Skip to main content

Advertisement

SpringerLink
Log in

Hemophagocytic lymphohistiocytosis as a harbinger of aggressive lymphoma: a case series

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome, which can manifest either secondary to a variety of underlying causes, or due to a primary genetic defect. Malignancy is the most common underlying disease in adults with HLH, with lymphomas being the most common malignancy. Lymphoma-associated hemophagocytic syndrome (LAHS) typically follows a rapidly progressive clinical course and is associated with poor prognosis. We herein present four patients with HLH associated with aggressive lymphoma. At initial presentation, the underlying etiology of the HLH was unclear. Two patients were eventually diagnosed with anaplastic large cell lymphoma, while the other two had diffuse large B cell lymphoma. Two of the patients experienced rapid clinical deterioration, one at diagnosis and the other at relapse, and both died prior to diagnosis of lymphoma despite HLH-directed therapy. These cases highlight the need for intensive management in adults with HLH without a clear etiology, especially in cases when lymphoma-associated HLH is suspected. We describe the current pitfalls in diagnosis and treatment of LAHS and discuss possible ways to improve patient management.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383:1503–16.

    Article  PubMed  Google Scholar 

  2. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.

    Article  PubMed  Google Scholar 

  3. Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematol Am Soc Hematol Educ Progr. 2013;2013:605–11.

    Article  Google Scholar 

  4. Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood. 2015;125:2908–14.

    Article  CAS  PubMed  Google Scholar 

  5. Machaczka M, Vaktnas J, Klimkowska M, Hagglund H. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk Lymphoma. 2011;52:613–9.

    Article  PubMed  Google Scholar 

  6. Vick EJ, Patel K, Prouet P, Martin MG. Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy. Blood Adv. 2017;1:779–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Henter JI, Samuelsson-Horne A, Arico M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G, Histocyte S. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367–73.

    Article  CAS  PubMed  Google Scholar 

  8. Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, Fardet L. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 2014;127:1118–25.

    Article  PubMed  Google Scholar 

  9. Veerakul G, Sanpakit K, Tanphaichitr VS, Mahasandana C, Jirarattanasopa N. Secondary hemophagocytic lymphohistiocytosis in children: an analysis of etiology and outcome. J Med Assoc Thai. 2002;85(Suppl 2):530–41.

    Google Scholar 

  10. Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, Kumar A, Minkov M, La Rosee P, Weitzman S. Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte S: Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015;100:997–1004.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, Yamamoto K, Horiuchi H, Takada K, Ohshima K, Nakamura S, Kinukawa N, Oshimi K, Kawa K. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007;86:58–65.

    Article  PubMed  Google Scholar 

  12. Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Muller I, Suttorp M, Bernig T, Beutel K, Bode SF, Kentouche K, Kolb R, Langler A, Minkov M, Schilling FH, Schmid I, Vieth S, Ehl S, Zur Stadt U, Janka GE. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol. 2015;170:539–49.

    Article  PubMed  Google Scholar 

  13. Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma. 2000;38:121–30.

    Article  CAS  PubMed  Google Scholar 

  14. Takahashi N, Nakahachi A. Clinicopathological characteristics of adult patients with lymphoma-associated hemophagocytic syndrome in Japan. Rinsho Ketsueki. 1999;40:96–8.

    CAS  PubMed  Google Scholar 

  15. Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, Coppo P, Hejblum G. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66:2613–20.

    Article  PubMed  Google Scholar 

  16. Tamamyan GN, Kantarjian HM, Ning J, Jain P, Sasaki K, McClain KL, Allen CE, Pierce SA, Cortes JE, Ravandi F, Konopleva MY, Garcia-Manero G, Benton CB, Chihara D, Rytting ME, Wang S, Abdelall W, Konoplev SN, Daver NG. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: relation to hemophagocytosis, characteristics, and outcomes. Cancer. 2016;122:2857–66.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tsuji T, Hirano T, Yamasaki H, Tsuji M, Tsuda H. A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol. 2014;93:821–6.

    Article  CAS  PubMed  Google Scholar 

  18. Chen W, Zhang S, Zhang W, Yang X, Xu J, Qiu H, Zhang X, Li J. Elevated serum adenosine deaminase levels in secondary hemophagocytic lymphohistiocytosis. Int J Lab Hematol. 2015;37:544–50.

    Article  CAS  PubMed  Google Scholar 

  19. Kim JE, Kim CW, Park SH, Chi JG. Hemophagocytic syndrome associated with occult B-cell lymphoma: an autopsy case. J Korean Med Sci. 1998;13:77–80.

    PubMed  PubMed Central  Google Scholar 

  20. Chang Y, Cui M, Fu X, Han L, Zhang L, Li L, Li X, Sun Z, Wu J, Zhang X, Li Z, Nan F, Yan J, Sheng G, Zhang M. Lymphoma associated hemophagocytic syndrome: A single-center retrospective study. Oncol Lett. 2018;16:1275–84.

    PubMed  PubMed Central  Google Scholar 

  21. Jing-Shi W, Yi-Ni W, Lin W, Zhao W. Splenectomy as a treatment for adults with relapsed hemophagocytic lymphohistiocytosis of unknown cause. Ann Hematol. 2015;94:753–60.

    Article  PubMed  Google Scholar 

  22. Daver N, McClain K, Allen CE, Parikh SA, Otrock Z, Rojas-Hernandez C, Blechacz B, Wang S, Minkov M, Jordan MB, La Rosee P, Kantarjian HM. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017;123:3229–40.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Huang W, Hu L, Cen X, Li L, Wang J, Shen J, Wei N, Wang Z. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood. 2015;126:2186–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shin HJ, Chung JS, Lee JJ, Sohn SK, Choi YJ, Kim YK, Yang DH, Kim HJ, Kim JG, Joo YD, Lee WS, Sohn CH, Lee EY, Cho GJ. Treatment outcomes with CHOP chemotherapy in adult patients with hemophagocytic lymphohistiocytosis. J Korean Med Sci. 2008;23:439–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jordan M: A novel targeted approach to the treatment of hemophagocytic lymphohistiocytosis (HLH) with an anti-interferon gamma (IFNγ) monoclonal antibody (mAb), NI-0501: first results from a Pilot Phase 2 study in children with primary HLH. Blood. 2015;126: LBA-3.

    Google Scholar 

  26. Ehl S. Etoposide for HLH: the limits of efficacy. Blood. 2017;130:2692–3.

    Article  CAS  PubMed  Google Scholar 

  27. Salluh JI, Soares M. ICU severity of illness scores: APACHE, SAPS and MPM. Curr Opin Crit Care. 2014;20:557–65.

    Article  PubMed  Google Scholar 

  28. d’Amore F, Gaulard P, Trumper L, Corradini P, Kim WS, Specht L, Bjerregaard Pedersen M, Ladetto M, Committee EG. Peripheral T-cell lymphomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v108–115.

    Article  PubMed  Google Scholar 

  29. Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, Walewski J, Andre M, Johnson PW, Pfreundschuh M, Ladetto M, Committee EG. Diffuse large B-cell lymphoma (DLBCL): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v116–125.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Davidoff Cancer Center, Rabin Medical Center, Institute of Hematology, Beilinson Hospital, 49100, Petah Tikva, Israel

    Oren Pasvolsky, Karyn Revital Geiger, Iuliana Vaxman, Pia Raanani & Avi Leader

  2. Department of Internal Medicine B, Meir Medical Center, Kfar Saba, Israel

    Adi Zoref-Lorenz

  3. Hematology Institute and Blood Bank, Meir Medical Center, Kfar Saba, Israel

    Uri Abadi

  4. Department of Pathology, Rabin Medical Center, Petah Tikva, Israel

    Lucille Hayman

  5. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Oren Pasvolsky, Adi Zoref-Lorenz, Uri Abadi, Karyn Revital Geiger, Lucille Hayman, Iuliana Vaxman, Pia Raanani & Avi Leader

Authors
  1. Oren Pasvolsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adi Zoref-Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Uri Abadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karyn Revital Geiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lucille Hayman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Iuliana Vaxman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pia Raanani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Avi Leader
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oren Pasvolsky.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pasvolsky, O., Zoref-Lorenz, A., Abadi, U. et al. Hemophagocytic lymphohistiocytosis as a harbinger of aggressive lymphoma: a case series. Int J Hematol 109, 553–562 (2019). https://doi.org/10.1007/s12185-019-02623-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-019-02623-z

Keywords

Search

Navigation