HLH and Lymphoma

Today, Dr. Baig-Lewis presented a case of hemophagocytic lymphohistiocytosis (HLH) in an older female who was ultimately found to have a peripheral T-cell lymphoma.

 Image courtsey of  ASH image bank  demonstrating a high magnification image of hemophagocytosis in a patient with CLL. 

Image courtsey of ASH image bank demonstrating a high magnification image of hemophagocytosis in a patient with CLL. 

First, remember that HLH is a rare syndrome of excessive inflammation and tissue destruction as a result of excess macrophage activation and impaired cytoxic function of NK and CTL (CD8) cells. This results in excess cytokine production of IFN-y, TNF-a, interleukons and soluble IL-2 (CD25) receptor. Key features are built into the diagnostic criteria. Diagnosis is made when there are 5 of the 8 present:

  • Fever ≥38.5°C
  • Splenomegaly
  • Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 data-preserve-html-node="true" g/dL ; platelets <100,000 data-preserve-html-node="true"/microL; absolute neutrophil count <1000 data-preserve-html-node="true"/microL
  • Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen <150 data-preserve-html-node="true" mg/dL)
  • Hemophagocytosis in bone marrow, spleen, lymph node, or liver
  • Low or absent NK cell activity
  • Ferritin >500 ng/mL
  • Elevated soluble CD25 (soluble IL-2 receptor alpha) two standard deviations above age-adjusted laboratory-specific norms [A 2017 article in Blood Advances showed a value of <2400U data-preserve-html-node="true"/mL was helpful in ruling out HLH with 100% sensitvitiy while a value of >10,000U/mL was helpful in ruling in HLH with 93% specificity)

Additional findings include lymphadenopathy, neurologic dysfunction (including PRES), rash and coagulation abnormalities.

For additional review, check-out the IMRESPDX blog post from 2016 on HLH. HLH occurs either as primary type felt secondary to a genetic mutation or, as a secondary type with a trigger (infection, malignancy, autoimmune disorder- in this instance it is called macrophage activation syndrome). In the diagnostic evaluation, a secondary cause is also persued. Dr. Baig-Lewis reviewed a 2014 article in the Annals of Hematology which found a found that an elevated soluble IL-2 (CD25) receptor to ferritin ratio was useful marker for diagnosing lymphoma associated HLH.