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Chronic Lymphocytic Leukemia: Pathophysiology

 

Chronic Lymphocytic Leukemia: PathophysiologyMature blood cells (red cells, white cells, and platelets) are produced in the bone marrow from pluripotent hematopoietic stem cells. (FIGURE.The hematopoietic cascade: development of mature blood cells from pluripotent hematopoietic stem cells shows the different lineages of blood cells and the stages involved in their maturation.) The blood cells mature and differentiate through a sequence of steps involving a series of complex — and incompletely understood — interactions with growth factors, cytokines, and other cells in the bone marrow. Once mature, the blood cells leave the bone marrow and enter the general circulation, where they have a limited life span.

T and B lymphocytes (often known as T and B cells) are white blood cells, and they are vital constituents of the immune system. When the body is infected with a pathogen, T and B cells are mobilized to target and kill the pathogen. Although other immune cells are involved in this process, lymphocytes possess unique qualities that allow them to adapt during infection and become specific to the invading pathogen. In addition, once an infection has been cleared from the body, most of these lymphocytes die, but a few “memory” lymphocytes remain. Upon future reinfection with the same pathogen, these cells are immediately activated, so each successive immune response is therefore quicker and more accurate than the one before.

Cancer occurs when a series of genetic mutations, which are hereditary and/or environmental in nature, takes place in a single cell. The resulting cell proliferates without control and disrupts the normal functioning of the organ in which it originates. A lymphoid leukemia results when this process occurs in a T or B lymphocyte, and the expanding malignant cells disrupt the balance of normal blood cells in the bone marrow, blood, and lymphoid organs.

Lymphoid leukemias can be acute or chronic and can arise from lymphocytes at different stages of developmentChronic lymphocytic leukemia is a malignancy of small, morphologically mature but immunologically less mature lymphocytes that accumulate in the blood, bone marrow, lymph nodes, spleen, and liver. No single defined genetic mutation or abnormality is solely responsible for all chronic lymphocytic leukemia cases; instead, this disease is characterized by an array of different chromosomal deletions (described later). Investigators have also described a multitude of aberrations associated with apoptotic proteins, suggesting that in most cases, chronic lymphocytic leukemia cells accumulate as a result of an abnormally long life span rather than an accelerated rate of proliferation.

The median age of onset of chronic lymphocytic leukemia is 65-68 years, although approximately 20% of cases occur in people younger than age 55. Survival is dependent on the stage of disease and ranges from a median of 12 years in patients with the earliest stage to 2-5 years in those with advanced disease. Chronic lymphocytic leukemia also tends to occur more in men than in women. Onset is usually insidious, and up to 70% of patients are asymptomatic. Diagnosis is often made following routine blood tests or investigations for an unrelated disease. In symptomatic patients, the most frequent clinical findings are fatigue, loss of appetite, weight loss, and enlarged lymph nodes. Table 1 lists laboratory features typical of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia has no single pattern of progression — approximately one-third of patients never require treatment and die from causes unrelated to chronic lymphocytic leukemia; one-third have an initial indolent phase followed by progression; and the remaining third have aggressive disease at the outset requiring immediate therapy.

Chronic lymphocytic leukemia’s progressive symptoms are related to leukocyte infiltration of the bone marrow, spleen, and lymphoid tissue. This infiltration, together with disruptions in normal hematopoietic function, results in anemia, neutropenia, thrombocytopenia, and immunological dysfunction. The most important immunological dysfunction is the lack of immunoglobulins (hypogammaglobulinemia), a condition that occurs in up to 60% of patients with advanced disease. This condition leaves the patient more susceptible to infection, which is a primary cause of death and morbidity.

Chronic Lymphocytic Leukemia: PathophysiologyAutoimmune disease, an immune response against the body’s own cells and tissues, occurs in 10-35% of untreated chronic lymphocytic leukemia patients. This condition is a natural complication of chronic lymphocytic leukemia but is also associated with purine analogue therapy (a common treatment for chronic lymphocytic leukemia); however, the exact frequency of treatment-induced autoimmune disease is unknown. The autoimmunity usually manifests as autoimmune hemolytic anemia. Immune thrombocytopenia, pure red-cell aplasia, and immune neutropenia occur less frequently. Autoimmunity is usually successfully treated with corticosteroids; steroid-refractory patients may have to undergo a splenectomy.

In 3-10% of patients with chronic lymphocytic leukemia, the disease undergoes a transformation into a more aggressive condition distinct from chronic lymphocytic leukemia. The transformation is usually into large-cell lymphoma (also known as Richter’s syndrome), and the prognosis for these patients is poor — median survival is six months. Transformation into prolymphocytic leukemia occurs occasionally, and transformation into acute leukemia is rare.

TABLE. Laboratory Features Characteristic of Chronic Lymphocytic Leukemia

Diagnostic Modality Features Characteristic of Chronic Lymphocytic Leukemia
Blood count • >5,000 lymphocytes/microliter of peripheral blood.• Anemia and thrombocytopenia present at the time of initial diagnosis in approximately 20% of patients; both are usually mild, but their presence denotes a poor prognosis.

• Polyclonal increases in gamma globulins (present in approximately 15% of patients).

• Hypogammaglobulinemia (8%).

• Autoimmune thrombocytopenia (3%).

• Pure red-cell aplasia (0.5%).

• Agranulocytosis (0.5%).

Blood smear • A large number of small, morphologically mature-appearing lymphocytes are visible; the nucleus is large, a nucleolus usually not evident, and only a thin band of cytoplasm is evident (a small proportion of lymphocytes may be larger with a larger nucleus and a visible nucleolus).
  • “Smudge cells” (ruptured cells) may be visible; these are lymphocytes that appear flattened or smudged in the process of slide preparation.
  • When leukocyte counts are extremely high (in excess of 200,000/mL), whole blood viscosity may be abnormally high.
Bone marrow biopsy • The proportion of mature-appearing lymphocytes in the bone marrow aspirate exceeds 30% of all nucleated cells.
  • Infiltrative patterns of lymphocytes that may be nodular (10%), interstitial (30%), or diffuse (35%). A mixture of infiltrative patterns is observed in 25% of patients.
  • The infiltration pattern is significant in determining prognosis; diffuse infiltration is associated with advanced disease and poorer prognosis, whereas nodular and interstitial patterns (nondiffuse) are associated with less-advanced disease and better prognosis.
Cytogenetic/molecular analysis • Cytogenetic analysis is undertaken in research settings only.
Immunophenotypical analysis • Low levels of surface immunoglobulin, only a single light chain.
  • Expression of one or more B-cell-associated antigens -CD19, CD20, andCD23.
  • Coexpression of CD5.

Classification

The World Health Organization (WHO) published a consensus classification system that categorizes lymphoid disorders based on morphology, immunophenotype, genetic features, and clinical characteristics. Under the WHO classification system, chronic lymphocytic leukemia and small lymphocytic lymphoma (the lymphoid form of chronic lymphocytic leukemia) are grouped into a single entity (chronic lymphocytic leukemia).

Advances in monoclonal antibody and flow cytometry technology have established immunophenotyping as a routine diagnostic test for chronic lymphocytic leukemia. Using these methods, chronic lymphocytic leukemia is easily distinguished from other B-cell neoplasms because the cells aberrantly express CD5, a T-cell marker.

Staging

Prognostic Factors

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