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Diagnosing Chronic Lymphocytic Leukemia

Background

In chronic lymphatic leukemia there is almost always a presence of clonal proliferation of B-lymphocytes with a characteristic immunophenotype CD5+C19+CD20+CD23+. The physiological parallel to the malignant cells is a small population of CD5+ B-lymphocytes localized in the mantel zone of secondary lymph node follicles. CD5+ B-lymphocytes belong to their own B-cell line. They dominate early in the oncogenesis and are known for secretion of natural auto-antibodies.

Cytogenetic anomalies

IgVH gene

Whether the IgVH gene has undergone somatic hypermutation or not, chronic lymphatic leukemia is separated into two disease groups: mutated and unmutated, which have very different prognoses. In patients with an unmutated IgVH gene, the median survival is 8–9 years, while it appears the survival for patients with a mutated IgVH gene is no different from an age-adapted normal population. The median survival is > 24 years.

Translocation

A series of cytogenetic anomalies have been described, but none of these are specific for chronic lymphatic leukemia. They are also not primary events in the disease development, but appear later in the disease course. They do not have a diagnostic value like the translocations t(14;18)(q32;q21) and t(11;14)(q13;q32) appearing in follicular lymphoma and mantel cell lymphoma respectfully, however, these cytogenetic anomalies still have a great prognostic value. 

Deletions

The most common cytogenetic anomalies are del 6q, del 13q, del 11q, del 17p, and trisomi 12, and are evident in 80% of patients using fluorescence in situ hybridization (FISH).

Median survival for the different deletions:

  • del 17p - median survival is 30 months 
  • del 11q - median survival is 68 months

These cytogentic anomalies are associated with poor prognosis and often poor and/or short-lasting effect of chemotherapy.

  • del 13q - median survival has not been reached in published studies, but 60% survive after 192 months

This karyotype is associated with a good prognosis.

Conventional chemotherapy is dependent on functioning signal pathways for apoptosis in the tumor cells to be effective. However, for del 17p in particular, this is not the case. The p53 signal pathway, which is a central signal pathway for apoptosis, is defective.

Expression of CD 38 and ZAP-70 (zeta-associated protein) was introduced as a possible surrogate marker for the unmutated IgVH gene, but none of the markers show full correlation to VH mutation status. They both appear to contribute with independent prognostic information.

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