Chronic lymphocytic leukemia

y is a neoplastic disease characterized by the

accumulation of small, mature-appearing lymphocytes in the blood, marrow, and lymphoid tissues. y the neoplastic lymphocytes are of the B cell lineage. In less than 2 % the neoplastic cells are of T cell origin.

Immunoglobulin Expression
y The leukemic cells from more than 90 % of patients

express low levels of monoclonal surface Ig with either or light chains. y 60 % express light chains; the other 40 % express light chains y 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

y Cytogenetic Abnormalities y del 13q14-23.1 is the most common chromosomal

abnormality in CLL, y 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
y Patient Population At diagnosis, most patients are

older than 60 years and 90 % are older than 50 years.

General Symptoms
y More than 25 % of patients are asymptomatic at diagnosis y patients may have only mild symptoms of reduced exercise tolerance, fatigue, or malaise y chronic rhinitis secondary to nasal involvement of CLL cells y advanced disease may experience involuntary weight loss, recurrent infections, bleeding secondary to thrombocytopenia, and/or symptomatic anemia. y night sweats and/or low-grade fevers (the so-called B symptoms) y viral or bacterial infections secondary to impaired T cell immunity or hypogammaglobulinemia, respectively

y Lymphadenopathy y 80 % of all CLL patients have nontender

lymphadenopathy at diagnosis, most commonly involving the cervical, supraclavicular, or axillary lymph nodes. y Splenomegaly y half of all CLL patients present with mild to moderate splenomegaly

Blood Findings
y The diagnosis of CLL requires a sustained monoclonal

lymphocytosis greater than 5000/µl (5 x 109/liter) y leukemic cells generally appear similar to normal resting lymphocytes. Typically these cells have scanty, bluish cytoplasm, moderately condensed and matureappearing nuclei, and a mean cell volume (MCV) of 170 fl

y smudge cells y anemia y thrombocytopenia

Marrow Findings

y Interstitial y Nodular y mixed nodular-interstitial y diffuse

Lymph Node Findings
y 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
yA y Blood and marrow lymphocytosis and <3 areas* of y y y y

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/ l)

y Leukemic Cell Doubling Time y Patients whose lymphocyte counts double within 1

year have progressive disease, whereas those with stable counts represent a good-risk population.

Disease Complications
y Infection y Autoimmune Disease y Second Malignancies

Course of the disease
y Richter transformation y transition from an indolent leukemia to an aggressive,

large B cell, high-grade lymphoma can occur at any time during the course of CLL y Nucleic acid sequence analyses of the Ig genes expressed by the original leukemic cells and the highgrade lymphomas of patients with Richter transformation demonstrated that such lymphomas can arise from the original CLL clone

y Trisomy 12 and chromosome 11 abnormalities are more

frequent in patients with Richter transformation than in the overall population of patients with CLL. y 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
y elevation of serum lactate dehydrogenase (82%) y rapid lymph node enlargement (64%) y systemic symptoms of fever and/or weight loss (59%) y monoclonal gammopathy on serum protein

electrophoresis (44%) y extranodal disease (41%).

C L L/P L L Transformation
y 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. y survival does not differ from that of CLL patients with comparable clinical-stage disease.

y The remaining patients with CLL/PLL undergo a

prolymphocytic transformation y acquired the t(6;12) translocation that commonly is associated with PLL y respond poorly to chemotherapy, and survival is limited

Acute Lymphoblastic Leukemia
y Blastic transformation has been associated with a

sevenfold to eightfold increase in the expression of cmyc and Ig genes. Leukemic blast cells generally express terminal deoxynucleotidyl transferase and high levels of surface Ig and HLA-DR.

B Cell Prolymphocytic Leukemia
y 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. y 55 % of the circulating leukemic lymphocytes have a prolymphocytic morphology. y 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. y 80 % of cases, the prolymphocytes are neoplastic B cells. y There is a 4:1 male to female predominance y B cell PLL can evolve from B cell CLL.

Cytogenetics
y The karyotype displays the 14q+ Trisomy 12 is another

recurrent abnormality. (6q ) , rearrangement affecting chromosomes 1 and 12 y cytogenetics and FISH analysis is deletion 13q14 ,trisomy 12 ,and 14q32 rearrangements (21%).

Clinical Features
y More than 50 % of patients are older than 70 years at

diagnosis. y Presenting symptoms include fatigue, weakness, weight loss, an acquired bleeding tendency, or early satiety with abdominal discomfort because of splenomegaly. y Splenomegaly is massive in nearly two thirds of patients. The liver may be enlarged. Nevertheless, patients typically have minimal palpable lymphadenopathy.

Laboratory Features
y More ¾ patients have blood lymphocyte counts y y

y y

greater than 100,000/ l. 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/ l. commonly have hypogammaglobulinemia. many patients have a monoclonal gammopathy

y expression of CD5 is variable y PLL cells generally express very high levels of surface

Ig, usually IgM with or without IgD and react strongly with the antibody FMC7 y PLL cells generally express high levels of CD22 and often are negative for CD23.

T Cell Prolymphocytic Leukemia
y Because of its aggressive clinical behavior, T cell CLL

was reclassified under the heading of T cell PLL y 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.

y overrepresented were 8q (75%), 5p (62%), and 14q

(37%), as well as 6p and 21 (both 25%). y chromosomal regions most often underrepresented were 8p and 11q (75%), 13q (37%), and 6q, 7q, 16q, 17p, and 17q (25%). y Patients with ataxia-telangiectasia are at high risk for developing T cell PLL.

Clinical Features
y Presenting symptoms include fatigue, weakness,

weight loss, and early satiety with abdominal discomfort because of splenomegaly y lymphadenopathy is a common finding in T cell PLL.

y Approximately one third of patients have cutaneous

involvement on the torso, arms, and face y The leukemia cells express the T cell differentiation antigens CD2, CD3, CD5, and CD7, but not CD1, HLADR, or terminal transferase, reflecting a mature T cell phenotype

y In more than 75 % of cases the leukemia cells have a

helper T cell phenotype as they express CD4 but not CD8. y Approximately 15 % of cases have leukemia cells that express CD8 but not CD4. y In less than 10 %of cases, the leukemic T cells express both CD4 and CD8

Differential Diagnosis
y Polyclonal T Cell Lymphocytosis y Large Granular Lymphocytic Leukemia y Adult T Cell Leukemia/Lymphoma y Mycosis Fungoides and SéZary Syndrome y T Cell Chronic Lymphocytic Leukemia

Hairy Cell Leukemia
y chronic lymphoproliferative disorder characterized by

circulating B lymphocytes that display prominent cytoplasmic projections. y Afflicted individuals often are elderly males who present with pancytopenia, splenomegaly, or recurrent serious infections.

Clinical Features
y The diagnostic triad of HCL consists of pancytopenia,

splenomegaly, and circulating

y 25 % of patients present with fatigue and weakness, y 25 % with easy bruising from thrombocytopenia or

opportunistic infections from leukopenia, y 25 % with early satiety or abdominal fullness from splenomegaly, y 25 % with an incidental finding of splenomegaly or abnormal blood counts on routine examination for an unrelated condition

y Splenomegaly, which may be massive, is found in 90

%of patients y Palpable peripheral lymphadenopathy is distinctly uncommon and when found usually is localized.

Laboratory Features
y Blood y Patients usually present with anemia,

thrombocytopenia, and leukopenia. y Occasional patients have elevated leukocyte counts as a result of circulating hairy cells.

y 80 % of patients have absolute neutropenia and

monocytopenia y 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
y 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 y The separation of individual hairy cells is characteristic and referred to as the "fried-egg" appearance y the marrow frequently is difficult or impossible to aspirate.

Spleen
y the hairy cells involve the splenic red pulp. y Later, the white pulp atrophies and is replaced. y 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.

y Cytochemistry y The hairy cell cytoplasm usually stains strongly

positive for TRAP y Electron Microscopy y 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

y Immunophenotypic Profile y 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 y Most distinctively, hairy cells express high levels of CD11c, CD22, CD25, and CD103.

y Differential Diagnosis y HCL must be considered in the differential diagnosis

of any disorder resulting in cytopenias and splenomegaly y Hairy cell leukemia variant is a unique clinicopathologic entity representing a hybrid between prolymphocytic leukemia and HCL. y The nucleus most closely resembles a prolymphocyte and the cytoplasm a hairy cell

y have higher nuclear to cytoplasmic ratios, more highly

condensed chromatin, and more conspicuous central nucleoli than seen in classic HCL y massive splenomegaly y The circulating cells in HCL variant usually are CD25negative and CD103-negative.

y 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 y Splenic lymphoma with circulating villous lymphocytes

Large Granular Lymphocytic Leukemia:
y clinical syndrome of chronic neutropenia associated

with increased numbers of circulating larger granular lymphocytes (LGL) y T-LGL leukemia is defined as a clonal proliferation of CD3+ LGL; y NK-LGL leukemia is defined as a clonal proliferation of CD3 LGL.

Clinical Features
y T-cell LGL leukaemia affects adults and is rare in children; y slightly more frequent in females. y Patients are asymptomatic y or manifest with symptoms derived from cytopenias, essentially recurrent infections, autoimmune disease or rarely present as pure red cell aplasia; y Physical examination shows splenomegaly in close to twothirds of patients and hepatomegaly in one-half; y skin lesions may be present but lymphadenopathy is exceedingly rare

Hematologic Findings
y 25 % of patients do not have an increased total lymphocyte count. y The median LGL count of patients with T-LGL leukemia, is 4200/ l (4.2 x 109/liter). y NK-LGL leukemia generally have much higher LGL counts, exceeding 50,000/ l (5.0 x 1010/liter). y (84%) with T-LGL leukemia have chronic neutropenia, and approximately half (48%) have neutrophil counts less than 500/ l (5 x 108/liter). y In contrast, less than one fifth (18%) of patients with NKLGL have severe neutropenia. y Anemia is observed in 50 % and 100 % of cases of T-LGL and NK-LGL leukemia,

y Pure red cell aplasia and Coombs positive hemolytic

anemia are seen with T-LGL leukemia. y Thrombocytopenia and coagulopathy are features of NK-LGL leukemia

Differential Diagnosis
y 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. y Cytomegalovirus or HIV infection can lead to a mildly increased concentration of LGL cells. However, the LGLs are not monoclonal