Approach

Most cases of CLL are diagnosed incidentally following a routine complete blood count (CBC) for an unrelated reason.[32] 

History

Patients may present with swollen lymph nodes. They are painless and usually not associated with any other symptoms.

A minority of patients (approximately 10%) present with B symptoms (fever, drenching night sweats, unintentional weight loss) or other symptoms (e.g., chills, fatigue).[4]

Patients with advanced disease may present with shortness of breath (from anemia), epistaxis (from thrombocytopenia), or recurrent infections (from hypogammaglobulinemia).

Physical examination

A complete physical exam should be performed, giving particular attention to the liver, spleen, and lymph nodes in the cervical, axillary, and inguinal areas.[33]

Pallor (from anemia), petechiae (from thrombocytopenia), and hepatomegaly, splenomegaly, and lymphadenopathy should be sought.

The presence of lymphadenopathy and/or organomegaly can guide staging and treatment. See Diagnostic criteria and Management sections.

Diagnostic tests

Blood tests used to diagnose CLL include:[2][28][29][30]​​[33][34][35][36][37][38][39]

  • CBC with differential: patients with CLL usually present with absolute lymphocytosis as an incidental finding on a routine CBC. A diagnosis of CLL requires a monoclonal B lymphocyte count ≥5000 cells/microliter (≥5 × 10⁹/L) in the peripheral blood that persists for at least 3 months (see flow cytometry). Patients may present with cytopenias (anemia, thrombocytopenia), which could be disease-related (i.e., leukemic cells infiltrating the bone marrow) or related to an autoimmune complication (e.g., autoimmune hemolytic anemia, immune thrombocytopenic purpura).​ The presence of cytopenias can guide staging and treatment. See Criteria and Management sections.

  • Peripheral blood smear: to identify (morphologically) the presence of CLL cells in the blood. Smudge cells (damaged lymphocytes) are a common finding on a blood smear of patients with CLL. Patients with higher numbers of smudge cells typically experience less aggressive disease.​ Smudge cells are not diagnostic of CLL.

  • Flow cytometry: confirms clonality and immunophenotype of circulating B lymphocytes. The typical immunophenotype of CLL is: CD5+, CD23+, CD43+/-, CD10-, CD19+, CD200+, CD20 dim, surface immunoglobulin (sIg) dim+ (with restricted expression of either kappa or lambda immunoglobulin light chains), and cyclin D1-. Flow cytometry may also identify markers for prognostication (e.g., zeta-associated protein [ZAP-70], CD38, and CD49d).​ Although expression of ZAP-70, CD38, or CD49d predict a worse prognosis, there is no evidence to suggest that early treatment improves survival in patients with these markers.

If the CLL diagnosis is premised on a lymph node biopsy or bone marrow biopsy, comprehensive hematopathologic review of peripheral blood smear and all slides is required.[33] Lymph node biopsy or bone marrow biopsy is, however, rarely needed for the diagnosis of CLL.

Other investigations

The diagnostic workup for CLL may include other investigations to help guide diagnosis, prognosis, and treatment.

Serum beta-2 microglobulin

An important prognostic factor included in the CLL International Prognostic Index (CLL-IPI; see Diagnostic criteria section).[33][40]​​​ Elevated serum beta-2 microglobulin is associated with a poor prognosis.[41][42]

Fluorescence in situ hybridization (FISH)

Peripheral blood should be subject to FISH (cytogenetic analysis) to help determine prognosis and to aid treatment decisions.[2][33][36]​​​​​​ Cytogenetic abnormalities of prognostic significance in CLL include: del(13q), del(11q), trisomy 12, and del(17p).[25]​ Del(17p) is associated with resistance to chemoimmunotherapy, rapid disease progression, and a poor prognosis.[25][43]

Molecular genetic tests

Used to determine TP53 and immunoglobulin heavy chain (IgHV) mutation status, which can inform prognosis and treatment.[2][33]​​​

Other genetic mutations of potential clinical relevance include NOTCH1, SF3B1, ATM, and BIRC3; however, their role in guiding management of CLL requires further investigation.[22][36][44]​​​​​​ 

Direct antiglobulin test (DAT)

Should be considered in patients who are anemic to detect autoimmune hemolytic anemia.

Serum quantitative immunoglobulins

Patients with recurrent infections should have their immunoglobulin levels analyzed to assess for hypogammaglobulinemia.

Staging CLL

Staging is based on physical exam and blood counts (see Diagnostic criteria section).[2][37]

Routine computed tomography (CT) scans are typically not required for diagnosis, staging, or follow-up.[2][33][36][37]​​​[45]​​​​​[46]

CT scans do not improve the outcome for patients with early-stage CLL and do not aid with staging or prognosis; they also expose patients to radiation and may detect incidental, clinically irrelevant findings that lead to further tests.[45]

CT scan may be used to assess symptoms of bulky disease, or to assess the risk for tumor lysis syndrome (TLS) prior to initiating treatment (e.g., venetoclax).[33][36]​​​

Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan may be used to direct nodal biopsy if histologic (Richter) transformation is suspected.[33][46]

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