Lymph nodes & spleen, nonlymphoid
Lymph nodes-inflammatory disorders
Hemophagocytic lymphohistiocytosis


Topic Completed: 14 February 2020

Minor changes: 30 July 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Hemophagocytic lymphohistiocytosis [title] (Review[ptyp] "loattrfree full text"[sb])

See also: Erythrophagocytosis

Mark G. Evans, M.D.
Sherif A. Rezk, M.D.
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Cite this page: Evans MG, Healey J, Rezk SA. Hemophagocytic lymphohistiocytosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphnodeshemophagocyticlymphohistiocytosis.html. Accessed October 24th, 2020.
Definition / general
  • Pathologic immune activation syndrome
  • Congenital or acquired defective natural killer (NK) / T cell function with uncontrolled hypercytokinemia and end organ damage
  • Histiocytic infiltration of reticuloendothelial organs with hemophagocytosis of erythrocytes, leukocytes, platelets and their precursor cells
  • Divided into genetic (primary) and acquired (secondary) forms
Essential features
  • Sudden onset of a systemic inflammatory response syndrome (SIRS) with symptoms including high unremitting fevers, malaise, rash, jaundice and myalgia, along with accompanying cytopenias, hepatosplenomegaly and generalized lymphadenopathy
  • Familial (primary) hemophagocytic lymphohistiocytosis is a progressive disease characterized by early age of onset, autosomal recessive inheritance pattern, decreased NK cell function and frequent perforin mutations
  • Secondary (acquired) hemophagocytic lymphohistiocytosis is often associated with immunodeficiency, normal or reduced NK cell numbers and normal perforin expression, and may be triggered by infectious agents, malignant neoplasms, graft versus host disease and (rarely) HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome
  • Primary and secondary hemophagocytic lymphohistiocytosis are invariably fatal when left untreated but new therapy protocols (including HLH-2004) have reported 5 year survival rates up to 54%
Terminology
  • Familial (primary) hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disease subdivided into subtypes FHL1-FHL5 based on the genetic alteration
  • Familial hemophagocytic lymphohistiocytosis may be associated with primary immunodeficiency syndromes such as Chédiak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2 and X-linked lymphoproliferative disorder types 1 and 2 (Hematology Am Soc Hematol Educ Program 2011;2011:178)
  • Secondary (acquired) hemophagocytic lymphohistiocytosis occurs in response to immune triggers including infection, malignancy and rheumatologic / inflammatory disorders (in such cases, known as macrophage activation syndrome [MAS])
ICD coding
  • ICD-10: D76.1 - hemophagocytic lymphohistiocytosis
Epidemiology
  • Familial hemophagocytic lymphohistiocytosis primarily affects young children with an incidence of approximately 1.5 per 100,000 live births (Pediatr Blood Cancer 2015;62:346)
  • Acquired hemophagocytic lymphohistiocytosis is more common in older children and adults; its incidence is unknown but is likely underdiagnosed
  • No race or sex predilection
Sites
  • Involves all reticuloendothelial organs (bone marrow, spleen, liver and lymph nodes)
  • Less commonly involves skin, lungs, meninges, cerebrospinal fluid and subcutaneous tissue
Pathophysiology
  • Failure of NK cells to induce apoptosis of the target cell, remove the antigenic stimulus and terminate the inflammatory response
  • Accentuated Th1 response leads to high levels of TNF-alpha and TNF-gamma, causing pancytopenia
  • Upregulation of ferritin production secondary to increased heme oxygenase
  • Hepatosplenomegaly due to organ infiltration by activated lymphocytes and histiocytes
  • Fever induced by interleukin-1 and interleukin-6 (Am J Clin Pathol 2013;139:713)
Etiology
  • Genetic or acquired impaired cytotoxic function of T lymphocytes and NK cells
  • Familial hemophagocytic lymphohistiocytosis is an inherited autosomal recessive disease involving mutations in perforin and other genes
  • Secondary hemophagocytic lymphohistiocytosis triggers (which may also initiate familial hemophagocytic lymphohistiocytosis symptoms) include:
    • Infection (particularly viruses that include Epstein-Barr virus and cytomegalovirus)
    • Malignancy (most often NK / T cell neoplasms, such as nasal-type extranodal NK / T cell lymphoma and cutaneous gamma / delta T cell lymphoma)
    • Rheumatologic / autoimmune disease
    • Immunosuppression
    • Pregnancy / HELLP syndrome (rare) (Clin Case Rep 2018;6:2466)
  • In children, a genetic defect characteristic of familial hemophagocytic lymphohistiocytosis should be ruled out
  • In adults, hemophagocytic lymphohistiocytosis should prompt an investigation for underlying malignancy
Clinical features
  • Fever
  • Malaise
  • Myalgia
  • Hepatosplenomegaly
  • Jaundice
  • Generalized lymphadenopathy
  • Cytopenias
  • Rash
  • Neurologic symptoms
Diagnosis
  • HLH-2004 criteria (updated 2007) includes the molecular diagnosis of familial hemophagocytic lymphohistiocytosis or the presence of at least 5 of 8 criteria:
    • 1. Fever
    • 2. Splenomegaly
    • 3. Cytopenias (affecting at least 2 lineages in the peripheral blood)
      • Hemoglobin levels < 90 g/L
      • Platelets < 100 x 10⁹/L
      • Neutrophils < 1.0 x 10⁹/L
    • 4. Hypertriglyceridemia or hypofibrinogenemia:
      • Fasting triglycerides ≥ 265 mg/dL
      • Fibrinogen ≤ 1.5 g/L
    • 5. Documented hemophagocytosis in the bone marrow, spleen or lymph nodes
    • 6. Low or absent NK cell activity
    • 7. Ferritin ≥ 500 µg/L
    • 8. Soluble CD25 ≥ 2,400 U/mL
  • Familial hemophagocytic lymphohistiocytosis should have no evidence of malignancy
  • Absence of hemophagocytosis during microscopic examination does not exclude the diagnosis of hemophagocytic lymphohistiocytosis (adapted from Pediatr Blood Cancer 2007;48:124)
Laboratory
  • Hypofibrinogenemia
  • Markedly elevated ferritin
  • Hypertriglyceridemia
  • Elevated transaminases
  • Elevated lactate dehydrogenase
  • Elevated serum soluble CD25 (interleukin-2 receptor)
  • Reduced or absent NK cell activity by 51-Cr release assay
Radiology description
  • Hepatosplenomegaly
  • Generalized lymphadenopathy
  • Alveolar interstitial opacities with pleural effusions
  • Gallbladder wall thickening
  • Hyperechoic kidneys
  • Ascites
  • Nonspecific periventricular white matter abnormalities, brain volume loss and enlargement of extra-axial fluid spaces (Pediatr Radiol 2003;33:392)
Prognostic factors
  • Almost invariably fatal if left untreated
  • Familial hemophagocytic lymphohistiocytosis tends to recur within the first year of life in 70 - 80% of cases (Am J Clin Pathol 2013;139:713)
  • Among the viral associated forms of hemophagocytic lymphohistiocytosis, Epstein-Barr virus carries the worst prognosis
  • Delay in diagnosis and multi-organ involvement are associated with an inferior prognosis
  • Hemophagocytic lymphohistiocytosis in the setting of HELLP syndrome, as well as hemophagocytic lymphohistiocytosis development during the third trimester with associated Epstein-Barr viremia have a poor prognosis (Clin Case Rep 2018;6:2466)
Case reports
Treatment
  • Immediate treatment of the underlying disease in secondary hemophagocytic lymphohistiocytosis
  • Eight week induction therapy with cyclosporine (HLH-2004 protocol), corticosteroids and etoposide (Am J Clin Pathol 2013;139:713)
    • Cyclosporine inhibits T cell activation
    • Corticosteroids suppress hypercytokinemia
    • Etoposide blocks cell proliferation
    • Has demonstrated a 5 year survival rate up to 54%
  • Stem cell transplantation is utilized in cases of familial hemophagocytic lymphohistiocytosis
Microscopic (histologic) description
  • Hemophagocytic histiocytes are best visualized on bone marrow aspirate smear
  • Liver sinusoids can demonstrate histiocytes with erythrophagocytosis
  • Splenic white pulp can be atrophic with extensive infiltration of histiocytes exhibiting erythrophagocytosis
  • Lymph nodes:
    • Early disease shows an intense immunoblastic response
    • Later stages demonstrate lymphoid depletion with massive sinusoidal infiltration by benign appearing histiocytes and erythrophagocytosis
  • Hemophagocytosis is cyclical; repeat biopsies may be helpful
  • Visualization of hemophagocytosis is not necessary to establish the diagnosis of hemophagocytic lymphohistiocytosis
  • Hemophagocytosis is not a specific finding and can be seen in up to 60% of patients with sepsis (Clin Case Rep 2018;6:2466)
Microscopic (histologic) images

Contributed by Sherif A. Rezk, M.D.

Bone marrow hemophagocytosis

Erythrophagocytosis

Neutrophil hemophagocytosis

Platelet hemophagocytosis



AFIP Images

Bone marrow in reactive hemophagocytic syndrome

Reactive hemophagocytosis in lymph node

Positive stains
Negative stains
  • Absent or diminished intracellular staining for perforin can indicate mutations in the protein encoding gene
Flow cytometry description
  • Flow cytometry may demonstrate decreased expression of CD107a (LAMP-1) surface expression on cytotoxic NK / T cells (Am J Clin Pathol 2013;139:713)
  • Reduced CD5 and CD7 expression has been observed in circulating and bone marrow CD8 positive T cells in some patients (Blood 2004;104:2007)
Molecular / cytogenetics description
  • Familial hemophagocytic lymphohistiocytosis is divided into subtypes (FHL1-FHL5) based on the specific genetic alteration:
    • The involved genes include PRF1 in 50% of cases (FHL2), UNC13D (FHL3), STX11 (FHL4) and STXBP2 (FHL5)
    • The gene responsible for FHL1 has yet to be identified but is located at 9q21_3-22
  • Secondary (acquired) hemophagocytic lymphohistiocytosis may demonstrate missense or splice-site changes in PRF1, MUNC13-4 and STXBP2 (Blood 2011;118:5794)
Sample pathology report
  • Bone marrow, right iliac crest, aspirate smears, touch imprints, clot and trephine biopsy section:
    • Normocellular marrow with active trilineage hematopoiesis, marked erythroid hyperplasia and evident hemophagocytosis
    • By immunohistochemistry, increased phagocytic histiocytes with no malignancy identified
Differential diagnosis
  • Sepsis due to various causes
    • The symptoms of hemophagocytic lymphohistiocytosis (including fever, malaise, myalgia, etc.) can often be seen in acute sepsis of various causes and the diagnosis of hemophagocytic lymphohistiocytosis requires fulfillment of the criteria defined previously
  • Myeloproliferative neoplasm / myelodysplastic syndrome (MDS / MPN)
    • Hemophagocytic lymphohistiocytosis can also present with cytopenias; careful examination of the bone marrow for dysplasia in various cell lineages will aid in diagnosing MDS / MPN
  • Rosai-Dorfman disease
    • A prominent histiocytic infiltration may also be present in hemophagocytic lymphohistiocytosis; however, Rosai-Dorfman disease rarely presents with constitutional symptoms and generally features emperipolesis, as opposed to erythrophagocytosis
  • Langerhans cell histiocytosis
    • In spite of the prominent histiocytes sometimes observed in hemophagocytic lymphohistiocytosis, these cells generally lack nuclear grooves and do not demonstrate erythrophagocytosis
  • Leishmaniasis / histoplasmosis
    • Platelets phagocytosed by histiocytes in hemophagocytic lymphohistiocytosis can visually mimic intracellular Leishmania donovani or Histoplasma capsulatum organisms
    • Clinical history and microbiology analyses, including indirect fluorescent antibody (IFA) testing and polymerase chain reaction (PCR), can confirm the infectious diagnosis
Board review style question #1
    A 45 year old Hispanic woman presents with mild normocytic anemia and thrombocytopenia. A representative photograph of her bone marrow aspirate smear is provided. Her medical history most likely includes which entity, which could be contributing to the current findings in the bone marrow biopsy?



  1. Triple negative breast cancer
  2. Panniculitis-like T cell lymphoma
  3. Acute myeloid leukemia
  4. Acute human immunodeficiency virus (HIV) infection
Board review answer #1
B. The patient’s aspirate smear demonstrates hemophagocytosis, consistent with HLH. Secondary (acquired) HLH is frequently associated with hematologic malignancies, in particular NK/T cell neoplasms like panniculitis-like T cell lymphoma. HLH has been only rarely reported in association with other cancers. HIV infection has been implicated in the development of HLH, but typically in the setting of other acute infections or HIV associated lymphomas, especially EBV related lymphoproliferative processes.

Reference: Hemophagocytic lymphohistiocytosis

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Board review style question #2
    Among the infectious etiologies of hemophagocytic lymphohistiocytosis, which of the following has been most commonly implicated?

  1. Cytomegalovirus
  2. Parvovirus B19
  3. Epstein-Barr virus
  4. Influenza virus
Board review answer #2
C. While all of viruses listed have been associated with hemophagocytic lymphohistiocytosis, Epstein-Barr virus infection is most commonly observed and is associated with the worst prognosis.

Reference: Hemophagocytic lymphohistiocytosis

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