Sandbox: leukemia

Pathophysiology

CLL affects a particular lymphocyte, the B cell, which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.

CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to a disease called small lymphocytic lymphoma (SLL), a type of non-Hodgkin's lymphoma which presents primarily in the lymph nodes. The World Health Organization considers CLL and SLL to be "one disease at different stages, not two separate entities".

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as T-cell prolymphocytic leukemias.

Acute lymphocytic leukemia (ALL) is a disease of children, but CLL is a disease of adults.

Uncommonly, CLL presents as enlargement of the lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as small lymphocytic lymphoma.

The increase in lymphocytes and precursors in the bone marrow impairs the production of other leucocytes causing a decrease in such cell types.

Differential

Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include:

• Mantle cell lymphoma
• Marginal zone lymphoma
• Lymphoplasmacytic lymphoma
• B cell prolymphocytic leukemia (B PLL), which is a related but more aggressive disorder, has cells with similar phenotype but that are signficantly larger than normal lymphocytes and have a prominent nucleolus suggests a related.
• Hairy cell leukemia is also a neoplasm of B lymphocytes but differs significantly from CLL by its morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surface) and marker molecule expression.

All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow and occasionally lymph node cells by a pathologist with specific training in blood disorders. A sophisticated instrument called a flow cytometer is necessary for cell marker analysis and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by fluorescent in situ hybridization (FISH). CLL is positive for CD5, CD19 & CD23; CLL is the only cell type that coexpresses CD5 & 19. It is negative for CD10 & cyclin D. CD20 is +/- as is sIg. 90% of B-CLL have bcl-2. The 2 most noteworthy lymphoproliferative diseases with CD5 positivity are CLL (which is CD23 positive) & mantle zone lymphoma (which is CD23 negative). Other CD5+ groups include peripheral & cutaneous T-cell lymphoma, lymphoblastic lymphoma, and adult T-cell leukemia/lymphoma.

Overview

Between 2004 and 2010, the 5-year relative survival of patients with chronic lymphocytic leukemia (CLL) was 83.5%.===5-Year Survival===

• Between 2004 and 2010, the 5-year relative survival of patients with CLL was 83.5%.

• When stratified by age, the 5-year relative survival of patients with CLL was 89.6% and 74.4% for patients <65 and ≥ 65 years of age respectively.

Overview

Clinical staging

Staging is done with the Rai staging system and the Binet classification (see details).

Rai staging system

Stage 0	Absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.
Stage 1	Absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
Stage 2	Absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
Stage 3	Absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
Stage 4	Absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

Binet Classification

Clinical stage A	No anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II).
Clinical stage B	No anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II).
Clinical stage C	Anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV).

The Binet classification integrates the number of nodal groups involved with the disease with bone marrow failure. Its major benefit derives from the recognition of a predominantly splenic form of the disease, which may have a better prognosis than in the Rai staging, and from recognition that the presence of anemia or thrombocytopenia has a similar prognosis and does not merit a separate stage. Neither system separates immune from nonimmune causes of cytopenia. Patients with thrombocytopenia or anemia or both, which is caused by extensive marrow infiltration and impaired production (Rai III/IV, Binet C) have a poorer prognosis than patients with immune cytopenias.[4] The International Workshop on CLL has recommended integrating the Rai and Binet systems as follows: A(0), A(I), A(II); B(I), B(II); and C(III), C(IV).