Symptoms and Diagnosis
Symptoms of leukemia often resemble those caused by other, less severe illnesses, so it may not be immediately obvious to patients or physicians that symptoms are attributable to leukemia. Common signs and symptoms of leukemia include weight loss, weakness, fatigue, anemia, infection, fever, swollen lymph nodes, bruises, skin pallor, and bleeding. Enlarged spleen and liver are observed in some cases. Other possible symptoms include bone pain, and possible changes in mental status, usually in cases with central nervous system involvement (Maslak 2012; Rao 2013). Signs and symptoms vary with type and stage of leukemia (Bansal 2013; LLS 2012b). Patients with acute leukemia, especially AML, may require emergency treatment at the time of presentation (Sekeres 2009; Zuckerman 2012; Maslak 2012).
Individuals suspected of having leukemia are tested first for elevated white blood cell count. The complete blood count (CBC) test includes the white blood cell count and may reveal additional blood cell abnormalities, which can provide sufficient evidence for physicians to make a tentative diagnosis (Ferri 2014). Different types of leukemia can cause different abnormalities on a CBC, which may allow pathologists to better identify the type of leukemia the patient has (LLS 2012c). The blood may be further analyzed under a microscope to check for cell structure abnormalities indicative of leukemia. Flow cytometry may also be used in the diagnosis of CLL. This test detects markers on the surface of blood cells to help identify them (ACS 2014c). Blood analysis may be followed with a bone marrow biopsy to confirm the diagnosis and learn more about the specific leukemia cell type (ACS 2014c). In this procedure, a sample of bone marrow is aspirated from the hipbone or other large bone and leukemia cells are analyzed by a pathologist to determine their properties (ACS 2014c; Dorantes-Acosta 2013; Zhao 2014).
Additional indicators of leukemia include elevated levels of lactate dehydrogenase and uric acid, decreased fibrinogen, and increased fibrin degradation products as a result of disseminated intravascular coagulation in AML. Elevated vitamin B12 levels and elevated blood histamine levels are indicative of CML (Agis 2007; Iseki 1993; Ferri 2014). Leukocyte alkaline phosphatase (LAP) is an enzyme that plays a crucial role in mature white blood cells called granulocytes. The activity of LAP is reduced or absent in CML; this is a characteristic marker of CML (Dotti 1999).
Furthermore, abnormal white blood cells are tested for the presence of specific genetic mutations. The “Philadelphia chromosome,” present in more than 95% of patients with CML, is a mutation involving exchange of genetic material between chromosomes 9 and 22, leading to the fusion of the BCR and ABL genes (Kawasaki 1988; Foroni 2009). The Philadelphia chromosome, also present in about 20–30% of adults with ALL, is associated with a poor prognosis (Fielding 2010). A test called fluorescence in situ hybridization (FISH) is used to detect the BCR-ABL gene fusion. Another testing method, called quantitative polymerase chain reaction (PCR), can be used to quantify the number of cells in blood or bone marrow that contain the BCR-ABL fusion gene, and PCR may be useful for tracking response to treatment (LLS 2012c). Another mutation commonly found in leukemia is in the FLT3 gene. Under healthy conditions, FLT3 makes a protein that plays an important role in the survival and proliferation of blood-forming precursor cells. Mutations in the FLT3 gene lead to unlimited production of this protein, ultimately resulting in uncontrolled proliferation of the blood-forming precursor cells. FLT3 is mutated in about one-third of AML patients (Zaker 2010; Small 2006).
Imaging studies are also used to evaluate leukemia patients. Chest radiography is helpful in the evaluation of possible cancer spread, such as when mediastinal masses are suspected (the mediastinum is the part of the chest that lies between the sternum and the spinal column, and between the lungs) (Raj 2013; O'Donnell 2012; Ferri 2014). For patients with neurologic symptoms, lumbar puncture may be performed to collect cerebrospinal fluid, which is then tested for infection and inflammation. However, if the patient has circulating leukemia cells, lumbar puncture has the potential to introduce those cells into the cerebrospinal fluid. For this reason, lumbar puncture in acute leukemia patients is performed only after a dose of chemotherapy is injected into the fluid surrounding the spinal cord (Debnam 2009; Gajjar 2000). A CT scan or magnetic resonance imaging (MRI) scan of the head may follow. A CT scan of the abdomen may be performed to look for an enlarged liver (hepatomegaly) or spleen (splenomegaly) (Ferri 2014).
Staging is a critical aspect of the diagnosis of all cancers; it helps determine how aggressive the cancer is, whether it has spread, and what treatment choices are appropriate (ACS 2012). Since leukemias are not solid tumors, staging is largely based on results of blood tests, bone marrow analysis, and determination of the molecular properties of leukemia cells (ACS 2014a).
CLL. In the United States, CLL is typically staged using the Rai system. Originally developed in 1968, the Rai system divides CLL into five stages starting from the least severe stage, Rai stage 0, in which patients have an increase in overall lymphocyte count (lymphocytosis) but no enlargement of lymph nodes, spleen, or liver and near normal red blood cell and platelet counts. In the most severe stage, Rai stage IV, patients have lymphocytosis along with too few platelets, with or without anemia, and enlarged lymph nodes, spleen, or liver. Rai stages are associated with escalating levels of risk of the disease worsening or treatment being required. Rai stage 0 is considered low risk, stages I and II are intermediate risk, and stages III and IV are high risk (ACS 2014a).
CML. The approach to staging CML differs from that of CLL in that, rather than being assigned stage numbers, cases are grouped into one of three “phases”: chronic, accelerated, or blast. Untreated CML will usually progress from chronic to blast, which is sometimes referred to as “acute blast crisis” (UMMC 2014). There is some variation as to how patients are grouped into the three CML phases; the descriptions here are based on commonly used criteria proposed by the World Health Organization (ACS 2014d).
- In chronic phase CML, patients have less than 10% blasts in their blood or bone marrow, usually have relatively mild symptoms, and respond well to standard-of-care treatment regimens. Most patients receive their diagnosis during this phase.
- The accelerated phase is characterized by 10–20% blasts in the patient’s blood or bone marrow, elevated basophil count, elevated white blood cell count that does not respond to treatment, abnormal (very high or very low) platelet count not caused by treatment, and evidence of genetic abnormalities in leukemia cells. Patients in the accelerated phase may experience fever, loss of appetite, and weight loss; accelerated phase CML is not as responsive to treatment as chronic phase CML.
- The blast phase may resemble an aggressive acute leukemia and is characterized by greater than 20% blasts in a blood or bone marrow sample. During this phase, the patient’s symptoms are often pronounced and include fever, poor appetite, and weight loss. Blast cells can spread to tissues and organs during the blast phase, and the prognosis worsens (UMMC 2014).
Acute leukemias. In the past, acute leukemias were classified in accordance with the French-American-British system, which was developed in the 1970s. However, this system has largely been superseded by classification based upon the morphologic, molecular, and genetic characteristics of leukemia cells. There are numerous subtypes of acute leukemias, and proper identification of each patient’s leukemia is critical because the treatment approach that works for one subtype may not work for others (ACS 2014e; ACS 2014f).