of all diagnosed leukemias. 7 The first detailed
characterization of HCL as a distinct clinical
entity was performed by Dr. Bouroncle and
colleagues at the Ohio State University in
1958.8 Originally called leukemic reticuloendotheliosis, it was renamed HCL following
more detailed description of the unique morphology of these malignant cells. 9 Significant
advances have recently been made in identifying distinctive genetic, immunophenotypic,
and morphologic features that distinguish
HCL from other B-cell malignancies.
HCL B cells tend to accumulate in the bone
marrow, splenic red pulp, and (in some cases)
peripheral blood. Unlike other lymphopro-
liferative disorders, HCL only rarely results
in lymphadenopathy. HCL derives its name
from the distinct appearance of the malig-
nant hairy cells (Figure). Morphologically,
HCL cells are mature, small lymphoid B-cells
with a round or oval nucleus and abundant
pale blue cytoplasm. Irregular projections of
cytoplasm and microvilli give the cells a ser-
rated, “hairy” appearance. 10 The biological
significance of these fine hair-like projections
remains unknown and is an area of ongoing
investigation. Gene expression profiling has
revealed that HCL B cells are most similar to
splenic marginal zone B cells and memory B
cells. 11–13 A recent analysis of common genetic
alterations in HCL suggests that the cell of
origin is in fact the hematopoietic stem cell. 14
Compared to other hematologic malignan-
cies, the genomic profile of HCL is relatively
stable, with few chromosomal defects or
translocations observed. A seminal study by
Tiacci and colleagues revealed that the BRAF
V600E mutation was present in 47 out of
47 cHCL cases examined, results that have
since been replicated by other groups,
confirming that BRAF V600E is a hallmark
mutation in cHCL. 15 The BRAF V600E gain-
of-function mutation results in constitutive
activation of the serine-threonine protein
kinase B-Raf, which regulates the mitogen-
activated protein kinase (MAPK)/RAF-MEK-
ERK pathway. Indeed, cHCL B cells have
elevated MAPK signaling, leading to enhance-
ment of growth and survival. 16 This specific
mutation in the BRAF gene is also seen
in a number of solid tumor malignancies
including melanoma and thyroid cancer, and
represents a therapeutic target using BRAF
inhibitors already developed to treat these
malignancies. 17 Testing for BRAF V600E by
polymerase chain reaction or immunohisto-
chemical staining is now routinely performed
when HCL is suspected.
While BRAF V600E is identified in nearly
all cases of cHCL, it is rare in vHCL. 18 The
variant type of HCL was classified as a distinct
clinical entity in 2008 and can now often be
distinguished from cHCL on the basis of
BRAF mutational status, among other differences. Interestingly, in the rare cases of
BRAF V600E–negative cHCL, other mutations in BRAF or downstream targets as well
Figure. Typical hairy cell.
