Clinical Presentation and Diagnosis in Leukemia

Clinical Presentation of Leukemia

The presentation of ALL in children typically includes symptoms such as anorexia, fatigue, irritability, bone or joint pain, and low-grade fever. Occasionally, the duration of symptoms prior to diagnosis can be several months and include joint swelling and significant bone pain that wakes the child at night. As bone marrow failure progresses, signs such as pallor, bruising, and mucosal bleeding develop, as well as lymphadenopathy and hepatosplenomegaly.1

These signs and symptoms can also be present in children with AML. However, the presence of subcutaneous nodules, infiltration of the gingiva, disseminated intravascular coagulation, and masses (chloromas or granulocytic sarcomas) are more specific to AML than ALL.1

Like pediatric patients, adults with acute leukemia present with symptoms resulting from bone marrow infiltration.14,15 However, chronic leukemias in adults are often diagnosed incidentally on routine blood tests because initial symptoms are mild.11,12

Patients with both CLL and CML are often asymptomatic early in the disease course and may slowly develop nonspecific symptoms such as weight loss, fever, and fatigue. Most patients will have lymphadenopathy that is either localized or generalized. Hepatosplenomegaly is less common than lymphadenopathy and skin involvement is uncommon.16

Patients with CML most commonly present in the chronic phase with nonspecific symptoms like those in patients with CLL. At time of clinical presentation of leukemia, 60 to 70% of patients will have splenomegaly, which is sometimes extreme. The development of fever, significant lymphadenopathy, or skin involvement is concerning. 

Diagnosis  

Acute Lymphoblastic Leukemia

As patients with ALL are typically symptomatic at presentation, a complete blood count (CBC) is usually the first test obtained. This will often reflect anemia and thrombocytopenia. Presentation often includes neutropenia, and 20 to 40% of patients may have profound neutropenia. Alternatively, leukocytosis can also be present at the time of diagnosis.1,6,7

Leukemic cells may be reported as atypical lymphocytes before further evaluation. Most patients have circulating blasts at the time of diagnosis.1,6,7

Bone marrow aspiration is required for diagnosis of ALL and is considered diagnostic if greater than 25% of the bone marrow cells are a homogenous population of lymphoblasts. Cerebral spinal fluid examination should also be performed to evaluate for leukocytosis and the presence of blast cells, which are poor prognostic indicators.1

Additionally, cytochemical staining, assessment of immunological markers, cytogenetic analysis, and evaluation of molecular markers should be performed to distinguish B-cell from T-cell lineage and further identify the specific subgroup of disease.1,6

Acute Myeloid Leukemia

Similar to patients with ALL, those with AML typically present with anemia and thrombocytopenia. Neutropenia, including profound neutropenia, or leukocytosis may be present at the time of diagnosis.8

Diagnosis of AML can be made when greater than 20% of bone marrow cells consist of a relatively homogenous population of blast cells that appear to be in early stages of myeloid differentiation. The 2016 World Health Organization (WHO) classification of leukemias incorporates morphology, chromosomal abnormalities, and gene mutations in determination of AML subtype, so evaluation for all of these entities is also an essential part of the diagnostic process. Identification of AML subtype allows for both increased prognostic accuracy and improved selection of appropriate treatment.1,12,13

Chronic Lymphocytic Leukemia

A routine CBC showing an elevated white blood cell (WBC) count with lymphocytic predominance or a normal WBC count with lymphocytosis on differential is often the first indication of an underlying diagnosis of CLL.10

When these findings are noted on CBC, flow cytometry should then be performed for further investigation. Flow cytometry demonstrating greater than or equal to 5 × 109/L clonal B cells is diagnostic of CLL. The typical immunophenotype identified in CLL includes B-cell markers CD19, CD20, CD22, CD23, T-cell marker CD-5, and dim surface immunoglobulin kappa or lambda type. Cells should additionally be negative for CD10, CD79b, and FMC7. There are also atypical phenotypes of CLL that are identified by their morphology, cytogenetics, or clinical presentation of leukemia.10,11

Patients with CLL will often have low levels of immunoglobulins A, G, and M at the time of diagnosis, with the degree of hypogammaglobulinemia correlating to the progression of the disease. This hypogammaglobulinemia makes patients more susceptible to sinopulmonary infections with encapsulated organisms.10,11   

Chronic Myeloid Leukemia

Like CLL, CML is often identified incidentally on routine blood work. The granulocyte count is elevated on CBC in patients with CML and the degree of elevation varies between symptomatic and asymptomatic patients. Asymptomatic patients will typically have a granulocyte count of less than 50 × 109/L, while symptomatic patients can have granulocyte counts of 200 to 1000 × 109/L. Neutrophilia, basophilia, and eosinophilia may also be noted on CBC, as well as thrombocytosis and polycythemia.17

Bone marrow examination should be undertaken in evaluation for CML. Identification of the Ph chromosome on cytogenetic or molecular studies confirms the diagnosis in the 95% of patients with this genetic abnormality. The 5% of patients with atypical CML require additional testing for diagnosis. CML has the potential to transform into an accelerated phase followed by a blast phase.13,17 

Stages in Leukemia 

Because leukemia is a cancer of blood cells and bone marrow, it is generally considered disseminated at diagnosis. Therefore, traditional staging systems that incorporate lymph nodes and metastases are used in other types of cancer and are not applicable to leukemia.18

The acute leukemias are not staged, but rather prognosis is determined by the genetic and immunophenotypic characteristics used to classify the subtype of disease. CML prognosis and classification are based on the phase of disease  (chronic, accelerated, or blast).18,19

CLL is the one form of leukemia that is classified using staging systems. The Rai system is most often used in the US to stage CLL and the Binet system is used more in Europe.10,11,18

Rai Staging System

  • Stage 0 (low risk): Lymphocytosis >5,000 cell/mm and >40% of cells in the bone marrow
  • Stage 1 (intermediate risk): Lymphocytosis and lymphadenopathy
  • Stage 2 (intermediate risk): Lymphocytosis and hepatomegaly and/or splenomegaly
  • Stage 3 (high risk): Lymphocytosis and anemia
  • Stage 4 (high risk): Lymphocytosis and thrombocytopenia

Binet Staging System

  • A: <3 areas of lymphadenopathy
  • B: >3 areas of lymphadenopathy
  • C: Hemoglobin < 10g/dL and/or platelets <100,000/µL

 

References

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