Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. The incidence of hairy cell leukemia (HCL) is 0.28-0.30 cases per 100,000 people in Europe and the United States. The prevalence is approximately 3.12 cases per 100,000 in Europe, with a lower prevalence in Asia, Africa, and the Middle East.
HCL has an indolent course, but patients frequently relapse. Despite this, with treatment, life expectancy is usually the same as that for the general population.
HCL was originally described as histiocytic leukemia, malignant reticulosis, or lymphoid myelofibrosis in publications dating back to the 1920s. The disease was formally named leukemic reticuloendotheliosis, and its characterization was significantly advanced by Bertha Bouroncle and colleagues at the Ohio State University College of Medicine in 1958. Its common name, which was coined in 1966, is derived from the "hairy" appearance of the cytoplasmic projections from malignant B cells under a microscope.
Signs and symptoms In HCL, the "hairy cells" (malignant B lymphocytes) accumulate in the bone marrow, interfering with the production of normal white blood cells, red blood cells, and platelets. Consequently, patients may develop infections related to low white blood cell count, anemia and fatigue due to a lack of red blood cells, or easy bleeding due to a low platelet count.
Platelet function may be somewhat impaired in HCL patients, although this does not appear to have any significant practical effect.
Patients with a high tumor burden may also have somewhat reduced levels of cholesterol, especially in patients with an enlarged spleen.
Those with HCL rarely have constitutional symptoms such as fevers, chills, weight loss or rigors. 20-30% may have opportunistic infections due to an impairment in immune function. Rarely, in recurrent disease, bone lesions may be present which can be confused for other malignancies such as multiple myeloma.
Cause As with many cancers, the cause of HCL is unknown. Exposure to tobacco smoke, ionizing radiation, or industrial chemicals (with the possible exception of diesel) does not appear to increase the risk of developing it. Farming and gardening correlate with an increased risk of HCL development in some studies which does not necessarily imply causation.
A 2011 study identified somatic BRAF V600E mutations in all 47 HCL patients studied, and no such mutations in the 193 peripheral B-cell lymphomas/leukemias other than HCL.
The U.S. Institute of Medicine (IOM) found a correlation that permits an association between exposure to herbicides and later development of chronic B-cell leukemias and lymphomas in general. The IOM report emphasizes that neither animal nor human studies indicate an association of herbicides with HCL specifically. However, the IOM extrapolated data from chronic lymphocytic leukemia and non-Hodgkin lymphoma to conclude that HCL and other rare B-cell neoplasms may share this risk factor.
Human T-lymphotropic virus 2 (HTLV-2) has been isolated in a small number of patients with the variant form of HCL. In the 1980s, HTLV-2 was identified in a patient with a T-cell lymphoproliferative disease; this patient later developed HCL, but HTLV-2 was not found in the hairy cell clones. There is no evidence that HTLV-II causes any sort of hematological malignancy, including HCL.
In a small population-based study, the incidence of HCL was higher in those who used or handled pesticides.
Pathophysiology Pancytopenia in HCL is caused primarily by bone marrow failure and enlargement of the spleen. Bone-marrow failure is caused by the accumulation of hairy cells and reticulin fibrosis in the bone marrow, as well as by the detrimental effects of dysregulated cytokine production. Splenomegaly reduces blood counts through sequestration, marginalization, and destruction of healthy blood cells inside the spleen.
Hairy cells are nearly mature B cells, which are activated clonal cells with signs of VH gene differentiation. They may be related to pre-plasma marginal zone B cells or memory B cells.
Cytokine production is disturbed in HCL. Hairy cells produce and thrive on TNF-alpha. This cytokine also suppresses normal production of healthy blood cells in the bone marrow.
Unlike healthy B cells, hairy cells express and secrete an immune system protein called interleukin-2 receptor (IL-2R). In HCL-V, only part of this receptor is expressed. As a result, disease status can be monitored by measuring changes in the amount of IL-2R in the blood serum.
Hairy cells respond to normal production of some cytokines by T cells with increased growth. Treatment with interferon-alpha suppresses the production of this pro-growth cytokine from T cells. A low level of T cells, which is commonly seen after treatment with cladribine or pentostatin, and the consequent reduction of these cytokines, is also associated with reduced levels of hairy cells.
Nearly all cases of HCL have the BRAF mutation V600E, and it is proposed that this is the disease's driver mutation. Until this point, only a few genomic imbalances had been found in the hairy cells, such as trisomy 5 had been found. The expression of genes is also dysregulated in a complex and specific pattern. The cells underexpress 3p24, 3p21, 3q13.3-q22, 4p16, 11q23, 14q22-q24, 15q21-q22, 15q24-q25, and 17q22-q24 and overexpress 13q31 and Xq13.3-q21. It has not yet been demonstrated that any of these changes have any practical significance to the patient.
Diagnosis The diagnosis of HCL may be suggested by abnormal results on a complete blood count (CBC), but additional testing is necessary to confirm the diagnosis. A CBC normally shows low counts for white blood cells, red blood cells, and platelets in HCL patients. However, if large numbers of hairy cells are in the bloodstream, then normal or even high lymphocyte counts may be found.
On physical examination, 80–90% of patients have an enlarged spleen, which can be massive. This is less likely among patients who are diagnosed at an early stage. Peripheral lymphadenopathy (enlarged lymph nodes) is uncommon (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding on computed tomography scans.
The most important laboratory finding is the presence of hairy cells in the bloodstream. Hairy cells are abnormal white blood cells with hair-like projections of cytoplasm; they can be seen by examining a blood smear or bone marrow biopsy specimen. The blood film examination is done by staining the blood cells with Wright's stain and looking at them under a microscope. Hairy cells are visible in this test in about 85% of cases. Along with the characteristic surface projections, hairy cells also have large amounts of cytoplasm, an oval (sometimes cleaved) nucleus with homogenous chromatin and without distinct nucleoli, giving the cells a "fried egg" appearance.
Most patients require a bone marrow biopsy for final diagnosis. The bone marrow biopsy is used both to confirm the presence of HCL and to exclude other diseases, such as Splenic marginal zone lymphoma or B-cell prolymphocytic leukemia. The bone marrow in HCL may show a diffuse infiltration of leukemic cells or an interstitial infiltration with partial preservation of fat and hematopoietic stem cells. The diagnosis can be confirmed by viewing the cells with a special stain known as tartrate resistant acid phosphatase (TRAP). More recently, DB44 testing assures more accurate results.
Definitely diagnosing HCL is also possible through flow cytometry on blood or bone marrow. The hairy cells are larger than normal and positive for CD19, CD20, CD22, CD11c, CD25, CD103, and FMC7 antigens. (CD103, CD22, and CD11c are strongly expressed.)
Annexin A1 and the BRAF v600E mutant protein are the most sensitive and specific cell markers associated with HCL. Diseases mimicking HCL are usually negative for both markers.
Hairy cell leukemia-variant (HCL-V), which shares some characteristics with B cell prolymphocytic leukemia (B-PLL), does not show CD25 (also called the interleukin-2 receptor, alpha).
The differential diagnoses include several kinds of anemia, including myelophthisis and aplastic anemia, and most kinds of blood neoplasms, including hypoplastic myelodysplastic syndrome, atypical chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, or idiopathic myelofibrosis.
Classification The "classic" form is often implied, but hairy cell leukemia-variant has also been described.
HCL-V Hairy cell leukemia-variant (HCL-V) is usually described as a prolymphocytic variant of HCL. It was first described in 1980. About 10% of people with HCL have this variant form of the disease, representing about 60-75 new cases of HCL-V each year in the U.S. While classic HCL primarily affects men, HCL-V is more evenly divided between males and females. While the disease can appear at any age, the median age at diagnosis is over 70.
Similar to B-cell prolymphocytic leukemia (B-PLL) in chronic lymphocytic leukemia, HCL-V is a more aggressive disease. Historically, it has been considered less likely to be treated successfully than is classic HCL, and remissions have tended to be shorter. The introduction of combination therapy with concurrent rituximab and cladribine therapy, though, has shown excellent results in early follow-up. As of 2016, this therapy is considered the first-line treatment of choice for many people with HCL-V.
Many older treatment approaches, such as interferon-alpha, the combination chemotherapy regimen "CHOP", and common alkylating agents such as cyclophosphamide, showed very little benefit. Pentostatin and cladribine administered as monotherapy (without concurrent rituximab) provide some benefit to many people with HCL-V, but typically induce shorter remission periods and lower response rates than when they are used in classic HCL. More than half of the people respond partially to splenectomy.
HCL-V differs from classic HCL principally in these respects: Higher white blood cell counts, sometimes exceeding 100,000 cells per microliter A more aggressive course of disease requiring more frequent treatment Hairy cells with an unusually large nucleolus for their size Production of little excess fibronectin produced by classic hairy cells to interfere with bone marrow biopsies Low or no cell-surface expression of CD25 (interleukin-2 [IL-2] receptor alpha chain, or p55).
Low levels of CD25, a part of the receptor for a key immunoregulating hormone, may explain why HCL-V cases are generally much more resistant to treatment by immune-system hormones.
HCL-V, which usually features a high proportion of hairy cells without a functional p53 tumor suppressor gene, is somewhat more likely to transform into a higher-grade malignancy. A typical transformation rate of 5-6% has been postulated in the UK, similar to the Richter's transformation rate for splenic lymphoma with villous lymphocytes (SLVL) and CLL. Among HCL-V patients, the most aggressive cases normally have the least amount of p53 gene activity. Hairy cells without the p53 gene tend, over time, to displace the less aggressive p53(+) hairy cells.
Some evidence suggests that a rearrangement of the immunoglobulin gene VH4-34, which is found in about 40% of HCL-V patients and 10% of classic HCL patients, may be a more important poor prognostic factor than variant status, with HCL-V patients without the VH4-34 rearrangement responding about as well as classic HCL patients.
Treatment Several treatments are available, and successful control of the disease is common.