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Clinical features and diagnosis of hairy cell leukemia

Martin S Tallman, MD
Jon C Aster, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Rebecca F Connor, MD


Hairy cell leukemia (HCL) is an uncommon chronic B cell lymphoproliferative disorder (lymphoid neoplasm) characterized by the accumulation of small mature B cell lymphoid cells with abundant cytoplasm and "hairy" projections within the peripheral blood, bone marrow, and splenic red pulp. This typically results in splenomegaly and a variable reduction in the production of normal red blood cells, platelets, mature granulocytes, and monocytes. The increased production of malignant cells, along with a reduction in these mature elements, results in a variety of systemic consequences, including splenomegaly, anemia, bleeding, and an increased risk of infection.

The clinical features and diagnosis of HCL will be reviewed here; treatment of this disorder is discussed separately. (See "Treatment of hairy cell leukemia".)


The pathogenesis of hairy cell leukemia (HCL) is largely unknown. However, studies indicate that virtually all cases are associated with a V600E activating mutation in the serine/threonine kinase BRAF (an isoform of RAF), implicating BRAF signaling in HCL. Response to BRAF inhibitor therapy has been described in a patient with refractory HCL [1], in line with the idea that oncogenic BRAF signaling enhances HCL proliferation and survival.

Exposures to ionizing radiation, Epstein-Barr virus, organic chemicals, woodworking, and farming have been mentioned as possible causes [2]. A number of familial cases have been described, with family members sharing the same HLA haplotype [3,4].

Cell of origin — HCL is postulated to arise from a late, activated memory B cell. The malignant cell in HCL has the following features that are consistent with a cell at a late stage of B cell development, such as a preplasma cell or postgerminal center memory B cell [5,6]:


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Literature review current through: Sep 2016. | This topic last updated: Sep 8, 2016.
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  1. Dietrich S, Glimm H, Andrulis M, et al. BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med 2012; 366:2038.
  2. Oleske D, Golomb HM, Farber MD, Levy PS. A case-control inquiry into the etiology of hairy cell leukemia. Am J Epidemiol 1985; 121:675.
  3. Ward FT, Baker J, Krishnan J, et al. Hairy cell leukemia in two siblings. A human leukocyte antigen-linked disease? Cancer 1990; 65:319.
  4. Colovic MD, Jankovic GM, Wiernik PH. Hairy cell leukemia in first cousins and review of the literature. Eur J Haematol 2001; 67:185.
  5. Tiacci E, Liso A, Piris M, Falini B. Evolving concepts in the pathogenesis of hairy-cell leukaemia. Nat Rev Cancer 2006; 6:437.
  6. Miranda RN, Cousar JB, Hammer RD, et al. Somatic mutation analysis of IgH variable regions reveals that tumor cells of most parafollicular (monocytoid) B-cell lymphoma, splenic marginal zone B-cell lymphoma, and some hairy cell leukemia are composed of memory B lymphocytes. Hum Pathol 1999; 30:306.
  7. Cleary ML, Wood GS, Warnke R, et al. Immunoglobulin gene rearrangements in hairy cell leukemia. Blood 1984; 64:99.
  8. Foroni L, Catovsky D, Luzzatto L. Immunoglobulin gene rearrangements in hairy cell leukemia and other chronic B cell lymphoproliferative disorders. Leukemia 1987; 1:389.
  9. Korsmeyer SJ, Greene WC, Cossman J, et al. Rearrangement and expression of immunoglobulin genes and expression of Tac antigen in hairy cell leukemia. Proc Natl Acad Sci U S A 1983; 80:4522.
  10. Arons E, Roth L, Sapolsky J, et al. Evidence of canonical somatic hypermutation in hairy cell leukemia. Blood 2011; 117:4844.
  11. Haglund U, Juliusson G, Stellan B, Gahrton G. Hairy cell leukemia is characterized by clonal chromosome abnormalities clustered to specific regions. Blood 1994; 83:2637.
  12. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011; 364:2305.
  13. Boyd EM, Bench AJ, van 't Veer MB, et al. High resolution melting analysis for detection of BRAF exon 15 mutations in hairy cell leukaemia and other lymphoid malignancies. Br J Haematol 2011; 155:609.
  14. Arcaini L, Zibellini S, Boveri E, et al. The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms. Blood 2012; 119:188.
  15. Schnittger S, Bacher U, Haferlach T, et al. Development and validation of a real-time quantification assay to detect and monitor BRAFV600E mutations in hairy cell leukemia. Blood 2012; 119:3151.
  16. Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood 2012; 119:3330.
  17. Shao H, Calvo KR, Grönborg M, et al. Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria. Leuk Res 2013; 37:401.
  18. Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 2012; 119:192.
  19. Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012; 120:2700.
  20. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010; 116:1919.
  21. Raess PW, Mintzer D, Husson M, et al. BRAF V600E is also seen in unclassifiable splenic B-cell lymphoma/leukemia, a potential mimic of hairy cell leukemia. Blood 2013; 122:3084.
  22. Pettirossi V, Santi A, Imperi E, et al. BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood 2015; 125:1207.
  23. Waterfall JJ, Arons E, Walker RL, et al. High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias. Nat Genet 2014; 46:8.
  24. Burthem J, Cawley JC. The bone marrow fibrosis of hairy-cell leukemia is caused by the synthesis and assembly of a fibronectin matrix by the hairy cells. Blood 1994; 83:497.
  25. Gruber G, Schwarzmeier JD, Shehata M, et al. Basic fibroblast growth factor is expressed by CD19/CD11c-positive cells in hairy cell leukemia. Blood 1999; 94:1077.
  26. Shehata M, Schwarzmeier JD, Hilgarth M, et al. TGF-beta1 induces bone marrow reticulin fibrosis in hairy cell leukemia. J Clin Invest 2004; 113:676.
  27. Lindemann A, Ludwig WD, Oster W, et al. High-level secretion of tumor necrosis factor-alpha contributes to hematopoietic failure in hairy cell leukemia. Blood 1989; 73:880.
  28. Barak V, Nisman B, Polliack A. The tumor necrosis factor family and and correlation with disease activity and response to treatment in hairy cell leukemia. Eur J Haematol 1999; 62:71.
  29. Eigler A, Waller-Fontaine K, Moeller J, et al. The hairy cell leukemia cell line Eskol spontaneously synthesizes tumor necrosis factor-alpha and nitric oxide. Leuk Res 1998; 22:501.
  30. Basso K, Liso A, Tiacci E, et al. Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors. J Exp Med 2004; 199:59.
  31. Falini B, Tiacci E, Liso A, et al. Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection of annexin A1 (ANXA1). Lancet 2004; 363:1869.
  32. Dietrich S, Hüllein J, Lee SC, et al. Recurrent CDKN1B (p27) mutations in hairy cell leukemia. Blood 2015; 126:1005.
  33. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107:265.
  34. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer 2011; 105:1684.
  35. Dores GM, Matsuno RK, Weisenburger DD, et al. Hairy cell leukaemia: a heterogeneous disease? Br J Haematol 2008; 142:45.
  36. Catovsky D. Hairy-cell leukaemia and prolymphocytic leukaemia. Clin Haematol 1977; 6:245.
  37. Golomb HM, Catovsky D, Golde DW. Hairy cell leukemia: a clinical review based on 71 cases. Ann Intern Med 1978; 89:677.
  38. Grever MR. How I treat hairy cell leukemia. Blood 2010; 115:21.
  39. Hasler P, Kistler H, Gerber H. Vasculitides in hairy cell leukemia. Semin Arthritis Rheum 1995; 25:134.
  40. Westbrook CA, Golde DW. Autoimmune disease in hairy-cell leukaemia: clinical syndromes and treatment. Br J Haematol 1985; 61:349.
  41. Rosen DS, Smith S, Gurbuxani S, Yamini B. Extranodal hairy cell leukemia presenting in the lumbar spine. J Neurosurg Spine 2008; 9:374.
  42. Summers TA, Jaffe ES. Hairy cell leukemia diagnostic criteria and differential diagnosis. Leuk Lymphoma 2011; 52 Suppl 2:6.
  43. Daniel MT, Flandrin G. Fine structure of abmormal cells in hairy cell (tricholeukocytic) leukemia, with special reference to their in vitro phagocytic capacity. Lab Invest 1974; 30:1.
  44. Golomb HM, Braylan R, Polliack A. 'Hairy' cell leukaemia (leukaemic reticuloendotheliosis): a scanning electron microscopic study of eight cases. Br J Haematol 1975; 29:455.
  45. Bartl R, Frisch B, Hill W, et al. Bone marrow histology in hairy cell leukemia. Identification of subtypes and their prognostic significance. Am J Clin Pathol 1983; 79:531.
  46. Brunning RD, McKenna RW. Small lymphocytic leukemias and related disorders. In: Tumors of the bone marrow, Atlas of Tumor Pathology, Third Series, Fascicle 9, Armed Forces Institute of Pathology, Washington, DC 1994. p.254.
  47. Burke JS, Rappaport H. The diagnosis and differential diagnosis of hairy cell leukemia in bone marrow and spleen. Semin Oncol 1984; 11:334.
  48. Burke JS. The value of the bone-marrow biopsy in the diagnosis of hairy cell leukemia. Am J Clin Pathol 1978; 70:876.
  49. Pangalis GA, Kittas C, Viniou N, et al. Hairy cell leukemia: bone marrow changes following splenectomy and alpha-interferon therapy. Leukemia 1987; 1:343.
  50. Katayama I. Bone marrow in hairy cell leukemia. Hematol Oncol Clin North Am 1988; 2:585.
  51. Lee WM, Beckstead JH. Hairy cell leukemia with bone marrow hypoplasia. Cancer 1982; 50:2207.
  52. VanderMolen LA, Urba WJ, Longo DL, et al. Diffuse osteosclerosis in hairy cell leukemia. Blood 1989; 74:2066.
  53. Verhoef GE, De Wolf-Peeters C, Zachee P, Boogaerts MA. Regression of diffuse osteosclerosis in hairy cell leukaemia after treatment with interferon. Br J Haematol 1990; 76:150.
  54. Leung R, Lopes D, Lam C, et al. Diffuse osteosclerosis complicating hairy cell leukemia. J Clin Oncol 2010; 28:e203.
  55. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
  56. Yam LT, Li CY, Lam KW. Tartrate-resistant acid phosphatase isoenzyme in the reticulum cells of leukemic reticuloendotheliosis. N Engl J Med 1971; 284:357.
  57. Forconi F, Sahota SS, Raspadori D, et al. Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing. Blood 2001; 98:1174.
  58. Robbins BA, Ellison DJ, Spinosa JC, et al. Diagnostic application of two-color flow cytometry in 161 cases of hairy cell leukemia. Blood 1993; 82:1277.
  59. Möller P, Mielke B, Moldenhauer G. Monoclonal antibody HML-1, a marker for intraepithelial T cells and lymphomas derived thereof, also recognizes hairy cell leukemia and some B-cell lymphomas. Am J Pathol 1990; 136:509.
  60. Cornfield DB, Mitchell Nelson DM, Rimsza LM, et al. The diagnosis of hairy cell leukemia can be established by flow cytometric analysis of peripheral blood, even in patients with low levels of circulating malignant cells. Am J Hematol 2001; 67:223.
  61. Barak V, Ginzburg M, Kalickman I, Polliack A. Serum soluble interleukin-2 receptor levels are associated with clinical disease status and histopathological grade in non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Leuk Lymphoma 1992; 7:431.
  62. Ellison DJ, Sharpe RW, Robbins BA, et al. Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia. Blood 1994; 84:4310.
  63. Hakimian D, Tallman MS, Kiley C, Peterson L. Detection of minimal residual disease by immunostaining of bone marrow biopsies after 2-chlorodeoxyadenosine for hairy cell leukemia. Blood 1993; 82:1798.
  64. Hounieu H, Chittal SM, al Saati T, et al. Hairy cell leukemia. Diagnosis of bone marrow involvement in paraffin-embedded sections with monoclonal antibody DBA.44. Am J Clin Pathol 1992; 98:26.
  65. Wheaton S, Tallman MS, Hakimian D, Peterson L. Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine. Blood 1996; 87:1556.
  66. Forconi F, Sozzi E, Cencini E, et al. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood 2009; 114:4696.
  67. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375.
  68. Kroft SH, Finn WG, Peterson LC. The pathology of the chronic lymphoid leukaemias. Blood Rev 1995; 9:234.
  69. Galton DA, Goldman JM, Wiltshaw E, et al. Prolymphocytic leukaemia. Br J Haematol 1974; 27:7.
  70. Melo JV, Catovsky D, Gregory WM, Galton DA. The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. IV. Analysis of survival and prognostic features. Br J Haematol 1987; 65:23.
  71. Melo JV, Catovsky D, Galton DA. The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. I. Clinical and laboratory features of 300 patients and characterization of an intermediate group. Br J Haematol 1986; 63:377.
  72. Isaacson PG, Matutes E, Burke M, Catovsky D. The histopathology of splenic lymphoma with villous lymphocytes. Blood 1994; 84:3828.
  73. Matutes E, Morilla R, Owusu-Ankomah K, et al. The immunophenotype of splenic lymphoma with villous lymphocytes and its relevance to the differential diagnosis with other B-cell disorders. Blood 1994; 83:1558.
  74. Mulligan SP, Matutes E, Dearden C, Catovsky D. Splenic lymphoma with villous lymphocytes: natural history and response to therapy in 50 cases. Br J Haematol 1991; 78:206.
  75. Troussard X, Valensi F, Duchayne E, et al. Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC). Br J Haematol 1996; 93:731.
  76. Catovsky D, O'Brien M, Melo JV, et al. Hairy cell leukemia (HCL) variant: an intermediate disease between HCL and B prolymphocytic leukemia. Semin Oncol 1984; 11:362.
  77. Cawley JC, Burns GF, Hayhoe FG. A chronic lymphoproliferative disorder with distinctive features: a distinct variant of hairy-cell leukaemia. Leuk Res 1980; 4:547.
  78. Sainati L, Matutes E, Mulligan S, et al. A variant form of hairy cell leukemia resistant to alpha-interferon: clinical and phenotypic characteristics of 17 patients. Blood 1990; 76:157.
  79. Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood 2009; 114:4687.
  80. Kiel MJ, Velusamy T, Betz BL, et al. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J Exp Med 2012; 209:1553.