Hemophagocytic Lymphohistiocytosis



Hemophagocytic Lymphohistiocytosis


Sa A. Wang, MD





Key Facts


Terminology



  • Cytokine dysfunction, resulting in activation of T lymphocytes and macrophages



    • Leads to systemic symptoms and organ damage


Etiology/Pathogenesis



  • Inherited genetic or acquired defect leading to depressed NK- &/or cytotoxic T-cell activity


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


Microscopic Pathology



  • In lymph nodes



    • Sinuses are infiltrated by bland histiocytes showing phagocytic activity


    • Underlying etiology may coexist in same lymph node


Top Differential Diagnoses



  • Rosai-Dorfman disease


  • Histiocytic sarcoma


  • Langerhans cell histiocytosis


Diagnostic Checklist



  • Clinical and laboratory criteria (5 out of 8 criteria)



    • Fever


    • Cytopenias


    • Splenomegaly


    • Hypertriglyceridemia &/or hypofibrinogenemia


    • Serum ferritin > 500 µg/L


    • Hemophagocytosis


    • Low or absent NK-cell activity


    • Soluble CD25 (sIL-2 receptor) > 2,400 U/mL


  • HLH diagnosed by molecular testing






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.


TERMINOLOGY



Abbreviations



  • Hemophagocytic lymphohistiocytosis (HLH)


Synonyms



  • Hemophagocytic syndrome


  • Erythrophagocytic lymphohistiocytosis


  • Viral-associated hemophagocytic syndrome



Definitions



  • Cytokine dysfunction, either due to inherited or secondary causes



    • Results in overwhelming activation of normal T lymphocytes and macrophages



      • Leads to systemic symptoms and organ damage


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Epidemiology



  • 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


Presentation



  • 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



Treatment



  • HLH-2004 protocol recommended by Histiocytosis Association of America



    • 8-week period with dexamethasone, etoposide, and cyclosporine



      • Resolved nonfamilial HLH does not require continuation of therapeutic regimen


      • Children with persistent nonfamilial disease or familial disease should continue therapy with cyclosporine, plus etoposide and dexamethasone pulses, until stem cell transplant


    • Intrathecal methotrexate is used for persistently abnormal CSF or progressive neurologic symptoms


  • Stem cell transplantation for patients with



    • Familial HLH


    • Children and adults with persistent nonfamilial disease


Prognosis



  • 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


IMAGE FINDINGS


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


MICROSCOPIC PATHOLOGY


Histologic Features



  • Proliferation of small mature histiocytes



    • Histiocytes show phagocytic activities


    • Tissue infiltrate and cellular injury


    • Increased lymphocytes; mostly T cells


Cytologic Features

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

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