Chronic lymphocytic leukemia

is a neoplastic disease characterized by the

accumulation of small, mature-appearing
lymphocytes in the blood, marrow, and lymphoid
tissues.
the neoplastic lymphocytes are of the B cell lineage. In
less than 2 % the neoplastic cells are of T cell origin.
Immunoglobulin Expression
The leukemic cells from more than 90 % of patients
express low levels of monoclonal surface Ig with either
κ or λ light chains.
60 % express κ light chains; the other 40 % express λ
light chains
heavy-chain isotypes, more than half have surface IgM
and IgD (55%), one fourth IgM, and 7 % have IgG or
IgA. Less than 5 % express IgD without detectable IgM
Cytogenetic Abnormalities
del 13q14-23.1 is the most common chromosomal
abnormality in CLL,
 followed in order by trisomy 12, del 11q22.3-q23.1, del
6q21-q23, deletions at 17p13.1 typically involving
deletions/mutations of the TP53 and 14q
abnormalities.
Clinical Features

Patient Population At diagnosis, most patients are

older than 60 years and 90 % are older than 50 years.
General Symptoms
More than 25 % of patients are asymptomatic at diagnosis
patients may have only mild symptoms of reduced exercise
tolerance, fatigue, or malaise
chronic rhinitis secondary to nasal involvement of CLL
cells
advanced disease may experience involuntary weight loss,
recurrent infections, bleeding secondary to
thrombocytopenia, and/or symptomatic anemia.
night sweats and/or low-grade fevers (the so-called B
symptoms)
viral or bacterial infections secondary to impaired T cell
immunity or hypogammaglobulinemia, respectively
Lymphadenopathy
80 % of all CLL patients have nontender
lymphadenopathy at diagnosis, most commonly
involving the cervical, supraclavicular, or axillary
lymph nodes.
Splenomegaly
half of all CLL patients present with mild to moderate
splenomegaly
Blood Findings
The diagnosis of CLL requires a sustained monoclonal
lymphocytosis greater than 5000/µl (5 x 109/liter)
leukemic cells generally appear similar to normal
resting lymphocytes. Typically these cells have scanty,
bluish cytoplasm, moderately condensed and mature-
appearing nuclei, and a mean cell volume (MCV) of
170 fl
smudge cells
anemia
thrombocytopenia
Marrow Findings
Interstitial
Nodular
mixed nodular-interstitial
diffuse
Lymph Node Findings
The lymph node architecture typically is effaced by a
diffuse infiltration of small lymphocytes that have the
same morphology as that of the circulating leukemic
cells.
Clinical Staging
A
Blood and marrow lymphocytosis and <3 areas* of
palpable lymphoid tissue enlargement
B
Blood and marrow lymphocytosis and 3 areas of
palpable lymphoid tissue enlargement
C
Same as B with anemia (hemoglobin <11 g/dl in men or
<10 g/dl in women) or thrombocytopenia (platelets
<100,000/μl)
Leukemic Cell Doubling Time
Patients whose lymphocyte counts double within 1
year have progressive disease, whereas those with
stable counts represent a good-risk population.
Disease Complications

Infection
Autoimmune Disease
Second Malignancies
Course of the disease
Richter transformation
transition from an indolent leukemia to an aggressive,
large B cell, high-grade lymphoma can occur at any
time during the course of CLL
Nucleic acid sequence analyses of the Ig genes
expressed by the original leukemic cells and the high-
grade lymphomas of patients with Richter
transformation demonstrated that such lymphomas
can arise from the original CLL clone
Trisomy 12 and chromosome 11 abnormalities are more
frequent in patients with Richter transformation than
in the overall population of patients with CLL.
 In some cases the lymphoma cells have inactivating
mutations or deletions in the p53 tumor suppressor
gene, the ATM gene, p16INK4A, the RB gene, or p21,
increased copy number of c-myc, and/or loss or
decreased expression of p27 or a-myb.
Clinical and Laboratory Features
elevation of serum lactate dehydrogenase (82%)
rapid lymph node enlargement (64%)
systemic symptoms of fever and/or weight loss (59%)
monoclonal gammopathy on serum protein
electrophoresis (44%)
extranodal disease (41%).
C L L/P L L Transformation
15 % of B cell CLL patients, the population of leukemic
cells consists of a mixture of small lymphocytes and
prolymphocytes, the latter cell type accounting for 10
to 50 % of the lymphoid cells.
survival does not differ from that of CLL patients with
comparable clinical-stage disease.
The remaining patients with CLL/PLL undergo a
prolymphocytic transformation
acquired the t(6;12) translocation that commonly is
associated with PLL
respond poorly to chemotherapy, and survival is
limited
Acute Lymphoblastic Leukemia
Blastic transformation has been associated with a
sevenfold to eightfold increase in the expression of c-
myc and Ig genes. Leukemic blast cells generally
express terminal deoxynucleotidyl transferase and
high levels of surface Ig and HLA-DR.
B Cell Prolymphocytic Leukemia
B cell PLL is a clinical and morphologic variant of CLL It is a
subacute lymphoid leukemia with an incidence that is
approximately 10 % that of CLL.
55 % of the circulating leukemic lymphocytes have a
prolymphocytic morphology.
cells are larger than resting lymphocytes and have a high n/c
ratio, a basophilic cytoplasm devoid of granules, moderately
condensed chromatin, and a single prominent nucleolus.
80 % of cases, the prolymphocytes are neoplastic B cells.
There is a 4:1 male to female predominance
 B cell PLL can evolve from B cell CLL.
Cytogenetics
The karyotype displays the 14q+ Trisomy 12 is another
recurrent abnormality. (6q–) , rearrangement affecting
chromosomes 1 and 12
cytogenetics and FISH analysis is deletion 13q14
,trisomy 12 ,and 14q32 rearrangements (21%).
Clinical Features
More than 50 % of patients are older than 70 years at
diagnosis.
Presenting symptoms include fatigue, weakness,
weight loss, an acquired bleeding tendency, or early
satiety with abdominal discomfort because of
splenomegaly.
Splenomegaly is massive in nearly two thirds of
patients. The liver may be enlarged. Nevertheless,
patients typically have minimal palpable
lymphadenopathy.
Laboratory Features
More ¾ patients have blood lymphocyte counts
greater than 100,000/μl.
 The marrow commonly is infiltrated diffusely with
neoplastic prolymphocytes.
 At presentation, patients commonly have a
normochromic and normocytic anemia, with blood
hemoglobin less than 11 g/dl and/or blood platelet
counts less than 100,000/μl.
commonly have hypogammaglobulinemia.
many patients have a monoclonal gammopathy
expression of CD5 is variable
PLL cells generally express very high levels of surface
Ig, usually IgM with or without IgD and react strongly
with the antibody FMC7
PLL cells generally express high levels of CD22 and
often are negative for CD23.
T Cell Prolymphocytic Leukemia
Because of its aggressive clinical behavior, T cell CLL
was reclassified under the heading of T cell PLL
There is a 3:2 male-to-female predominance. Infection
with HTLV-I has been speculated to play a role in the
development of at least some cases of T cell PLL.
overrepresented were 8q (75%), 5p (62%), and 14q
(37%), as well as 6p and 21 (both 25%).
chromosomal regions most often underrepresented
were 8p and 11q (75%), 13q (37%), and 6q, 7q, 16q, 17p,
and 17q (25%).
Patients with ataxia-telangiectasia are at high risk for
developing T cell PLL.
Clinical Features
Presenting symptoms include fatigue, weakness,
weight loss, and early satiety with abdominal
discomfort because of splenomegaly
lymphadenopathy is a common finding in T cell PLL.
Approximately one third of patients have cutaneous
involvement on the torso, arms, and face
The leukemia cells express the T cell differentiation
antigens CD2, CD3, CD5, and CD7, but not CD1, HLA-
DR, or terminal transferase, reflecting a mature T cell
phenotype
In more than 75 % of cases the leukemia cells have a
helper T cell phenotype as they express CD4 but not
CD8.
 Approximately 15 % of cases have leukemia cells that
express CD8 but not CD4.
 In less than 10 %of cases, the leukemic T cells express
both CD4 and CD8
Differential Diagnosis

Polyclonal T Cell Lymphocytosis

Large Granular Lymphocytic Leukemia
Adult T Cell Leukemia/Lymphoma
Mycosis Fungoides and SéZary Syndrome
T Cell Chronic Lymphocytic Leukemia
Hairy Cell Leukemia
chronic lymphoproliferative disorder characterized by
circulating B lymphocytes that display prominent
cytoplasmic projections.
Afflicted individuals often are elderly males who
present with pancytopenia, splenomegaly, or recurrent
serious infections.
Clinical Features

The diagnostic triad of HCL consists of pancytopenia,

splenomegaly, and circulating
25 % of patients present with fatigue and weakness,
 25 % with easy bruising from thrombocytopenia or
opportunistic infections from leukopenia,
 25 % with early satiety or abdominal fullness from
splenomegaly,
 25 % with an incidental finding of splenomegaly or
abnormal blood counts on routine examination for an
unrelated condition
Splenomegaly, which may be massive, is found in 90
%of patients
Palpable peripheral lymphadenopathy is distinctly
uncommon and when found usually is localized.
Laboratory Features
Blood
Patients usually present with anemia,
thrombocytopenia, and leukopenia.
 Occasional patients have elevated leukocyte counts as
a result of circulating hairy cells.
80 % of patients have absolute neutropenia and
monocytopenia
Hairy cells are mononuclear cells with eccentric or
central nuclei. Nuclear morphology is variable: round,
ovoid, reniform, or convoluted. Nuclear forms tend to
have a reticular chromatin pattern. Hairy cells have
variable amounts of cytoplasm that is blue–gray in
appearance, exhibiting thin cytoplasmic projections
Marrow
Marrow involvement may be diffuse or focal. The most
subtle pattern of HCL infiltration is a hypocellular
marrow with scant infiltration by hairy cells admixed
with residual hematopoietic tissue
The separation of individual hairy cells is
characteristic and referred to as the "fried-egg"
appearance
the marrow frequently is difficult or impossible to
aspirate.
Spleen
the hairy cells involve the splenic red pulp.
 Later, the white pulp atrophies and is replaced.
 Red cell lakes, which are blood-filled spaces lined by
hairy cells that have disrupted the normal sinus
architecture, are characteristic. These blood-filled
spaces sometimes are referred to as pseudosinuses.
Cytochemistry
The hairy cell cytoplasm usually stains strongly
positive for TRAP
Electron Microscopy
In HCL, electron microscopy shows circumferential
cytoplasmic projections with fewer and blunter
microvilli than seen in splenic lymphoma with
circulating B lymphocytes in which the projections
tend to be more polarized at one end of the cell
Immunophenotypic Profile
Hairy cells, being mature B cells, express the pan B cell
antigens CD19, CD20, and CD22, but not CD21, an
antigen lost in the later stages of B cell development
 Most distinctively, hairy cells express high levels of
CD11c, CD22, CD25, and CD103.
Differential Diagnosis
HCL must be considered in the differential diagnosis
of any disorder resulting in cytopenias and
splenomegaly
Hairy cell leukemia–variant is a unique
clinicopathologic entity representing a hybrid between
prolymphocytic leukemia and HCL.
The nucleus most closely resembles a prolymphocyte
and the cytoplasm a hairy cell
have higher nuclear to cytoplasmic ratios, more highly
condensed chromatin, and more conspicuous central
nucleoli than seen in classic HCL
massive splenomegaly
The circulating cells in HCL–variant usually are CD25-
negative and CD103-negative.
In a blastic variant of HCL, patients have massive
splenomegaly, peripheral adenopathy, and cytopenias.
The cells are positive with TRAP staining and negative
for myeloperoxidase
Splenic lymphoma with circulating villous
lymphocytes
Large Granular Lymphocytic Leukemia:
clinical syndrome of chronic neutropenia associated
with increased numbers of circulating larger granular
lymphocytes (LGL)
T-LGL leukemia is defined as a clonal proliferation of
CD3+ LGL;
 NK-LGL leukemia is defined as a clonal proliferation
of CD3– LGL.
Clinical Features
T-cell LGL leukaemia affects adults and is rare in children;
slightly more frequent in females.
 Patients are asymptomatic
or manifest with symptoms derived from cytopenias,
essentially recurrent infections, autoimmune disease or
rarely present as pure red cell aplasia;
 Physical examination shows splenomegaly in close to two-
thirds of patients and hepatomegaly in one-half;
 skin lesions may be present but lymphadenopathy is
exceedingly rare
Hematologic Findings
25 % of patients do not have an increased total lymphocyte count.
The median LGL count of patients with T-LGL leukemia, is
4200/μl (4.2 x 109/liter).
NK-LGL leukemia generally have much higher LGL counts,
exceeding 50,000/μl (5.0 x 1010/liter).
(84%) with T-LGL leukemia have chronic neutropenia, and
approximately half (48%) have neutrophil counts less than 500/μl
(5 x 108/liter).
 In contrast, less than one fifth (18%) of patients with NK-LGL
have severe neutropenia.
Anemia is observed in 50 % and 100 % of cases of T-LGL and NK-
LGL leukemia,
Pure red cell aplasia and Coombs positive hemolytic
anemia are seen with T-LGL leukemia.
Thrombocytopenia and coagulopathy are features of
NK-LGL leukemia
Differential Diagnosis
The diagnosis of T-LGL leukemia should be
considered in patients with chronic or cyclic
neutropenia or in patients with pure red cell aplasia or
rheumatoid arthritis who have increased
concentrations of LGL cells.
 Cytomegalovirus or HIV infection can lead to a mildly
increased concentration of LGL cells. However, the
LGLs are not monoclonal