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1554 Part XI: Malignant Lymphoid Diseases Chapter 93: Hairy Cell Leukemia 1555

The remarkable advances in diagnosis and therapeutics with purine have hypermutated immunoglobulin genes in approximately 90 per-
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analogues over the past 25 years have clearly changed the natural history cent of the cases. In those patients who have unmutated immuno-
of this disease. Patients may now lead a near-normal life, despite the like- globulin genes, the disease appears to be more aggressive, as is the
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lihood of intermittent relapses requiring retreatment. 19,20 Although the risk case in chronic lymphocytic leukemia. Leukemic cells use a variety
for serious bacterial infection is greatest during initial therapy, there are of VH gene families. In those patients showing a VH4–34 gene, the
some delayed risks associated with impaired recovery of T-lymphocyte cell clinical course has also been noted to be less favorable. 32,33 Molecular
numbers and function following administration of purine analogues. 19,21 parameters may have prognostic value. For example, patients with a
In patients who achieve a complete morphologic remission, mutation in p53 have been less responsive to purine analogue therapy.
the presence of minimal residual disease (MRD) has been repeat- Therefore, characterization of the molecular and genetic profile of the
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edly shown by immunohistochemical staining of the marrow. Some leukemic cells may elucidate the cell of origin and have prognostic
patients in hematologic remission with MRD may live normal lives, and value with respect to clinical outcome and responsiveness to standard
do not require retreatment unless there is deterioration in their blood therapy.
counts. 22,23 Consequently, further research to define the optimal thera- The identification of a mutation in BRAF V600E in almost 100 per-
peutic approach and timing for evaluation of response is needed. cent of patients with HCL-c has had a major impact on classification of
The excellent results achieved with purine nucleoside induction the previously defined subsets of this disease. The leukemic cells from
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associated with high percentages of complete remission have contrib- patients with the variant of HCL (HCL-v) express BRAF wild-type. This
uted to the improvement in overall survival for patients with this dis- genetic difference confirms that these two entities are clearly unrelated
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ease. Using Surveillance, Epidemiology, and End Results Program with a completely separate clinical course and therapeutic responsive-
(SEER) data after 1984, extensive analysis over the past 3 decades shows ness. It is interesting that the small subset of patients with an immuno-
a progressive improvement in patient survival with HCL. Despite these phenotype consistent with HCL-c, yet using VH4–34 rearrangement,
truly remarkable results, at least 40 percent of patients will relapse. appear to be BRAF wild-type, further suggesting that there are multiple
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Many of these patients will be successfully retreated, but the failure of unique clonal patterns with distinct clinical courses. Despite immu-
the disease-free survival curve to flatten attests to the fact that this dis- nophenotypic features consistent with HCL-c, the lack of expression of
ease has been controlled but not cured. Strategies to predict who will be BRAF V600E identifies a clinical course unlike the highly responsive
prone to relapse will enable new treatments to be risk-stratified. Fur- form of the leukemia.
thermore, new agents are being developed to successfully treat patients The presence of BRAF V600E mutation appears to activate the
who have developed resistant disease. 19,24,25 MEK-ERK signaling pathway responsible for leukemic cell survival
and proliferation. Downstream activation of pERK correlates with pres-
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EPIDEMIOLOGY ence of this mutational pathway. Hematopoietic stem cells expressing
this mutation have been identified in the marrow of murine models of
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HCL is a rare chronic B-cell lymphoid malignancy accounting for the disease, as well as in the marrow of patients with HCL. BRAF
approximately 2 percent of adult leukemias. The estimated annual inci- V600E in marrow stem cells may explain the impairment in normal
dence in the United States is approximately 3.3 persons per million per- hematopoiesis that occurs in HCL-c. Furthermore, cytokines secreted
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son-years in the United States. The mean age at diagnosis is 55 years, by the leukemic cells may be responsible for the areas of hypocellular-
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but there is a wide range in age of onset. Patients may present in their ity observed in some patients with HCL-c. 38,39 Alternatively, impaired
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20s and 30s, and a report on 88 patients who were diagnosed at age hematopoiesis may result from inadequate growth factor production.
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40 or younger showed that these patients do well long-term. Younger Pancytopenia may also result either from extensive marrow infiltration
patients respond better to therapy, but may relapse and require retreat- with leukemia or fibrosis induced by the overproduction of transform-
9,19
ment in order to experience long-term survival benefits. There is an ing growth factor (TGF)-β by leukemic cells. 41
unexplained male predominance with this disease with a ratio of 4:1
males to females. There is also an unexplained racial difference with CLINICAL FEATURES
more than 90 percent of patients being white. 20
There is a bimodal presentation in age raising the possibility of dif- The most common presenting symptoms are weakness and fatigue,
ferent etiologies in the younger and older patient groups. The search for which occur in 50 percent of patients with HCL. Although many
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causative relationships in the older subset of patients has included exten- patients also have an enlarged spleen, the gradual onset of symptoms
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sive investigation of environmental and occupational exposures. There is described as fullness in left abdomen, early satiety, and discomfort.
is a suggestion of increased cases associated with farming and in jobs with Initially, Bouroncle reported that splenomegaly was found in 96 percent
1
extensive exposure to insecticides. Extensive investigation of the risk for of patients. However, more recently the percentage with a markedly
secondary malignancies identified an increased overall risk (standardized enlarged spleen may be less at diagnosis because of earlier detection
incidence ratio [SIR] 1.24) in a large population-based study according of the disease. Patients may present with a history of increased infec-
to SEER data from 1973 through 2000. In this study of more than 3000 tions, and approximately 17 percent have an active infection at the time
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patients with HCL, three separate malignancies were identified as being of diagnosis. Bleeding manifestations are also noted in patients with
of particular concern (SIR 6.61 Hodgkin lymphoma; SIR 5.03 non-Hodgkin severe thrombocytopenia. Patients may present with few symptoms, but
lymphoma; and SIR 3.56 thyroid cancer). Whether or not these second an abnormal laboratory report suggesting a hematologic disorder may
malignancies are related to an immune deficit from the leukemia or a emerge during a routine health examination.
result of the therapy for the leukemia is unknown. Infection has been the leading cause of death in patients with HCL,
and accounted for 55 percent of the fatalities in a large longitudinal
ETIOLOGY AND PATHOGENESIS review of 725 patients in an Italian series. In general, the infections
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occur as a result of granulocytopenia, monocytopenia, and impaired
HCL represents a clonal population of leukemic cells predominantly function of immune effector cells. Approximately 30 percent of patients
infiltrating the marrow, the spleen, and the liver. These cells are char- are found to have a documented source of infection, but an equal num-
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acterized as mature activated memory B cells based upon their immu- ber of suspected infections cannot be documented microbiologically.
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nophenotypic profile. The neoplastic cells in classic HCL (HCL-c) Fever in this patient population should prompt a search for infection. It

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