Bone marrow nonneoplastic

• 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

• 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])

• 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)

• Newborn twins with thrombocytopenia, coagulation defects and hepatosplenomegaly (N Engl J Med 2004;351:1120)
• 18 month old girl presenting with fluctuating fevers and leishmaniasis (Indian Pediatr 2004;41:605)
• 6 year old boy with fever, headache, abdominal pain and typhoid fever (J Emerg Med 2003;25:321)
• 30 year old pregnant female with HELLP syndrome and persistent fevers upon delivery (Clin Case Rep 2018;6:2466)
• 72 year old woman with Escherichia coli meningitis (J Formos Med Assoc 2006;105:756)

• 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

• 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)

Contributed by Sherif A. Rezk, M.D. and AFIP Images

Contributed by Sherif A. Rezk, M.D. and AFIP images

• Foucar: Diagnostic Pathology: Blood and Bone Marrow, 2nd Edition, 2017
• Hsi: Hematopathology: A Volume in the Series: Foundations in Diagnostic Pathology, 3rd Edition, 2017

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.

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Reference: Hemophagocytic lymphohistiocytosis

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.

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Reference: Hemophagocytic lymphohistiocytosis