Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias, including anemia, thrombocytopenia, neutropenia, and monocytopenia. HCL typically affects middle-aged men and presents with weakness, fatigue, opportunistic infections, and splenomegaly (which is often severe). Hairy cell leukemia is diagnosed by identifying hairy cells on a peripheral blood smear, characteristic cytopenias on CBC/DIFF, bone marrow biopsy, and immunophenotyping. Management consists of observation for asymptomatic patients and purine analogs for symptomatic patients. Both the disease itself and its treatments can cause immunosuppression, so prevention and prompt treatment of infections is also important.

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Overview

Definition

Hairy cell leukemia (HCL) is a rare, chronic B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have hair-like projections visible on microscopy.

Epidemiology

  • Incidence: 
    • 3 per 1 million persons per year in the United States
    • Rare: approximately 2% of all leukemia cases
  • Median age at diagnosis: approximately 50 years
  • Sex: male > female (4:1)
  • Race/ethnicity:
    • More common in Caucasians (incidence is 3× higher than in African Americans)
    • Rare in people of African and Japanese descent
  • First-degree family members have an 8× higher risk than the general population.

Etiology

Hairy cell leukemia is a clonal B-cell malignancy. The exact etiology is unknown, but several environmental exposures appear to increase the risk of developing HCL.

  • Exposures as possible causes:
    • Ionizing radiation
    • Organophosphorus pesticides
    • Farming and agricultural chemicals
    • Wood dust
    • Previous history of infectious mononucleosis
  • Familial relationships: due to sharing an HLA haplotype

Pathophysiology

The underlying issue in HCL is that the bone marrow produces far too many B lymphocytes, which crowd out the other types of blood cells. These abnormal B cells are unable to protect the body from infectious invaders the way normal B cells can.

Pathophysiology

  • B-cell lymphocytes with hair-like projections (hairy cells) undergo clonal proliferation
  • Hairy cells accumulate in:
    • Peripheral blood
    • Bone marrow
    • Spleen
    • Liver (less common)
    • Lymph nodes (uncommon)
  • Infiltration of the reticuloendothelial system:
    • Interferes with bone marrow function
    • Results in bone marrow failure and/or pancytopenia
  • Infiltrates the liver and spleen: results in organomegaly
  • Infections due to disease- and treatment-related immunosuppression:
    • Major cause of death
    • Infections may be bacterial, viral, fungal, or nontuberculous mycobacterial.

Pathogenesis

The pathogenesis is incompletely understood, but most cases appear to arise from late activated memory B cells, which acquire an activating BRAF V600E gene mutation.

  • BRAF V600E activating mutation (fundamental cause of biologic features of HCL): 
    • Results in constitutive activation of the RAF-MEK-ERK signaling pathway → leads to inhibition of apoptosis/enhanced cell survival
    • Acts as a molecular trigger and marker
    • Present in nearly 100% of cases
  • Hairy cells have the following features:
    • Expression of pan-B-cell surface antigens: CD19, CD20, and CD22
    • Nonexpression of immature B-cell markers CD10 and CD21
    • Expression of surface antigens that are not common on B cells, such as:
      • ≥1 Ig heavy chains and monotypic light chains
      • CD11c (typically found in monocytes and neutrophils)
      • CD25 (typically found in activated T cells)
      • CD103 (typically found in intraepithelial T cells)
  • Other mutations that may play a role in the molecular pathogenesis:
    • Overexpression of cyclin D1 protein (an important cell-cycle regulator)
    • Mutations in CDKN1B/p27 (a cell-cycle inhibitor)
    • Mutations in KLF2 (a transcription factor)
  • Associated with other systemic immunologic disorders:
    • Scleroderma
    • Polymyositis
    • Polyarteritis nodosa
    • Erythematous maculopapules
    • Pyoderma gangrenosum

Clinical Presentation

Symptoms related to cytopenias

  • Anemia (most common presenting symptoms):
    • Weakness
    • Fatigue
  • Thrombocytopenia → bleeding symptoms (⅓ of patients):
    • Ecchymosis
    • Epistaxis
    • Gingival bleeding
    • Menorrhagia
  • Neutropenia (⅓ of patients):
    • Fever (due to infection)
    • Infections

Symptoms related to infiltration in the spleen and liver

  • Splenomegaly causing abdominal discomfort (classic feature of HCL, seen in 80%–90% of patients):
    • Spleen may be massive: splenic edge extending > 8 cm beyond the left costal margin in 25% of patients 
    • Incidence and severity of splenomegaly may be decreasing as patients are being diagnosed earlier.
    • Spontaneous splenic rupture may occur → a medical emergency
  • Hepatomegaly and lymphadenopathy are not major features of HCL:
    • Hepatomegaly present in 20% of HCL patients
    • Lymphadenopathy present in 10% of HCL patients

Asymptomatic

  • Incidental finding during workup for unrelated cause
  • ¼ of patients

Diagnosis

The diagnosis is based on identifying hairy cells on a peripheral blood smear, immunohistochemistry, and/or flow cytometry and, potentially, a bone marrow biopsy.

Laboratory

Laboratory findings may include:

  • Peripheral blood smear: identification of hairy cells
    • Fine, hairlike cytoplasmic projections
    • Large mononuclear cells 
    • Nuclei are most commonly ovoid and eccentrically located.
    • Can be identified with a Romanowsky stain
  • CBC/DIFF:
    • Anemia (normochromic–normocytic): 85% of patients
    • Thrombocytopenia: 80%
    • Neutropenia: 80%
    • Monocytopenia: 80%
    • Leukocytosis (> 10,000 cells/µL): 10%–20% of patients
  • Other serologic testing:
    • BUN elevated: 30%
    • Liver function tests abnormal: 20%
    • Hepatitis B and C serologies for patients whose planned treatment is with rituximab
  • Flow cytometry of peripheral blood: can confirm immunophenotype of circulating B cells
Peripheral blood smear showing a hairy cell

Peripheral blood smear showing a hairy cell

Image: “Primary hairy cell leukemia/lymphoma of the breast: a case report and review of the literature” by Pilichowska M, Shariftabrizi A, Mukand-Cerro I, Miller K. License: CC BY 3.0

Biopsy

  • Difficult or impossible to aspirate (“dry tap”) due to HCL-induced marrow fibrosis
  • Requires a trephine bone marrow biopsy
  • Immunohistochemistry (IHC) staining:
    • Best method to determine diagnosis and extent of involvement 
    • To distinguish classic HCL from other peripheral small B-cell neoplasms
    • Assess for the BRAF V600E somatic mutation: highly sensitive but not specific to HCL (also detected in other entities)
    • Allows for assessment of typical HCL antigens: CD19, CD20, CD22, CD11c, CD25, and CD103
Bone marrow biopsy hairy cell leukemia

Bone marrow biopsy:
(a): Rather inconspicuous diffuse infiltrate of small mature lymphocytes (H&E, ×200).
(b): Immunohistochemical staining for CD20 reveals B-cell nature of the infiltrate (immunoperoxidase, ×200).

Image: “Bone marrow biopsy” by Pilichowska M, Shariftabrizi A, Mukand-Cerro I, Miller K. License: CC BY 3.0

Management

Goals of care

  • Improve symptoms.
  • Reverse cytopenias.
  • Prolong survival to a near-normal lifespan (though the disease is technically not curable)

Asymptomatic patients: observation

Asymptomatic patients should be observed rather than treated.

  • Can be observed for months or years
  • Approximately 10% of patients never require therapy.
  • No clear advantage to early treatment (risk of therapy may be greater than benefit)
  • Patients can be followed with interval histories, exams, and CBC/DIFF approximately every 3 months.

Symptomatic patients: treatment

Treatment is indicated in the following clinical situations:

  • Significant cytopenias: 
    • Absolute neutrophil count: < 1000/µL
    • Hemoglobin: < 11 g/dL
    • Platelet count: < 100,000/µL
  • Less severe cytopenias with the following:
    • Repeated infections
    • Clinical bleeding
    • Progressive lymphocytosis
  • Symptomatic splenomegaly (common)
  • Symptomatic adenopathy (uncommon)
  • Constitutional symptoms: fever and/or night sweats (signs of infection), weight loss

Treatment options

  • Purine analogs: cladribine, pentostatin
    • Cytotoxic effects on both B and T lymphocytes
    • 1st-line treatment for patients with normal renal function
    • Complete remission is achieved in > 90% of patients with progression-free survival (PFS) of 9‒11 years.
    • Induces a profound neutropenia → risk of infection due to treatment
  • Interferon alfa:
    • Inhibits cell growth, interferes with oncogene and surface antigen expression
    • Can be used as an alternative agent in patients who would benefit from ↑ blood counts prior to starting purine analog therapy.
    • Indications: 
      • Severe pancytopenia
      • Active infections
      • Pregnancy (though most can just be observed until after delivery)
  • Rituximab:
    • A monoclonal antibody against CD20 (found on B lymphocytes)
    • May be added to purine analog therapies to improve response
    • Associated with immunosuppression
    • Hepatitis B and C patients are at risk for reactivation and severe hepatitis.
  • Splenectomy:
    • May temporarily improve blood counts
    • Not done routinely, but indications include:
      • Palliative therapy for symptomatic splenomegaly (e.g., pain, severe enlargement)
      • Emergency treatment for splenic rupture
      • Pancytopenia due to splenic sequestration
      • Pregnancy
  • Other therapies:
    • Antibiotics to treat infections
    • Vaccines to prevent infections 
    • Transfusions to treat severe/symptomatic cytopenias (patients require irradiated blood products)

Prognosis

  • With treatment, patients can achieve long-term remission.
  • 5-year survival rate: 84%–94%
  • Long treatment-free periods
  • Patients with symptomatic relapses should be given further therapy.

Differential Diagnosis

  • Primary myelofibrosis: myeloproliferative neoplasm due to mutations in the hematopoietic stem cells that is characterized by chronic myeloproliferation with fibroblastic deposition, resulting in bone marrow fibrosis. Symptoms are primarily related to anemia and extramedullary hematopoiesis and include severe fatigue, weight loss, and hepatosplenomegaly. Laboratory studies show anemia (and other cytopenias), and bone marrow biopsy reveals extensive fibrosis. Management is with hematopoietic cell transplantation (HCT) and symptom-directed interventions.
  • CLL: mature B-cell neoplasm characterized by a progressive accumulation of functionally incompetent monoclonal B lymphocytes. Most cases of CLL are asymptomatic, with exam findings of painless lymphadenopathy and splenomegaly. CLL can be differentiated from HCL on the basis of differences in the peripheral blood smear, bone marrow biopsy, and immunophenotype of circulating lymphocytes on flow cytometry. Management is with observation for asymptomatic patients and chemotherapy in later stages. 
  • Aplastic anemia: rare life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow, in the absence of any abnormal cells, reflecting damage to the hematopoietic stem cells (HSCs). Aplastic anemia can be acquired or inherited. Multiple causes are known, including autoimmune damage to HSCs, medications, chemicals, whole-body radiation, viral infections, immune diseases, pregnancy, Fanconi anemia, and Down syndrome.
  • Mantle-cell lymphoma: aggressive, rare form of non-Hodgkin lymphoma (NHL) involving mature B cells. Mantle-cell lymphoma is caused by overexpression of cyclin D2 and tends to occur in older men. Patients tend to present with advanced disease and may have symptoms including fever, night sweats, and unintentional weight loss (B-cell symptoms). Diagnosis is by tissue biopsy and immunohistochemistry. Management may include chemotherapy, immunotherapy, and possibly hematopoietic stem cell transplantation.

References

  1. Tallman, M. (2021). Treatment of hairy cell leukemia. In Larson, R. (Ed.), UpToDate. Retrieved April 25, 2021, from https://www.uptodate.com/contents/treatment-of-hairy-cell-leukemia 
  2. Tallman, M., Aster, J. (2021). Clinical features and diagnosis of hairy cell leukemia. In Larson, R. (Ed.), UpToDate. Retrieved April 25, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-hairy-cell-leukemia 
  3. Besa, E. (2020). Hairy cell leukemia. In Krishnan, K. (Ed.), Medscape. Retrieved April 25, 2021, from https://reference.medscape.com/article/200580-overview
  4. Monnereau, A., Slager, S.L., Hughes, A.M., et al. (2014). Medical history, lifestyle, and occupational risk factors for hairy cell leukemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014(48), 115‒124. https://pubmed.ncbi.nlm.nih.gov/25174032/
  5. Orsi, L., Delabre, L., Monnereau, A., et al. (2009). Occupational exposure to pesticides and lymphoid neoplasms among men: results of a French case-control study. Occup Environ Med 66:291–298. https://pubmed.ncbi.nlm.nih.gov/19017688/
  6. Grever, M.R., Abdel-Wahab, O., Andritsos, L.A., et al. (2017). Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood 129:553–560. https://pubmed.ncbi.nlm.nih.gov/27903528/
  7. Kraut, E. (2011). Infectious complications in hairy cell leukemia. Leuk Lymphoma. 52 (Suppl 2), 50‒52. https://pubmed.ncbi.nlm.nih.gov/21504285/
  8. Grever, M.R. (2010). How I treat hairy cell leukemia. Blood 115(1):21‒28. https://pubmed.ncbi.nlm.nih.gov/19843881/

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