and may spread to other sites in the body, such as lymph nodes, the mediastinum, the spleen, the testicles, and the brain, leading to the common symptoms of the disease. Diagnosis Diagnosing ALL begins with a thorough medical history, physical examination, complete blood count, and blood smears. While many symptoms of ALL can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. Because many features on the medical history and exam are not specific to ALL, further testing is often needed. A large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for ALL because they indicate a rapid production of lymphoid cells in the marrow. The higher these numbers typically point to a worse prognosis. While white blood cell counts at initial presentation can vary significantly, circulating lymphoblast cells are seen on peripheral blood smears in the majority of cases. A bone marrow biopsy provides conclusive proof of ALL, typically with >20% of all cells being leukemic lymphoblasts. A lumbar puncture (also known as a spinal tap) can determine whether the spinal column and brain have been invaded. Brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of CNS leukemia as described above. Laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests. Pathological examination, cytogenetics (in particular the presence of Philadelphia chromosome), and immunophenotyping establish whether the leukemic cells are myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes). Cytogenetic testing on the marrow samples can help classify disease and predict how aggressive the disease course will be. 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. Immunophenotyping In addition to cell morphology and cytogenetics, immunophenotyping, a laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of ALL. The preferred method of