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Chronic lymphocytic leukemia
Diagnosis

The diagnosis of chronic lymphocytic leukemia rests on the finding of an absolute lymphocytosis of more than 5,000 in the peripheral blood.

The International Workshop on CLL (IW-CLL) and the National Cancer Institute–sponsored Working Group on CLL (NCI-WG) have outlined diagnostic criteria for CLL.

IW-CLL Criteria

• A sustained peripheral blood lymphocyte count greater than 10 x 109/L
• A bone marrow aspirate showing greater than 30% lymphocytes
• Peripheral blood lymphocytes identified as monoclonal B cells

Two of the three criteria are enough to establish a diagnosis.

NCI-WG Criteria

• A peripheral blood lymphocyte count greater than 5 x 109/L, with less than 55% of the cells being atypical.
• The lymphocytes should be monoclonal B lymphocytes expressing B-cell surface antigens (CD19, CD20, CD23), low-density surface immunoglobulin (M or D), and CD5 positivity.

A lymphocyte count greater than 5 x 109/L was specified by the NCI-WG to distinguish CLL from small lymphocytic lymphoma. However, it is arguable as to whether that distinction is clinically relevant.

Other B-cell malignancies may also present with increased circulating lymphoid cells and should be differentiated from CLL. The diseases that may be confused with CLL are prolymphocytic leukemia (PLL), the leukemic phase of non-Hodgkin's lymphoma (mantle cell lymphoma, follicular lymphoma, or splenic lymphoma with circulating villous lymphocytes), and hairy cell leukemia (HCL). Immunophenotyping is helpful in differentiating these disorders.

Laboratory Findings

Blood counts

Lymphocytosis, consisting of mature lymphocytes, is almost universal. Absolute lymphocyte counts range from 5 x 109/L to 500 x 109/L. Rarely, patients with a white blood cell count of less than 5 x 109/L may be found to have CLL based on phenotyping of the lymphocytes.

The lymphocyte count usually increases over time, but fluctuations in the lymphocyte counts of untreated patients may occur, particularly in the setting of infection.

The requirement that the blood lymphocytosis must be sustained to diagnose CLL was introduced to exclude those conditions in which blood lymphocyte counts return to normal after a few weeks, such as infectious mononucleosis, pertussis, and toxoplasmosis. Nowadays this is not recommended as bone marrow examination can easily exclude nonmalignant causes. Only in CLL and similar lymphoid malignancies is lymphocytosis in the blood accompanied by bone marrow lymphocytosis.

Unlike in acute myeloid leukemia, leukostasis is uncommon in CLL, probably because of the small size and pliable nature of the cells. 

Anemia (hemoglobin less than 11 g/dL) and thrombocytopenia (platelet count less than 100 x 109/L) are frequent with disease progression but occur in only a minority of patients at the time of initial diagnosis.

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Bone marrow examination

Marrow infiltration by lymphocytes varies from 30% to 100%, with normal or increased cellularity.

Three types of lymphoid infiltration of the marrow can be seen in biopsy specimens:

• Nodular
• Interstitial
• Diffuse

Sometimes, a mixture of the first two patterns is seen. Patients with diffuse infiltration usually have advanced disease and a worse prognosis. Nodular and interstitial patterns may be grouped together as "nondiffuse" and are associated with less advanced disease and better outcome.

A bone marrow biopsy examination is not required for establishing the diagnosis of CLL, but it has considerable prognostic value.

Antiglobulin test

A positive direct antiglobulin test is seen in approximately 25% of cases, but overt autoimmune hemolytic anemia (AIHA) occurs less frequently. The incidence of a positive direct antiglobulin test (Coombs') increases significantly with disease stage.

Autoimmune thrombocytopenia is usually diagnosed on the basis of a low platelet count in the presence of adequate numbers of megakaryocytes in the bone marrow. Neutropenia may also be encountered. These cytopenias may be the result of bone marrow failure due to "packed" marrow by CLL or occur as a result of an immune-mediated process or hypersplenism.

Hypogammaglobulinemia

Hypogammaglobulinemia occurs in approximately 50% of patients with CLL. At diagnosis, it may be noted in fewer than 10% of patients, but its incidence increases significantly with disease progression. Usually, all three immunoglobulin classes (G, A, and M) are decreased, but in some patients only one or two may be low. Significant hypogammaglobulinemia and neutropenia result in increased susceptibility of patients with CLL to bacterial infections.

Chromosomal abnormalities

Chromosomal abnormalities occur in 50%-65% of CLL patients with analyzable metaphases. Because of the low mitotic rate in CLL, traditional karyotypic methods frequently fail. Fluorescent in situ hybridization (FISH) has improved the detection of clonal genetic abnormalities in CLL patients. In a landmark study, Dohner et al evaluated 325 patients with CLL. Using a variety of fluorescent probes, they identified chromosomal aberrations in 82%.

Among these findings was the recognition that some subtypes (17p and 11q) had more pronounced lymphadenopathy as well as markedly shorter time to initiate chemotherapy and shorter overall survival than did other types.

One of the most frequent changes is a deletion in 13q14 (55% of patients). Patients with 13q deletions tend to have modest or absent lymphadenopathy.

Other typical abnormalities included deletion 11q22-23 (18%), trisomy 12q13 (16%), and deletion 17p13 (7%). Patients with deletion 17p or 11q frequently have bulky adenopathy.

Prognostic importance

These chromosomal abnormalities were potent predictors of outcome with the following median survivals:

• Deletion 17p, 32 months
• Deletion 11q, 79 months
• Trisomy 12, 114 months
• Deletion 13q, 133 months

Disease progression also is heavily influenced by the underlying genetic abnormality. Time from diagnosis to treatment averaged only

• 17p abnormalities, 9 months
• 13q deletions, 92 months

Molecular abnormalities

No single gene has been implicated in the pathogenesis of CLL. However, several genetic abnormalities have biologic and/or prognostic implications.

Retinoblastoma gene

The retinoblastoma 1 (rb1) gene is located in the long arm of chromosome 13, but despite the frequent abnormalities in this region, the retained RB1 allele is usually unaffected. A more telomeric region to the rb1 gene (D13S25) is frequently affected, and in at least some cases, the abnormality is homozygous, suggesting the presence of a tumor- suppressor gene in this region.

Mutations of ras

Despite the frequent involvement of chromosome 12, ras mutations are uncommon in CLL.

Overexpression of bcl-2

Abnormalities of the long arm of chromosome 14 frequently involve region 14q32, the site encoding for the immunoglobulin heavy-chain gene. However, gene translocations, such as t(11;14)(q13;q32) and t(14;18)(q32;q21) (which juxtapose genes bcl-1 and bcl-2 to the heavy-chain immunoglobulin gene), are relatively uncommon and should prompt consideration of alternative diagnoses (mantle cell or follicular lymphoma). Nevertheless, increased expression of bcl-2 mRNA and protein are very common in CLL. Since overexpression of bcl-2 inhibits apoptosis, it is possible that this gene participates in the pathogenesis of CLL.

Mutations in p53

Mutations in the p53 tumor- suppressor gene are seen in 15% of all patients with CLL (17p abnormality detected by FISH). These mutations are more common in patients with advanced- stage disease or transformation. Multidrug resistance gene Approximately 40% of patients with CLL have overexpression of the multidrug resistance gene (MDR1).

Immunophenotyping

More than 95% of all cases have a B-cell phenotype. In these patients, CD19 and/or CD20 are essentially always coexpressed with CD5, which is expressed on T cells and a subset of normal B cells. Other markers, such as CD21 and CD22, may also be expressed.

Expression of CD23 helps to differentiate CLL from mantle cell lymphoma, in which cells coexpress CD19 and CD5 but lack CD23. Furthermore, the monoclonal antibody FMC7 (which recognizes an epitope on CD20) rarely reacts with CLL cells but frequently stains the cells of patients with mantle cell lymphoma.

Expression of surface immunoglobulins is usually weak and is lower than in normal B lymphocytes or most other B-cell lymphomas. Expression of CD38 on the surface of CLL cells portends a significantly worse prognosis than that for patients whose cells do not express CD38.

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