Acute lymphoblastic leukemia

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Acute lymphoblastic leukemia, also known as acute lymphocytic leukemia or acute lymphoid leukemia (ALL), is an acute form of leukemia, or cancer of the white blood cells, characterized by the overproduction and accumulation of cancerous, immature white blood cells, known as lymphoblasts.

In persons with ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells (such as red and white blood cells and platelets) in the bone marrow and by spreading (infiltrating) to other organs. ALL is most common in childhood, with a peak incidence at 2–5 years of age and another peak in old age.

The symptoms of ALL are indicative of a reduced production of functional blood cells, because leukemia wastes the resources of the bone marrow that are normally used to produce new, functioning blood cells.

These symptoms can include fever, increased risk of infection (especially bacterial infections like pneumonia, due to neutropenia; symptoms of such an infection include shortness of breath, chest pain, cough, vomiting), increased tendency to bleed (due to thrombocytopenia), and signs indicative of anemia, including pallor, tachycardia (high heart rate), fatigue, and headache.

About 6,000 cases are reported in the United States every year. Internationally, ALL is more common in Caucasians than in Africans; it is more common in Hispanics and in Latin America.

Cure is a realistic goal and is achieved in more than 80% of affected children, although only 20-40% of adults are cured.

“Acute” is defined by the World Health organization standards, in which greater than 20% of the cells in the bone marrow are blasts. Chronic lymphocytic leukemia is defined as having less than 20% blasts in the bone marrow.

ALL was one of the first cancers for which an effective chemotherapeutic treatment was developed. Antifolates like aminopterin and methotrexate were developed in the late 1940s by Sidney Farber and Yellapragada Subbarow.

At that time, a doctor did not need a patient’s or parent’s consent to try an experimental treatment as the Nuremberg code had not yet been signed. Desperate to save his patients, Farber initially tried folic acid supplementation as a treatment for ALL. This had disastrous consequences and he likely accelerated the children’s deaths.

Signs and symptoms

Initial symptoms are not specific to ALL, but worsen to the point that medical help is sought. They 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. Laboratory tests that might show abnormalities include blood count tests, renal function tests, electrolyte tests, and liver enzyme tests

The signs and symptoms of ALL are variable but follow from bone marrow replacement and/or organ infiltration.

  • Generalized weakness and fatigue
  • Anemia
  • Dizziness
  • Frequent or unexplained fever and infection
  • Weight loss and/or loss of appetite
  • Excessive and unexplained bruising
  • Bone pain, joint pain (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
  • Pitting edema (swelling) in the lower limbs and/or abdomen
  • Petechiae, which are tiny red spots or lines in the skin due to low platelet levels

Causes

Functional germline mutations of some cancer-related genes have been found in familial ALL or enriched in radic cases (e.g., PAX5, ETV6 and CDKN2A) accounting for ALL susceptibility for a small proportion of people, while large genome wide association studies revealed multiple inherited predisposition to ALL risk, including single nucleotide polymorphisms (SNPs) at ARID5B, IKZF1, CEBPE, PIP4K2A, GATA3, and CDKN2A loci among diverse populations.Epidemiological studies suggest that environmental factors on their own make only a minor contribution to disease risk, but environmental factors may interact with genetics.

Genome-wide association studies have found associations with a number of genetic single-nucleotide polymorphisms, including ARID5B, IKZF1 and CEBPE.

There is an increased incidence in people with Down syndrome, Fanconi anemia, Bloom syndrome, ataxia telangiectasia, X-linked agammaglobulinemia, and severe combined immunodeficiency. There is an increased risk in people with a family history of autoimmune diseases, particularly autoimmune thyroid diseases (namely Graves’ disease or Hashimoto’s thyroiditis).

Pathophysiology

In general, cancer is caused by damage to DNA that leads to uncontrolled cellular growth and spreads throughout the body, either by increasing chemical signals that cause growth or by interrupting chemical signals that control growth.

Damage can be caused through the formation of fusion genes, as well as the dysregulation of a proto-oncogene via juxtaposition of it to the promoter of another gene, e.g. the T-cell receptor gene.

This damage may be caused by environmental factors such as chemicals, drugs or radiation, and occurs naturally during mitosis or other normal processes (although cells have numerous mechanisms of DNA repair that help to reduce this).

Acute lymphoblastic leukemia is associated with exposure to radiation and chemicals in animals and humans. High level radiation exposure is a known risk factor for developing leukemia, as found by studies of survivors of atom bomb exposure in Hiroshima and Nagasaki.In animals, exposure to benzene and other chemicals can cause leukemia.

Epidemiological studies have associated leukemia with workplace exposure to chemicals, but these studies are not as conclusive. Some evidence suggests that secondary leukemia can develop in individuals treated for other cancers with radiation and chemotherapy as a result of that treatment.

Diagnosis

Diagnosing acute lymphoid leukemia begins with a medical history, physical examination, complete blood count, and blood smears. Because the symptoms are so general, many other diseases with similar symptoms must be excluded. Typically, the higher the white blood cell count, especially if the number of cancerous malignant abnormal blast cells are also high, the worse the prognosis.

Blast cells are seen on blood smear in the majority of cases (blast cells are precursors — stem cells — to all immune cell lines). A bone marrow biopsy provides conclusive proof of acute lymphocytic leukemia .

A lumbar puncture (also known as a spinal tap) will indicate whether the spinal column and brain have been invaded.

Pathological examination, cytogenetics (in particular the presence of Philadelphia chromosome), and immunophenotyping establish whether myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes) cells are the problem.

RNA testing can establish how aggressive the disease is; different mutations have been associated with shorter or longer survival. Immunohistochemical testing may reveal TdT or CALLA antigens on the surface of leukemic cells.

TdT is a protein expressed early in the development of pre-T and pre-B cells, whereas CALLA is an antigen found in 80% of ALL cases and also in the “blast crisis” of CML.

Medical imaging (such as ultrasound or CT scanning) can find invasion of other organs,  commonly the lung, liver, spleen, lymph nodes, brain, kidneys, and reproductive organs.