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Hemophagocytic Lymphohistiocytosis
Michael R. Aquino, MD, MHSc; Swathi Selvam, BSc, MBBS, FRCR
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KEY FACTS

  • Terminology

    • Imaging

      • Clinical Issues

        TERMINOLOGY

        • Abbreviations

          • Hemophagocytic lymphohistiocytosis (HLH)
        • Synonyms

          • Hyperferritinemic inflammation
          • Macrophage activation syndrome (MAS) when occurring in those with underlying rheumatologic or autoimmune syndrome
          • Cytokine release syndrome (CRS) if related to iatrogenic immunosuppression therapy
        • Definitions

          • Rare, life-threatening disorder of pathological immune activation resulting in extreme systemic hyperinflammation
          • Despite name, hemophagocytosis is not required for diagnosis
          • Likely to represent wide spectrum, divided into 2 types
            • Genetic/primary/familial
            • Acquired/secondary
          • Genetic/primary or familial HLH
            • Inherited genetic abnormalities
            • Familial HLH: Autosomal recessive pattern, commonly associated with familial HLH genes
            • Primary HLH: Associated with immune deficiency syndromes, such as X-linked lymphoproliferative disease, Griscelli type 2, & Chediak Higashi
          • Acquired/secondary HLH
            • Environmental or acquired mechanisms, such as infection, malignancy, autoimmune conditions, immunocompromise

        IMAGING

        • General Features

          • Radiographic Findings

            • CT Findings

              • MR Findings

                • Ultrasonographic Findings

                  • Imaging Recommendations

                    DIFFERENTIAL DIAGNOSIS

                      PATHOLOGY

                      • General Features

                        • Staging, Grading, & Classification

                          CLINICAL ISSUES

                          • Presentation

                            • Demographics

                              • Natural History & Prognosis

                                • Treatment

                                  Selected References

                                  1. Bergsten E et al: Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study. Blood Adv. 4(15):3754-66, 2020
                                  2. Canna SW et al: Pediatric hemophagocytic lymphohistiocytosis. Blood. 135(16):1332-43, 2020
                                  3. Shieh AC et al: Hemophagocytic lymphohistiocytosis: a primer for radiologists. AJR Am J Roentgenol. 214(1):W11-9, 2020
                                  4. Benson LA et al: Pediatric CNS-isolated hemophagocytic lymphohistiocytosis. Neurol Neuroimmunol Neuroinflamm. 6(3):e560, 2019
                                  5. Al-Samkari H et al: Hemophagocytic lymphohistiocytosis. Annu Rev Pathol. 13:27-49, 2018
                                  6. Bergsten E et al: Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 130(25):2728-38, 2017
                                  7. Emile JF et al: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 127(22):2672-81, 2016
                                  8. Allen CE et al: Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program. 2015:177-82, 2015
                                  9. Lehmberg K et al: Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol. 170(4):539-49, 2015
                                  10. George MR: Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 5:69-86, 2014
                                  11. Guandalini M et al: Spectrum of imaging appearances in Australian children with central nervous system hemophagocytic lymphohistiocytosis. J Clin Neurosci. 21(2):305-10, 2014
                                  12. Rosado FG et al: Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. 139(6):713-27, 2013
                                  13. Zhang K et al: Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 118(22):5794-8, 2011
                                  14. Niece JA et al: Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer. 54(3):424-8, 2010
                                  15. Janka G: Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr. 221(5):278-85, 2009
                                  16. Henter JI et al: HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 48(2):124-31, 2007
                                  17. Janka GE: Hemophagocytic syndromes. Blood Rev. 21(5):245-53, 2007
                                  18. Histiocyte Society: HLH-2004 Study Group. Published January, 2004. Accessed November 20, 2020. https://www.skion.nl/workspace/uploads/HLH-2004-protocol1.pdf
                                  19. Fitzgerald NE et al: Imaging characteristics of hemophagocytic lymphohistiocytosis. Pediatr Radiol. 33(6):392-401, 2003
                                  20. Rooms L et al: Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics. 111(5 Pt 1):e636-40, 2003
                                  Related Anatomy
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                                  Related Differential Diagnoses
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                                  References
                                  Tables

                                  Tables

                                  KEY FACTS

                                  • Terminology

                                    • Imaging

                                      • Clinical Issues

                                        TERMINOLOGY

                                        • Abbreviations

                                          • Hemophagocytic lymphohistiocytosis (HLH)
                                        • Synonyms

                                          • Hyperferritinemic inflammation
                                          • Macrophage activation syndrome (MAS) when occurring in those with underlying rheumatologic or autoimmune syndrome
                                          • Cytokine release syndrome (CRS) if related to iatrogenic immunosuppression therapy
                                        • Definitions

                                          • Rare, life-threatening disorder of pathological immune activation resulting in extreme systemic hyperinflammation
                                          • Despite name, hemophagocytosis is not required for diagnosis
                                          • Likely to represent wide spectrum, divided into 2 types
                                            • Genetic/primary/familial
                                            • Acquired/secondary
                                          • Genetic/primary or familial HLH
                                            • Inherited genetic abnormalities
                                            • Familial HLH: Autosomal recessive pattern, commonly associated with familial HLH genes
                                            • Primary HLH: Associated with immune deficiency syndromes, such as X-linked lymphoproliferative disease, Griscelli type 2, & Chediak Higashi
                                          • Acquired/secondary HLH
                                            • Environmental or acquired mechanisms, such as infection, malignancy, autoimmune conditions, immunocompromise

                                        IMAGING

                                        • General Features

                                          • Radiographic Findings

                                            • CT Findings

                                              • MR Findings

                                                • Ultrasonographic Findings

                                                  • Imaging Recommendations

                                                    DIFFERENTIAL DIAGNOSIS

                                                      PATHOLOGY

                                                      • General Features

                                                        • Staging, Grading, & Classification

                                                          CLINICAL ISSUES

                                                          • Presentation

                                                            • Demographics

                                                              • Natural History & Prognosis

                                                                • Treatment

                                                                  Selected References

                                                                  1. Bergsten E et al: Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study. Blood Adv. 4(15):3754-66, 2020
                                                                  2. Canna SW et al: Pediatric hemophagocytic lymphohistiocytosis. Blood. 135(16):1332-43, 2020
                                                                  3. Shieh AC et al: Hemophagocytic lymphohistiocytosis: a primer for radiologists. AJR Am J Roentgenol. 214(1):W11-9, 2020
                                                                  4. Benson LA et al: Pediatric CNS-isolated hemophagocytic lymphohistiocytosis. Neurol Neuroimmunol Neuroinflamm. 6(3):e560, 2019
                                                                  5. Al-Samkari H et al: Hemophagocytic lymphohistiocytosis. Annu Rev Pathol. 13:27-49, 2018
                                                                  6. Bergsten E et al: Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 130(25):2728-38, 2017
                                                                  7. Emile JF et al: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 127(22):2672-81, 2016
                                                                  8. Allen CE et al: Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program. 2015:177-82, 2015
                                                                  9. Lehmberg K et al: Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol. 170(4):539-49, 2015
                                                                  10. George MR: Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 5:69-86, 2014
                                                                  11. Guandalini M et al: Spectrum of imaging appearances in Australian children with central nervous system hemophagocytic lymphohistiocytosis. J Clin Neurosci. 21(2):305-10, 2014
                                                                  12. Rosado FG et al: Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. 139(6):713-27, 2013
                                                                  13. Zhang K et al: Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 118(22):5794-8, 2011
                                                                  14. Niece JA et al: Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer. 54(3):424-8, 2010
                                                                  15. Janka G: Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr. 221(5):278-85, 2009
                                                                  16. Henter JI et al: HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 48(2):124-31, 2007
                                                                  17. Janka GE: Hemophagocytic syndromes. Blood Rev. 21(5):245-53, 2007
                                                                  18. Histiocyte Society: HLH-2004 Study Group. Published January, 2004. Accessed November 20, 2020. https://www.skion.nl/workspace/uploads/HLH-2004-protocol1.pdf
                                                                  19. Fitzgerald NE et al: Imaging characteristics of hemophagocytic lymphohistiocytosis. Pediatr Radiol. 33(6):392-401, 2003
                                                                  20. Rooms L et al: Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics. 111(5 Pt 1):e636-40, 2003