What are the criteria for diagnosing Chronic Lymphocytic Leukemia (CLL) on a peripheral smear?

Diagnostic Criteria for CLL on Peripheral Smear

The diagnosis of CLL on peripheral smear requires small, mature-appearing lymphocytes with narrow cytoplasm borders and dense nuclei lacking discernible nucleoli with partially aggregated chromatin, accompanied by an absolute lymphocyte count ≥5,000/µL sustained for at least 3 months. 1

Morphologic Features on Blood Smear

The characteristic cells you should identify include:

• Small, mature lymphocytes with a narrow border of cytoplasm 1
• Dense nucleus lacking discernible nucleoli 1
• Partially aggregated chromatin pattern 1
• Smudge cells (nuclear shadows from ruptured lymphocytes) are characteristic but not required for diagnosis 2

Important Morphologic Caveats

• Larger atypical lymphocytes or prolymphocytes may be present but must not exceed 55% of the lymphocyte population 1
• If prolymphocytes exceed 55% OR absolute prolymphocyte count exceeds 15,000/µL, this establishes a diagnosis of prolymphocytic leukemia (PLL) rather than CLL 1

Quantitative Threshold

The absolute lymphocyte count must be ≥5,000 monoclonal B lymphocytes/µL in peripheral blood 1

Duration Requirement

• The lymphocytosis must be sustained for at least 3 months to distinguish CLL from transient reactive lymphocytosis 1
• In the 1996 NCI guidelines, only patients with questionable or indolent presentations required reassessment after 4 weeks 1

Essential Confirmatory Testing

Flow cytometry is mandatory to confirm B-cell clonality and establish the diagnosis—the peripheral smear alone is insufficient 1, 3

The characteristic immunophenotype includes:

• CD5+, CD19+, CD20+ (low), CD23+ co-expression 1, 3
• Low surface immunoglobulin, CD20, and CD79b expression compared to normal B cells 1
• Monoclonal light chain restriction (either kappa or lambda, not both) 1

Critical Differential Diagnosis

When you see CD5+ lymphocytes on smear, you must distinguish CLL from:

Mantle Cell Lymphoma

• CD23 is typically negative in mantle cell lymphoma (versus positive in CLL) 1
• If CD23 is positive, perform cyclin D1 staining or FISH for t(11;14) translocation to exclude mantle cell lymphoma 1

Small Lymphocytic Lymphoma (SLL)

• SLL has the same morphology and immunophenotype as CLL but lymphocyte count is <5,000/µL 1, 3
• SLL requires lymphadenopathy and/or splenomegaly for diagnosis 1

Common Pitfalls to Avoid

• Do not diagnose CLL based on morphology alone—flow cytometry confirmation of clonality is essential 1, 3
• Do not confuse reactive lymphocytosis with CLL—the 3-month duration requirement and flow cytometry prevent this error 1
• Do not miss mantle cell lymphoma—always check CD23 expression when evaluating CD5+ lymphocytes 1
• Do not overlook prolymphocyte percentage—exceeding 55% changes the diagnosis to PLL 1