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Despite the significant progress that has been made regarding the incidence, risk factors, and symptoms of hairy cell leukemia, diagnosis remains a challenge, due in part to the low incidence of the disease.
Hairy cell leukemia (HCL) is a rare lymphoid malignancy.1 HCL accounts for only 2% of all lymphoid leukemias, with 600 to 800 new cases diagnosed in the United States each year.1,2 The name of the disease is attributed to the appearance of the hairlike projections from mononuclear cells, which resemble a frayed cell surface.1 The majority (80%) of patients achieve a complete response with single-agent purine nucleoside analog treatment with either pentostatin or cladribine as a first-line therapy.3 Minimal residual disease, which has been reported in nearly 40% of patients treated with a single dose of cladribine,4 may be associated with relapse.5,6 Between 34% and 42% of patients with HCL relapse at 5 to 10 years after initial treatment, and additional therapeutic options are available.3
This article reviews the discovery and characterization of HCL, its epidemiology, and the clinical presentation of the disease. The next article will examine the pathogenesis, diagnostic criteria, and prognosis of this rare lymphoid neoplasm.
Historical Perspective on the Characterization of Hairy Cell Leukemia
In the 1920s, the term “leukemic reticuloendotheliosis” was used to describe a case of leukemia that showed hyperplasia of the reticulum tissue in blood-forming organs, with reticuloendothelial cells detected in the bloodstream.7 It was recognized as a unique hematologic malignancy, with the typical presentation thought to include pancytopenia, circulating monocytic cells, and splenomegaly.8 Further attempts to guide classification of the disorder with the use of microscopy revealed 3 additional subtypes of reticuloendotheliosis that involve primitive cells, monocytoid cells, and lymphoid cells.8
Several key studies have contributed to our understanding of leukemic reticuloendotheliosis as a clinical entity. Gosselin and colleagues described the clinical course of the disease, having reviewed smears of bone marrow, blood, and splenic aspirates from 49 patients with leukemic reticuloendotheliosis seen at the Mayo Clinic in Rochester, Minnesota, between 1944 and 1953.9 The investigators noted that the presenting symptoms of leukemic reticuloendotheliosis were typically nonspecific, including a history of flulike illness or respiratory infection; fatigability, low-grade fever, night sweats, and weight loss; splenomegaly and occasionally hepatomegaly; mild or variable generalized lymphadenopathy; and such cutaneous manifestations as generalized erythroderma and other nonspecific skin lesions.9
Hematologic findings in the peripheral blood and bone marrow smears from the patients evaluated included the presence of reticuloendothelial cells, reticular lymphocytes, transitional stages to mature lymphocytes, anemia, leukopenia, thrombocytopenia, and hypoplasia of the bone marrow.9 The clinical course of the disease was variable and could be divided into acute, subacute, and chronic forms.9 The acute form was most commonly observed in patients with the monocytic and primitive cell types, and the rapidly progressive course could result in death within a few weeks to 6 months.9 The subacute form of the disease was the most frequently encountered, with patients typically experiencing 2 successive phases. In the first phase, the disease is slowly progressive, which is followed by the second phase—acute exacerbations and death.9 Lastly, the chronic form of the disease involved patients in whom the symptoms were mild and almost latent for prolonged periods, followed by an exacerbation of weakness and fatigability, with relapses occurring in varying intensities and durations.9
The first study to fully characterize leukemic reticuloendotheliosis, which was reported in 1958, described 26 patients with the disease and their detailed follow-up.7,8 The researchers estimated that leukemic reticuloendotheliosis accounted for approximately 2% of all leukemias treated annually at the The Ohio State University Hematology Department in Columbus, Ohio.7 Of the 26 patients evaluated, 21 were male and 5 were female.7 The disease onset was usually insidious, with common presenting symptoms including easy fatigability and weakness; hemorrhagic diathesis manifested by repeated epistaxis, spontaneous purpura, and ecchymosis; left upper quadrant pain; low-grade fever; and infections.7 The most common physical findings included splenomegaly (96%), hepatomegaly (58%), infections (58%), and hemorrhagic manifestations (20%).7 Hematologic features most frequently involved normocytic normochromic anemia; leukopenia; thrombocytopenia; and hypocellular bone marrow with predominantly reticulum cells.7 Free reticulum cells or histiocytes, which were detected in the bone marrow or peripheral blood in all patients, confirmed the diagnosis.7
This series of patients with leukemic reticuloendotheliosis contributed substantially to our understanding of the morphologic characteristics of the malignant cells that trigger the disease.8 With the use of supravital staining on living preparations, pseudopods protruding from the cytoplasm were observed, creating the appearance of a serrated or lacelike border, with long, irregular extensions.7 Published photographs of these cells are now recognized as the classic “hairy cells” for which HCL was later named.7,8
The investigators observed a variable clinical course, with 31% of patients experiencing a rapidly progressive course, while 46% had extremely mild disease for prolonged periods, followed by exacerbations, and 23% experienced a subacute course.7 The survival from the onset of symptoms was <1 year in 4 patients; 1 to 2 years in 6 patients; 2 to 5 years in 4 patients; 7 years in 1 patient; and 15 years, 10 months in 1 patient.7
Despite these discoveries, progress to reach a scientific consensus regarding the cell of origin, diagnostic criteria, and the classification of HCL among other hematologic malignancies was slow.8 Leukemic reticuloendotheliosis was often confused with other types of leukemia, including histiocytic medullary reticulosis, malignant histiocytosis, and the leukemic phase of reticulum-cell sarcoma.10 In 1974, Catovsky and colleagues reviewed 170 published reports and 30 cases in detail from their own medical center, along with selected cases that appeared to be clearly distinct from other disorders.10
Detailed cytochemical characterization allowed Catovsky and coworkers to propose the diagnostic criteria of leukemic reticuloendotheliosis. The diagnostic criteria included the presence of hairy cells in the bone marrow, peripheral blood, or other organs, such as the spleen, liver, or lymph nodes.10 In addition, the hairy cells needed to test negative for myeloperoxidase, Sudan Black B, and chloroacetate esterase, all of which are cytochemical reactions characteristic of granulocytic cells.10 Moreover, naphthol AS-acetate esterase should yield negative to moderately positive results. Together with a lack of inhibition by sodium fluoride, these findings can distinguish hairy cells from leukemic monocytes. Furthermore, hairy cells should lack lysozyme activity—another marker of monocytic differentiation.10 The periodic acid Schiff reaction usually presents weakly positive with the appearance of fine, small granules, in contrast to the stronger reaction and larger granules observed in leukemic lymphocytes.10 A majority of hairy cells were shown to exhibit positive acid phosphatase reactions with tartrate resistance.10 In contrast, weak to moderate acid phosphatase activity would be expected in lymphocytes and strong activity would be associated with monocytes. Nevertheless, the acid phosphatase activities in both cell types would be completely inhibited by L(+)-tartaric acid.10 Thus, tartrate-resistant acid phosphatase activity allowed leukemic reticuloendotheliosis to be distinguished from other lymphocytic or monocytic proliferative disorders.
Catovsky and colleagues also studied the appearance of hairy cells under electron microscopy.10 The majority of hairy cells exhibited numerous cytoplasmic villi.10 The dense nuclear chromatin, sparse and rough endoplasmic reticulum, and lack of lysosomes and phagocytic or pinocytotic activity in these hairy cells suggested a lymphocytic origin.10 The cytoplasmic ribosome-lamellae complex in the hairy cell may be a distinct feature; it was present in 50% of the cases of leukemic reticuloendotheliosis and was suggested by the authors to be potential marker of the disease.10
Jansen and Hermans further contributed to the characterization of HCL by developing a clinical staging system based on a retrospective analysis of clinical outcomes in 391 patients.11 The investigators reported that the number of hairy cells was a factor that contributed to patient survival.11 As the number of hairy cells was based on interobserver variation and the duration of symptoms was prone to subjective patient reports, the researchers used only the degree of splenomegaly and the patient’s hemoglobin level to develop a model for survival prediction.11 A clinical staging system that comprised 3 prognostic groups was proposed, based on hemoglobin level and spleen size.11 The investigators also found that hemoglobin levels contributed significantly to the prognostic value following splenectomy.11
These early efforts to characterize HCL have contributed to our current understanding of the disease. The lack of available advanced technologies during this period of initial work, however, diminished our full understanding of the molecular characteristics of HCL. Techniques in immunophenotyping, flow cytometry, and genetic sequencing further elucidated the cell of origin of HCL, as well as our current knowledge of the antigens and markers expressed on the hairy cell. This knowledge informed a broader understanding of the growth properties and infiltration patterns of HCL, along with targets of treatment.
Incidence and Prevalence
HCL is a rare hematologic neoplasm. According to 1992 to 2001 data, approximately 1000 new cases of HCL are diagnosed each year in the United States,12 HCL accounts for 2% of all leukemias and 1% of all lymphoid neoplasms in the United States.7,12-14 Because most patients achieve a durable initial response to therapy, the prevalence of HCL is actually considerably higher.15
The male predominance of HCL has been well documented, with a male-to-female ratio of about 4:1.14 Data suggest that in the United States, the median age at diagnosis is 50 years (range, 28 to 79 years).16
The incidence of HCL varies according to ethnicity and genetic background. The disease is less common among individuals of Asian, African, and Arab descent,13,14,17 and it is more common in Caucasians, particularly among Jewish individuals.13,14 Data from one study reported the age-adjusted incidence of HCL (per 1 million population ≥20 years of age) in men was 0.7 in blacks, 1.5 in Asians, and 3.5 in non-Hispanic whites.13 In women, the age-adjusted incidence was 0.3 in Asians and 0.8 in non-Hispanic whites (per 1 million population ≥20 years of age).13 The incidence of HCL is approximately 1.5 times higher in Jewish men compared with non-Jewish men.13,17
Although several large studies have attempted to elucidate occupational, lifestyle, and environmental risk factors associated with HCL, the definitive risk factors have not yet been identified.14
An early pooled analysis of 2 Swedish case-control studies that combined patients with both non-Hodgkin lymphoma (NHL) and HCL suggested that exposure to herbicides, fungicides, insecticides, and impregnating agents was associated with an increased risk for disease in univariate models.18 In line with these results, a study that was conducted in Mexico revealed that although the incidence of HCL was lower in that country than in the United States, significantly more patients with HCL resided in the northern farming and agricultural areas (3.07%), compared with the central (1.03%) or southeastern regions (0%; P <.05).19
Most recently, the International Lymphoma Epidemiology Consortium (InterLymph) NHL Subtypes Project investigated the association of lifestyle and environmental risk factors with HCL in a pooled analysis of 5 case-control studies, which included 154 cases of HCL and 8834 controls, from Europe and Australia.20 The pooled analysis revealed that those individuals who had ever worked as a mixed animal and crop farmer had an increased risk for HCL (OR, 2.34; 95% CI, 1.36 to 4.01).20 In addition, a dose-response relationship was observed (based on a small number of cases), with a longer duration of occupation as a farmer associated with a higher risk for HCL. A positive trend was observed for those who were employed as a mixed animal and crop farmer (OR, 1.82; 95% CI, 0.85 to 3.88 for 1 to 10 years and OR, 2.98; 95% CI, 1.50 to 5.93 for >10 years; P = .025).20
Data suggest that cigarette smoking may be inversely associated with HCL (OR, 0.51; 95% CI, 0.37 to 0.71).20 The frequency and duration of cigarette smoking, as well as lifetime cigarette exposure, were all significantly associated with a reduced risk for the disease
(P <.001).20 It has been hypothesized that smoking may alter metabolic pathways of toxic endogenous or exogenous metabolites, modulate inflammatory responses, and induce apoptosis involved in the pathogenesis of HCL.20 How these processes may influence the development of HCL remains to be elucidated.
Genetic Risk Factors
There have been rare anecdotal case reports of familial HCL.14 Although in some cases of familial HCL, affected family members have been reported to share human leukocyte antigen (HLA) haplotypes. a specific HLA antigen or haplotype common to most cases of familial HCL has not been identified.21 Familial HCL is unlikely to occur due to random patterning.22 Currently, insufficient data are available to establish genetic susceptibility to HCL independent of a shared environment.14,22 Similarly, the male predominance of HCL may reflect genetic influences and/or environmental and occupation risks.14
Clinical Presentation of Disease
Patients with HCL may present with a number of clinical features. Many patients report weakness, fatigue, and symptoms related to pancytopenia (eg, easy bruising/bleeding, infections) and splenomegaly (eg, left upper quadrant pain) (Figure 1).23 Although early studies reported that splenomegaly, often massive, was present in >90% of patients, current earlier detection of HCL through routine blood work has made splenomegaly a less prominent feature of the disease.23,24 Rather, patients may more commonly present with the disease because of incidental findings of pancytopenia.24 Replacement of marrow by hairy cells, reticulin fibrosis, and the secretion of tumor necrosis factor-α by the hairy cells may lead to bone marrow failure.23,25 Sequestration of blood cells due to splenomegaly also contributes to pancytopenia.23
Other less common presenting symptoms of HCL include adenopathy, which may be related to the disease duration.26 Autoimmune hemolytic anemia or immune thrombocytopenia purpura appear to occur rarely.27,28 Lytic bone lesions have also been reported but are considered an unusual finding.29
The most characteristic laboratory features of HCL and their relative incidence are listed in Figure 2.23 A majority of patients present with marked cytopenias, with one-third of patients having a hemoglobin level of <8.5 g/L, neutrophil count of <0.5 x 109/L, and platelets count of <50 x 109/L.23 Severe pancytopenias have decreased over the past 2 decades, however, and account for <10% of patients who present with HCL. When patients present with anemia it is often mild in degree, with about 80% of patients having a hemoglobin level of >10 g/dL.23 Moderate to severe neutropenia is reported in approximately 60% of cases and thrombocytopenia in about 50% of cases.23
Hairy cells in the peripheral blood are present in >85% of patients.23 Although monocytopenia is almost ubiquitous in HCL, automated hemogram analyzers may incorrectly classify hairy cells as monocytes because of the increased size and light scatter of these cells.23,30 Thus, monocytopenia may be masked without a review of peripheral blood smears.30 Lymphocytosis is uncommon and occurs in only about 7% of cases,23 and an increased mean erythrocyte blood cell volume can also be observed.23 Alkaline phosphatase may be increased because of liver involvement,23 whereas serum lactate dehydrogenase levels are typically normal.31 Hypocholesterolemia is frequently observed among patients with HCL, although this finding is nonspecific in nature.23
Prior to the advent of effective treatments for HCL, infections were a leading cause of death among patients with the disease.23 Current data suggest that one-third of patients will develop ≥1 infections during the course of their disease. Among patients with infections, roughly two-thirds of the infections are considered serious.23 Approximately half of all the infections that occur consist of pyogenic infections, with gram-negative and gram-positive bacteria identified with equal frequencies. Nonpyogenic infections (approximately 30%) may occur with unusual organisms, including atypical mycobacteria (eg, Mycobacterium kansasii), Toxoplasma gondii, Legionella, Listeria monocytogenes, Pneumocystis jirovecii, fungi, and viruses.23 As fever is an uncommon feature of the underlying HCL disease process, the presence of fever should prompt the clinician to evaluate the patient for a possible an infectious process.23
Several features of HCL contribute to patients’ susceptibility to infections. Neutrophil dysfunction and neutropenia increase the risk for bacterial infections.23,32 Monocytopenia may account for the susceptibility to fungal and atypical mycobacterial infections reported among patients with HCL.23,33 T-cell abnormalities are also common in patients with HCL, with an abnormal cluster of differentiation (CD)4:CD8 ratio34 and an absence of CD28, which leads to a poor antigen response.23 Decreases in T-helper cells and T-suppressor cells have also been documented among individuals with HCL.23 Moreover, the delayed-type hypersensitivity to recall antigens is impaired, with antibody-dependent cellular cytotoxicity nearly nonexistent.23 These immune dysregulations are all associated with the propensity for infections in patients with HCL.
Prior to the introduction of HCL-directed treatments, the median survival following diagnosis of the disease was about 4 years.35 Cytopenia-related complications, such as infection and hemorrhage, were common causes of death.35
Recent data suggest that autoimmune disorders are common among patients with HCL, with about 25% of individuals having ≥1 autoimmune condition.23,36 Autoimmune complications are also a cause of morbidity in HCL.23 The available literature on autoimmune disorders associated with HCL, however, is limited to individual case reports and small case series.36 Hematologic autoimmune conditions, including autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia, antiphospholipid syndrome, and cryoglobulinemia, have been reported in association with HCL.36 Rheumatologic autoimmune conditions related to HCL include polyarteritis nodosa, leukocytoclastic vasculitis, arthritis, proliferative synovitis, scleroderma, Behçet disease, dermatomyositis, and systemic lupus erythematosus.36
Furthermore, autoimmune neurologic disorders, including multiple sclerosis and myasthenia gravis, have also been reported in patients with HCL.36 Autoimmune disorders may develop before, during, or after the onset of HCL. Although some autoimmune conditions could be a result of the dysfunctional immune response associated with HCL, others are thought to share a potential, common pathogenetic pathway with HCL, as evidenced by their response to HCL-targeted therapy.36 The exact pathophysiologic mechanisms underlying these autoimmune disorders, however, remain to be explained.36
Unusual Clinical Features
There are rare case reports of osteolytic bone lesions in patients with HCL, which typically present as back or hip pain.23 One report noted bone lesions in the proximal femur in most affected patients.37 Although lytic bone lesions have been associated with a high tumor burden in the bone marrow,37 the unusual presentation in one patient in whom the painful lesions were sparsely infiltrated in the bone marrow in the absence of pancytopenia or splenomegaly has also been reported.38 The skeletal abnormalities typically respond well to radiation therapy.37
Despite the initial reports of cutaneous involvement in HCL,9 skin involvement is uncommon and more often related to infections, vasculitis, or rashes associated with HCL-targeted therapies.23 A review of the literature suggests that skin lesions occur in only about 8% of cases of HCL.39 Erythematous maculopapules typically present as HCL infiltrative skin lesions.23
Despite marked splenomegaly, splenic rupture is unusual, especially because of the initiation of purine nucleoside therapy.23 Central nervous system involvement by hairy cells has been reported occasionally, with infection influencing neurologic complications.23
Despite the significant progress that has been made regarding the incidence, risk factors, and symptoms of HCL, diagnosis remains a challenge, due in part to the low incidence of the disease. For patients with risk factors, the potential for HCL should be considered. The next article in this publication will explore the pathogenesis and diagnostic criteria of HCL.