Diagnosis and Staging

The onset of Chronic Lymphocytic Leukemia (CLL) is often subtle and it is not unusual for CLL to be discovered incidentally during a blood test performed for another reason; up to 50% of patients are asymptomatic when diagnosed.¹ In patients who are symptomatic, enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients. Other typical symptoms include enlargement of the liver or spleen, recurrent infections, loss of appetite or early satiety, abnormal bruising, fatigue, and night sweats.¹

Diagnosis

The following criteria are used to definitively diagnose CLL, as detailed in the European Society for Medical Oncology (ESMO) guidelines:²

1. The presence of ≥5,000 monoclonal B-lymphocytes/μL; the clonality of the B-lymphocytes should be confirmed using flow cytometry.
2. The leukemia cells found in the blood smear should be characteristically small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli, and having partially aggregated chromatin

CLL cells express the CD5 antigen and B-cell surface antigens: CD19, CD20 and CD23. CD20 and CD79b levels are characteristically low compared with those found on normal B-cells. Each clone of leukemia cells expresses either kappa or lambda immunoglobulin light chains.²

Small Lymphocytic Lymphoma (SLL) and CLL are considered to be the same entity by the World Health Organization (WHO) classification system and their cells share the same immunophenotype. SLL patients exhibit lymphadenopathy and/or splenomegaly, with the number of B-lymphocytes in the peripheral blood ≤5x10⁹/L; its specific diagnosis can be confirmed by lymph node biopsy.²

Monoclonal B-lymphocytosis (MBL) is defined as the presence of <5,000 monoclonal B-lymphocytes/μL in the absence of lymphadenopathy and organomegaly, cytopenias or clinical symptoms. Progression from MBL to CLL occurs in only 1–2% of cases per year, however, this progression is the origin of most CLL cases.²

Staging

CLL has an extremely heterogeneous prognosis, with median survival rates varying between 18 months and >10 years.¹ Two prognostic staging systems are used: the Binet system (more commonly used in Europe) and the revised Rai system (more commonly used in United States).^3,4 These staging systems describe three subgroups with discrete clinical outcomes and assist clinicians in categorizing patients by prognosis. Both systems are established by physical examination and blood counts.²

The Binet staging system is based on the number of involved areas, as defined by the presence of enlarged lymph nodes of greater than 1 cm diameter or organomegaly, and whether there is anemia or thrombocytopenia (Table 1).² The areas of involvement considered for staging are head and neck, axillae, groins, palpable spleen, and palpable liver.

The Rai staging system was introduced in the mid-1970s and consisted of five stages.⁵ A simpler, modified version, consisting of three stages was later proposed in 1987 (Table 2).² The modified Rai classification defines low-risk disease as patients who have lymphocytosis with leukemia cells in the blood and/or marrow. Patients with lymphocytosis, enlarged nodes in any site, and splenomegaly and/or hepatomegaly are defined as having intermediate-risk disease. High-risk disease includes patients with disease-related anemia or thrombocytopenia.⁴

Table 1. Binet staging system.²

Stage

Clinical features

Median survival (years)

A

·         Hemoglobin ≥10 g/dL

·         Thrombocytes ≥100,000/μL

·         <3 node-bearing areas

>10

B

·         Hemoglobin ≥10 g/dL

·         Thrombocytes ≥100,000/μL

·         ≥3 node-bearing areas

>8

C

·         Hemoglobin <10 g/dL

·         Thrombocytes <100,000/μL

6.5

 

Table 2. Rai staging system.¹

Stage

Clinical features

Stage

Median survival (years)

0

Lymphocytosis

>15 x 10⁹/l

Low

>10

I

Lymphocytosis Lymphadenopathy

Medium

>8

II

Lymphocytosis
Splenomegaly
± hepatomegaly
± lymphadenopathy

>8

III

Lymphocytosis
Anemia (hemoglobin, <11.0 g/L) 
± organomegaly
± lymphadenopathy

High

1.5

IV

Lymphocytosis

thrombocytopenia (platelets, <100,000 /μL)
± organomegaly
± lymphadenopathy

 1.5

Additionally, further markers such as TP53, del(17p), ZAP70, and CD38 can be used to predict the prognosis of patients with CLL particularly at the early stage.¹