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Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis): Differential Diagnoses & Workup

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Aug 21, 2009

Differential Diagnoses

Other Problems to Be Considered

Primary versus secondary hemophagocytic lymphohistiocytosis (HLH) 
Langerhans cell histiocytosis
Rosai-Dorfman disease
Solitary histiocytoma with macrophage phenotype
Leukemias
Lymphomas
Sarcomas
X-linked lymphoproliferative syndrome
Chediak-Higashi syndrome
Griscelli syndrome
DiGeorge syndrome
Metabolic disorders
Seborrheic dermatitis
Juvenile xanthogranuloma
Acquired immunodeficiency syndrome (AIDS)
Macrophage activation syndrome
Tuberculosis17

Workup

Laboratory Studies

  • Because natural killer (NK) cell function or activity is decreased in as many as 90% of patients with hemophagocytic lymphohistiocytosis (HLH), it is one of the most useful laboratory tests. NK cell number is usually not diagnostic.
  • In addition to pancytopenia, hypofibrinogenemia, and hypertriglyceridemias, as previously mentioned, other laboratory abnormalities have been linked to hemophagocytic lymphohistiocytosis. Ferritin has been observed as a marker for hemophagocytic lymphohistiocytosis, with the serum levels paralleling the course of the disease.18 Liver damage has also been reported as evidenced by hyperbilirubinemia, hypoalbuminemia, and elevated findings on liver function tests including aspartate aminotransferase (AST) and alanine aminotransferase (ALT).19
  • The presence of a PRF1 gene mutation can be determined based on flow cytometry by staining perforin contained in lymphocytes.

Imaging Studies

  • No specific imaging patterns are diagnostic of hemophagocytic lymphohistiocytosis.
  • CT or ultrasonography findings may include ascites, gallbladder wall thickening, increased periportal echogenicity, lymphadenopathy, and pleural effusion.
  • MRI may show CNS involvement, but the diagnosis is clinical and molecular, as is discussed below.20

Other Tests

In October 2002, Arico et al proposed an approach to the diagnostic workup of a patient with suspected hemophagocytic lymphohistiocytosis.3

  • A detailed clinical history should be obtained to exclude other associated conditions, such as metabolic disorders or the DiGeorge syndrome. However, if the diagnostic hemophagocytic lymphohistiocytosis criteria are fulfilled, and the findings for associated conditions are negative, initial testing involves perforin expression by NK cells using flow cytometry.
  • Patients lacking perforin expression should be analyzed for the PRF1 gene mutation.
  • NK cell activity should also be determined to aid in differentiating between the hemophagocytic lymphohistiocytosis subtypes.
  • Normal activity is suggestive of the reactive form of hemophagocytic lymphohistiocytosis rather than the familial type.
  • DNA samples and fresh cells are suggested to be stored in case of need for future use in familial cases for which no genetic defect can be identified.

Procedures

  • A skin biopsy can be performed for histological examination.
  • Lymph node biopsy, bone marrow biopsy, or liver biopsy may demonstrate the characteristic hemophagocytosis.

    A lymph node biopsy is performed. Note that a mar...

    A lymph node biopsy is performed. Note that a marking pen has been used to outline the node before removal and that a silk suture has been used to provide traction to assist the removal.

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    A lymph node biopsy is performed. Note that a mar...

    A lymph node biopsy is performed. Note that a marking pen has been used to outline the node before removal and that a silk suture has been used to provide traction to assist the removal.

Histologic Findings

  • A skin biopsy can assist in distinguishing this disorder from other systemic and potentially neoplastic diseases, such as Langerhans cell histiocytosis, myofibrosis, extramedullary hematopoiesis, and leukemia cutis.1 However, skin biopsy findings are usually not diagnostic and only rarely show hemophagocytosis.
  • Because hemophagocytosis must be demonstrated in the bone marrow, spleen, or lymph nodes, appropriate specimens should be collected for documentation.15  RBCs are affected more often than the white cells or platelets.
  • Findings in up to two thirds of initial bone marrow aspirates may be nondiagnostic; thus, a negative examination finding may not rule out hemophagocytic lymphohistiocytosis.
  • An additional bone marrow finding includes dyserythropoiesis, which has been observed in the absence of hemophagocytic histiocytes.
  • Additional studies, including lymph node biopsy, should be performed, and treatment should not be delayed if all other criteria have been met.21
  • Although problematic in a patient with a coagulopathy, a liver biopsy demonstrating a picture similar to chronic persistent hepatitis can support the diagnosis, as can the presence of mononuclear cells in the cerebrospinal fluid (CSF).

More on Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)

Overview: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Differential Diagnoses & Workup: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Treatment & Medication: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Follow-up: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Multimedia: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
References
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References

  1. Morrell DS, Pepping MA, Scott JP, et al. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. Sep 2002;138(9):1208-12. [Medline].

  2. Feldmann J, Le Deist F, Ouachee-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. Jun 2002;117(4):965-72. [Medline].

  3. Arico M, Allen M, Brusa S, et al. Haemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. Br J Haematol. Oct 2002;119(1):180-8. [Medline].

  4. Imashuku S, Ueda I, Teramura T, et al. Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients. Eur J Pediatr. May 2005;164(5):315-9. [Medline].

  5. Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest. Jan 2006;116(1):182-92. [Medline]. [Full Text].

  6. Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br J Haematol. Mar 2005;128(6):739-50. [Medline].

  7. Rieux-Laucat F, Le Deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med. Jan 20 2005;352(3):306-7; author reply 306-7. [Medline].

  8. Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. Feb 2005;203:165-79. [Medline].

  9. zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. Mar 15 2005;14(6):827-34. [Medline]. [Full Text].

  10. Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol. Sep 2001;114(4):761-9. [Medline].

  11. Malloy CA, Polinski C, Alkan S, et al. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. Jul 2004;24(7):458-60. [Medline].

  12. Sung L, King SM, Carcao M, et al. Adverse outcomes in primary hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. Oct 2002;24(7):550-4. [Medline].

  13. Ericson KG, Fadeel B, Andersson M, et al. Sequence analysis of the granulysin and granzyme B genes in familial hemophagocytic lymphohistiocytosis. Hum Genet. Jan 2003;112(1):98-9. [Medline].

  14. Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. Feb 1996;10(2):197-203. [Medline].

  15. [Guideline] Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. Feb 1991;18(1):29-33. [Medline].

  16. Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. Apr 1991;80(4):428-35. [Medline].

  17. Su NW, Chen CK, Chen GS, Hsieh RK, Chang MC. A case of tuberculosis-induced hemophagocytic lymphohistiocytosis in a patient under hemodialysis. Int J Hematol. Apr 2009;89(3):298-301. [Medline].

  18. Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of haemophagocytic lymphohistiocytosis. Expert Opin Pharmacother. Sep 2001;2(9):1437-48. [Medline].

  19. Hafsteinsdottir S, Jonmundsson GK, Kristinsson Jr, et al. Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation. Acta Paediatr. 2002;91(8):974-7. [Medline].

  20. Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. Sep 15 2002;100(6):2266-7. [Medline].

  21. Macheta M, Will AM, Houghton JB, Wynn RF. Prominent dyserythropoiesis in four cases of haemophagocytic lymphohistiocytosis. J Clin Pathol. Dec 2001;54(12):961-3. [Medline].

  22. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. Oct 1 2002;100(7):2367-73. [Medline].

  23. Emmenegger U, Spaeth PJ, Neftel KA. Intravenous immunoglobulin for hemophagocytic lymphohistiocytosis?. J Clin Oncol. Jan 15 2002;20(2):599-601. [Medline].

  24. Thompson PA, Allen CE, Horton T, Jones JY, Vinks AA, McClain KL. Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. May 2009;52(5):621-5. [Medline].

  25. Cooper N, Rao K, Gilmour K, et al. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. Feb 1 2006;107(3):1233-6. [Medline].

  26. Filipovich AH. Life-threatening hemophagocytic syndromes: current outcomes with hematopoietic stem cell transplantation. Pediatr Transplant. Dec 2005;9 Suppl 7:87-91. [Medline].

  27. Gupta AA, Tyrrell P, Valani R, Benseler S, Abdelhaleem M, Weitzman S. Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution. J Pediatr Hematol Oncol. Feb 2009;31(2):81-4. [Medline].

  28. Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics. May 2003;111(5 Pt 1):e636-40. [Medline].

  29. Chen RL, Lin KH, Lin DT, et al. Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. Feb 1995;89(2):282-90. [Medline].

  30. Goransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet. Mar 2001;68(3):590-7. [Medline].

  31. Pradalier A, Teillet F, Molitor JL, Drappier JC. [Macrophage activation syndrome, hemophagocytic syndrome]. Pathol Biol (Paris). Sep 2004;52(7):407-14. [Medline].

  32. Schmidt MH, Sung L, Shuckett BM. Hemophagocytic lymphohistiocytosis in children: abdominal US findings within 1 week of presentation. Radiology. Mar 2004;230(3):685-9. [Medline]. [Full Text].

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Further Reading

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Keywords

lymphohistiocytosis, hemophagocytic lymphohistiocytosis, HLH, familial hemophagocytic lymphohistiocytosis, FHL, familial erythrophagocytic lymphohistiocytosis, FEL, primary hemophagocytic lymphohistiocytosis, primary HLH, secondary hemophagocytic lymphohistiocytosis, secondary HLH, acquired hemophagocytic lymphohistiocytosis, acquired HLH, infection-associated hemophagocytic syndrome, IAHS, reactive HLH, hepatosplenomegaly, pancytopenia, lymphadenopathy, ascites, gallbladder wall thickening, treatment, diagnosis

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA
Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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