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C H A P T E R 78

HAIRY CELL LEUKEMIA

Farhad Ravandi

INTRODUCTION chemicals, and a previous history of infectious mononucleosis have
also been suggested as predisposing factors, but a direct, causal
Hairy cell leukemia (HCL) is one of the diseases exemplifying the association has not been established with any of these or other factors.
importance of the application of appropriate diagnostic techniques Morphologically and phenotypically, the cells in HCL have no
and treatment strategies to obtain the best treatment outcomes for resemblance to any of the normal stages of B-cell development and
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the individual patient. The disease was first described by Bouroncle maturation; past studies have debated the cell of origin. Initially,
and colleagues in 1958. The term hairy cell leukemia was first used because of morphologic and functional similarities between hairy
to describe the disorder by Schreck and Donnelly in 1966 and is cells and cells of the monocyte/macrophage system, HCL tumor cells
derived from the observation of hair-like projections from mono- were thought to be derived from a cell transformed from the reticu-
nuclear cells giving rise to a frayed cell surface appearance. loendothelium. Korsmeyer demonstrated the rearrangement of the
The evolution of therapeutic strategies in patients with HCL over B-cell receptor (BCR) immunoglobulin genes in HCL, demonstrat-
the past 25 years has led to a significant change in the natural history ing for the first time the B-cell origin of the disease. Recently, several
of the disease. Using the currently available drugs, the majority of studies have increased our understanding of the cell of origin in HCL
patients with this disease achieve complete response (CR), and the allowing for a better description of pathogenic mechanisms respon-
published survival curves from several large series are similar to those sible for its development. 2
for appropriate age-matched individuals without the disease. At the In lymphoid cells, the analysis of the immunoglobulin variable
same time, recent research efforts have led to a better understanding region genes provides a tool for the delineation of the clonal history
of the molecular mechanisms responsible for the disease pathogenesis. of cells at which lymphoid neoplasms originate, identifying whether
Several studies, using modern techniques, have demonstrated the antigen encountered by a normal mature B cell has resulted in somatic
persistence of minimal residual disease (MRD) after therapy with mutation (Fig. 78.1). This process occurs within the germinal centers
nucleoside analogs in the majority of patients without consensus on (GCs) of lymph tissues and may be associated with isotype switching.
the significance of such MRD. The role of monoclonal antibodies, The enzyme activation−induced cytidine deaminase (AICD) is criti-
naked or conjugated with toxins, in the management of HCL, as well cal for both processes. Tumor cells from various B-cell malignancies
as their ability to eradicate MRD, is under investigation. The possibil- are arrested at a number of stages along normal B-cell differentiation,
ity of such strategies of chemoimmunotherapy leading to further conserving the immunogenetic characteristics of the stage-specific
improvements in the outcome of patients with HCL needs to be cell. The analysis of immunoglobulin variable gene regions can
further investigated. provide information about whether the cell of origin has undergone
somatic mutation and isotype switching. Several reports have clearly
demonstrated that in more than 85% of patients with HCL, the
EPIDEMIOLOGY tumor cells express switched immunoglobulin isotypes, and their
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rearranged variable region genes have undergone somatic mutations.
HCL is an uncommon lymphoid malignancy, accounting for only Furthermore, HCL cells express AICD, the enzyme that is critical for
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2% of lymphoid leukemias, with approximately 600 to 800 new both processes. This suggests that the cell of origin in the majority
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patients diagnosed each year in the United States. The disease is of HCL cases has transited through the GCs of peripheral lymphoid
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more common in whites and occurs more frequently in men than tissue having undergone the GC reaction. Of interest, in about 40%
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women by a ratio of 4 : 1. The median age at diagnosis is reported of cases of HCL, the leukemia cells express multiple immunoglobulin
by most studies to be 50 to 59 years. However, it is possible that the heavy chain isotypes, with dominance of immunoglobulin G3 (IgG3)
disease is underreported in the older population. The Swedish Cancer but only a single light chain, suggesting that clonally related multiple
Registry has maintained records on the incidence of the disease for isotypes coexist in single hairy cells. Therefore, this subset of the
several decades and has shown a stable incidence since the 1980s. It disease may be arrested at a point after isotype switching and before
reports the median age at diagnosis of 62 years, suggesting less rigid exit from the GC. However, other lines of evidence suggest a post-GC
diagnostic efforts in older patients. origin. 2
HCL has been diagnosed in patients aged in their 20s and 30s Arons and colleagues have provided evidence that in the majority
but is exceptionally rare in children. Using data from the 17 of patients with classic HCL (83% of 102 cases), the cell of origin is
population-based cancer registry areas in the United States, the post-GC with a mutated immunoglobulin heavy chain variable
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National Cancer Institute’s Surveillance Epidemiology and End region. This is contrasted with historic data for patients with chronic
Results program reported that the incidence of the disease was stable lymphocytic leukemia, in which case, about half of the time the cell
in the decades between 1978 and 2004 with a rapid rise in age- of origin is unmutated. They also reported higher usage of certain
specific incidence ratios until approximately age 40 years and then at immunoglobulin gene families and a difference in mutational fre-
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a slower pace beyond that age. quency among these genes. Furthermore, by demonstrating that the
mutations fulfilled predefined characteristics of a canonic and non-
random event, Arons and colleagues provided further evidence sug-
ETIOLOGY AND CELL OF ORIGIN gestive of an antigen-driven process.
The post-GC origin of HCL is supported by gene expression
Several reports have suggested an association between development profiling studies comparing HCL cells with cells from other lymphoid
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of HCL and exposure to benzene, organophosphorus insecticides, neoplasms, as well as with naive and memory B cells. HCL patients
and other solvents. However, such association has not been confirmed displayed a homogeneous pattern of gene expression that was clearly
by other reports. Exposure to radiation, wood dust, or agricultural distinct from other B-cell lymphomas and was related to post-GC
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