Acute lymphoblastic leukemia

 Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a form of leukemia, characterised by the overproduction and continuous multiplication of malignant and immature white blood cells (also known as lymphoblasts) in the bone marrow. It is a hematological malignancy. It could be fatal if left untreated as ALL spreads into the bloodstream and other vital organs quickly. ALL is most common in childhood with a peak incidence of 4-5 years of age.12-16 die more easily from it than others. Currently, at least 80% of childhood ALL are considered curable. 'Acute' refers to the undifferentiated, immature state of the circulating lymphocytes ("blasts"), and that the disease progresses rapidly with life expectancy of weeks to months if left untreated.

Symptoms

Initial symptoms are not specific to ALL, but worsen to the point that medical help is sought. The signs and symptoms of ALL are variable but follow from bone marrow replacement and / or organ infiltration. 

    * Generalised weakness and fatigue

    * Anemia

    * Frequent or unexplained fever and infections

    * Weight loss and/or loss of appetite

    * Excessive bruising or bleeding from wounds, nosebleeds, petechiae (red pinpoints on the skin)

   * Bone pain, joint pains (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow

     cavity)

    * Breathlessness

    * Enlarged lymph nodes, liver and/or spleen

The signs and symptoms of ALL result from the lack of normal and healthy blood cells because they are crowded out by malignant and immature leukocytes (white blood cells). Therefore, people with ALL experience symptoms from malfunctioning of their erythrocytes (red blood cells), leukocytes, and platelets not functioning properly. Laboratory tests which might show abnormalities include blood count tests, renal function tests, electrolyte tests and liver enzyme tests.

Diagnosis

Diagnosing leukemia usually begins with a medical history and physical examination. If there is a suspicion of leukemia, the patient will then proceed to undergo a number of tests to establish the presence of leukemia and its type. Patients with this constellation of symptoms will generally have had blood tests, such as a full blood count.

 These tests may include complete blood count (blasts on the blood film generally lead to the suspicion of ALL being raised). Nevertheless, 10% have a normal blood film, and clinical suspicion alone may be the only reason to perform a bone marrow biopsy, which is the next step in the diagnostic process.

 Bone marrow is examined for blasts, cell counts and other signs of disease. Pathological examination, cytogenetics (e.g. presence of the Philadelphia chromosome) and immunophenotyping establish whether the "blast" cells began from the B lymphocytes or T lymphocytes.

 If ALL has been established as a diagnosis, a lumbar puncture is generally required to determine whether the malignant cells have invaded the central nervous system (CNS).

 Lab tests (mentioned above) and clinical information may also be used to determine whether other medical imaging (such as ultrasound or CT scanning) may be required to find invasion of other organs such as the lungs or liver.

Pathophysiology 

The etiology of ALL remains uncertain, although some doctors believe that ALL develops from a combination of genetic and environmental factors. However, there is no definite way of determining the cause of leukemia.

 Scientific research has shown that the malignancies are due to subtle or less subtle changes in DNA that lead to unimpaired cell division and breakdown of inhibitory processes. In leukemias, including ALL, chromosomal translocations occur regularly. It is thought that most translocations occur before birth during fetal development. These translocations may trigger oncogenes to "turn on", causing unregulated mitosis where cells divide too quickly and abnormally, resulting in leukemia. There is little indication that propensity for ALL is passed on from parents to children.

 There have been indications that excessive exposure to high doses of radiation (such as that of nuclear reactors, notably Chernobyl, and the atomic bombs in Nagasaki and Hiroshima, Japan 1945) increases the risk of developing acute leukemia. There has also been inconclusive evidence suggesting that exposure to chemicals such as benzene can cause an increased risk for developing acute leukemia.

Cytogenetics

Cytogenetics, the study of characteristic large changes in the chromosomes of cancer cells, has been increasingly recognized as an important predictor of outcome in ALL.

Classification

 Subtyping of the various forms of ALL is done according to the French-American-British (FAB) classification, which is used for all acute leukemias (including acute myelogenous leukemia, AML). As ALL is not a solid tumour, the TxNxMx notation used in those cancers is of little use.

The FAB classification is:

     * ALL-L1: small uniform cells

    * ALL-L2: large varied cells

    * ALL-L3: large varied cells with vacuoles (bubble-like features)

 Note: The recent WHO International panel on ALL recommends that this classification be abandoned, since the morphological classification has no clinical or prognostic relevance. It instead advocates the use of the immunophenotypic classification mentioned below.

 Each subtype is then further classified by determining the surface markers of the abnormal lymphocytes, called immunophenotyping. There are three main immunologic types: B-cell, pre-B cell and T-cell. Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.

 Some cytogenetic subtypes have a worse prognosis than others. These include:

     * A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of ALL.

    * A transloca