reported to be associated with HLH

    • Viruses

      • EBV is most common, CMV, parvovirus B19, herpes simplex

      • Herpes varicella-zoster, measles, human herpesvirus 8, HIV

      • Adenovirus, respiratory syncytial virus, parainfluenza virus, enteroviruses

    • Bacteria

      • Pseudomonas aeruginosa, staphylococci, streptococci

      • Escherichia coli and Brucella abortus

      • Mycobacteria: Mycobacterium tuberculosis

    • Parasites: Leishmania donovani; Plasmodium species

    • Fungi

      • Histoplasma capsulatum, Penicillium marneffei, Aspergillus

      • Cryptococcal meningitis, histoplasmosis, and disseminated Trichosporon beigelii

    • Autoimmune disorders

      • Systemic lupus erythematosus, rheumatoid arthritis

      • Still disease, polyarteritis nodosa

      • Mixed connective tissue disease, systemic sclerosis, Sjögren syndrome

    • Malignancies associated with HLH

      • T- and NK-cell lymphomas

      • Acute myeloid leukemias and myelodysplastic syndromes

      • Acute lymphoblastic leukemia/lymphoma (B or T cell)

      • B-cell lymphomas; carcinomas

    • Other diseases reported associated with HLH

      • Post-transplant

      • Pulmonary sarcoidosis

Common Etiologies of Inherited & Secondary/Acquired HLH

  • Inappropriate immune reaction caused by

    • Proliferation &/or activation of T cells either due to genetic defects or secondary causes

    • Defect in packaging, exocytosis, or function of cytotoxic granules

    • Production of large quantities of cytokines including

      • Interferon-γ, TNF-α, and granulocyte-macrophage colony-stimulating factor

      • Interleukin-1 (IL-1) and interleukin-6 (IL-6)

      • Associated with macrophage activation

      • Inadequate apoptosis of immunogenic cells



  • Incidence

    • 1.2 children per million per year or 1 case per every 50,000 births

    • Incidence in adults is unknown

  • Age

    • Familial form frequently affects infants

      • Birth to age 18 months most common (70-80%)

      • Rare familial cases can affect adolescents and adults

    • Acquired form can occur at any age

  • Gender

    • M:F = 1:1

  • Ethnicity

    • No predilection for any race


  • Fever: ≥ 7 days of fever as high as 38.5°C (101.3°F)

  • Easy bruisability and pallor related to cytopenia(s) or coagulopathy

  • Splenomegaly: Spleen palpable > 3 cm below costal margin

  • Central nervous system symptoms

    • Seizures, ataxia, hemiplegia, mental status changes, irritability

  • Skin rash: Scaly and waxy lesions; rashes on scalp and behind ear

  • Lymphadenopathy

  • Hepatomegaly, jaundice

  • Pleural effusion; ascites

  • HLH occurring in the context of malignancies

    • May mask underlying malignancies

    • Often associated with severe infection due to intrinsic or iatrogenic immunocompromised state

Laboratory Tests

  • Cytopenia(s), often pancytopenia

    • Hemoglobin < 9.0 g/dL

    • Platelets < 100,000/µL

    • Absolute neutrophil count < 1,000/µL

  • Hypofibrinogenemia

    • Fibrinogen < 1.5 g/L, or > 3 standard deviations (SD) below normal value for age

  • Hypertriglyceridemia

    • Fasting triglycerides ≥ 2.0 mmol/L, or > 3 SD above normal value for age

  • Increased serum ferritin

    • > 500 µg/L

    • Glycosylated ferritin < 20% of total ferritin

    • Levels parallel to course of disease

      • Can use to monitor disease activity

    • 80% specific for diagnosis of HLH

  • Abnormal liver function

    • Hyperbilirubinemia

    • Hypoalbuminemia

    • Increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels

  • Serum lactate dehydrogenase (LDH) increased

  • Defect in NK-cell activity; adequate NK-cell number

    • Can differentiate between the HLH subtypes

  • Increased concentrations of circulating soluble interleukin receptor (sIL-2R)

  • Molecular diagnosis

    • Gene mutation analysis


  • With HLH-2004 protocol

    • 3-year probability of survival was 51% for verified familial cases

    • 55% for entire group of HLH patients

  • Stem cell transplant

    • Matched transplant: Long-term disease-free rate ˜ 70%

Special Form of HLH-Macrophage Activation Syndrome (MAS)

  • Occurs in children and adults with autoimmune diseases, especially

    • Systemic-onset juvenile rheumatoid arthritis (or systemic juvenile idiopathic arthritis): 10-50% of patients

    • Adult-onset Still disease

    • Lupus erythematosus

    • Kawasaki disease

    • Different rheumatic conditions exploit different pathways to arrive at an MAS phenotype

  • Clinical and laboratory features

    • Share many characteristics with HLH

      • Defective NK-cell function and low perforin expression

      • Clinical signs and symptoms similar to HLH

      • Hemophagocytosis is present in bone marrow, spleen, lymph node

      • High ferritin levels

    • Features that differ from HLH

      • Less severe cytopenias

      • Not associated with severe infection

      • More severe cardiac impairment and more pronounced coagulopathy

      • Very high C-reactive protein level

  • Therapy

    • Cyclosporine and steroids

    • If these do not work, use HLH-2004 protocol


General Features

  • No specific imaging patterns are diagnostic of HLH

  • CT or ultrasonography findings

    • Ascites, pleural effusion

    • Gallbladder wall thickening

    • Lymphadenopathy

  • MR for CNS involvement


Histologic Features

  • Proliferation of small mature histiocytes

    • Histiocytes show phagocytic activities

    • Tissue infiltrate and cellular injury

    • Increased lymphocytes; mostly T cells

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hemophagocytic Lymphohistiocytosis
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