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Small mature lymphocytes, CLL and MBL

14 min

Skills you'll build2 skills
  • Recognize a small mature lymphocytosis that needs flow cytometry for clonality
  • Name the flow cytometry result that separates CLL from monoclonal B-cell lymphocytosis

At the bench: Recognize abnormal cell findings that need further review

Try first

Try first

A routine CBC on an asymptomatic 74-year-old shows an absolute lymphocytosis of small mature lymphocytes with dense, clumped chromatin and scant cytoplasm. Smudge cells are frequent. Does this establish chronic lymphocytic leukemia (CLL)?

Keep going to see the reasoning.

Right. Keep going to follow the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Get the idea

Use the explanation to check your first decision.

The CLL-compatible film

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western populations, and many patients are found through a routine CBC showing absolute lymphocytosis of small mature lymphocytes with dense, clumped chromatin and scant cytoplasm.1 Smudge cells, fragile lymphocytes broken during film preparation, are common in CLL and also occur in other lymphocytoses, so they are not specific for it.1 A compatible film pattern calls for flow cytometry.

The clonal B-cell threshold

The International Workshop on CLL (iwCLL) diagnostic threshold is at least 5 × 10³/µL clonal B cells in blood, sustained for at least 3 months.2 A lower clonal count without lymphadenopathy, organomegaly, disease-related cytopenias, or symptoms is monoclonal B-cell lymphocytosis (MBL).1 A cytopenia caused by a typical marrow infiltrate can establish CLL despite a lower blood clonal B-cell count.2 Disease-associated lymphadenopathy with a lower blood clonal count and no cytopenia from a clonal marrow infiltrate calls for assessment for small lymphocytic lymphoma (SLL), usually with tissue confirmation. Organomegaly at a lower count also requires further assessment.2 Flow cytometry demonstrates clonality by showing CD19, CD20 dim, CD23, and aberrant CD5 with dim surface immunoglobulin and light-chain restriction.1 The threshold applies to the clonal B-cell count. A lymphocytosis this size also contains T cells and NK cells, so applying the threshold to the total lymphocyte count can misclassify MBL as CLL.

Prognostic markers in CLL

Unmutated IGHV arises from a pre-germinal-center cell and behaves aggressively. Mutated IGHV arises from a post-germinal-center cell and behaves indolently, so IGHV mutation status is a major prognostic factor once CLL is established.1 TP53 disruption is a major predictive marker assessed with it.1 These markers guide risk assessment and treatment planning once the diagnosis is established. Classification as CLL, SLL or MBL depends on the clonal B-cell count, its persistence, and evidence of marrow or other tissue involvement.1,2

Follow the bench demonstration

Sources for this step
References
  1. Alaggio R, Amador C, Agnarsson I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-1748. doi:10.1038/s41375-022-01620-2
  2. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398

Watch one

Read each decision and its explanation.

A CBC shows an absolute lymphocyte count of 6.2 × 10³/µL, with a film pattern of small mature lymphocytes and frequent smudge cells. Flow cytometry reports 4.1 × 10³/µL clonal B cells with a CD5-positive, CD23-positive phenotype. The patient has no lymphadenopathy, organomegaly, or cytopenias. What do you report?

  1. Use the clonal count from the flow result. The threshold is applied to the 4.1 × 10³/µL clonal B cells, and the 6.2 × 10³/µL total lymphocyte count is not used.

    The iwCLL threshold applies to the clonal B-cell count. The total lymphocyte count is a separate number.

  2. Compare with the threshold. 4.1 × 10³/µL is below 5 × 10³/µL.

    The iwCLL threshold is 5 × 10³/µL clonal B cells sustained for at least 3 months.

  3. Check for cytopenias, lymphadenopathy and organomegaly. None is present.2

    A cytopenia caused by a typical marrow infiltrate can establish CLL below the blood threshold. Disease-associated lymphadenopathy at a lower count calls for SLL assessment.

Report monoclonal B-cell lymphocytosis, and note the phenotype for follow-up. A clonal count below the threshold, with the characteristic phenotype and no qualifying findings, defines MBL.2

Practice this skill

Your turn

Problem 1 of 3 · Hints available

A film shows an absolute lymphocytosis of small, mature-appearing lymphocytes with scant cytoplasm. No smudge cells are seen on this preparation. Does the absence of smudge cells rule out a CLL-compatible pattern?

Smudge cells are common in CLL, but their absence on one preparation does not change the compatible pattern of the lymphocytes.

Treated smudge cells as specific for CLL

Smudge cells are fragile lymphocytes broken during film preparation. They are common in CLL and also occur in other lymphocytoses. CLL needs a sustained clonal B-cell count of at least 5 × 10³/µL with the characteristic phenotype, so smudge cells support referral for flow cytometry.

Small mature lymphocytes with dense, clumped chromatin and an absolute lymphocytosis define the compatible pattern. Smudge cells are a common but inconsistent feature of the preparation.

The pattern is based on the lymphocytes. A preparation with few smudge cells can still be a CLL-compatible film.

Hint
  1. Smudge cells are a preparation artifact and are not required for the pattern.
  2. The chromatin pattern, the cell size and the lymphocytosis define a CLL-compatible film.

Review Chronic lymphocytic leukemia

Problem 2 of 3 · Hints available

Flow cytometry shows 3.5 × 10³/µL clonal B cells with a CD5-positive, CD23-positive phenotype in a patient with no lymphadenopathy, organomegaly, cytopenias, or symptoms. What does this finding represent under the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria?

Correct. The iwCLL threshold is at least 5 × 10³/µL clonal B cells in blood sustained for at least 3 months. A lower clonal count without lymphadenopathy, organomegaly, disease-related cytopenias, or symptoms is monoclonal B-cell lymphocytosis.

Incorrect. The phenotype identifies the type of clone, and the clonal B-cell count determines the category. CLL needs at least 5 × 10³/µL clonal B cells for 3 months, or a cytopenia caused by a typical marrow infiltrate.

Incorrect. The threshold applies to clonal B cells, and here that count is 3.5 × 10³/µL. The total lymphocyte count also includes T cells and NK cells, so it overstates the clone.

Hint
  1. The iwCLL threshold applies to the clonal B-cell count. The total lymphocyte count is a separate number.
  2. Check for lymphadenopathy, organomegaly, cytopenias, or symptoms with the count.
  3. A count below the threshold, with no qualifying findings, has its own classification.

Review Chronic lymphocytic leukemia

Problem 3 of 3 · On your own

Flow cytometry reports 3.0 × 10³/µL clonal B cells with the characteristic CLL phenotype, sustained on a repeat count 4 months later. The patient's hemoglobin has fallen to 9.8 g/dL, and a marrow biopsy shows a diffuse infiltrate of the same clonal population accounting for the anemia. Is this CLL or MBL?

The blood clonal count alone would suggest MBL. A cytopenia caused by a typical marrow infiltrate can establish CLL despite a lower blood count.

The marrow infiltrate of the same clonal population explains the anemia. A disease-related cytopenia from a typical infiltrate establishes CLL even with a blood clonal count below the threshold.

The blood threshold is one criterion for CLL. A qualifying cytopenia from a typical marrow infiltrate is a separate criterion that does not require the blood count to reach 5 × 10³/µL.

Review Chronic lymphocytic leukemia

Use it

Read the case evidence, then make each decision. The step is complete without it.

  • A 68-year-old man (MRN 0492117) has a CBC ordered for a routine physical.
  • He reports no fatigue, weight loss, or night sweats.
  • Examination notes no palpable lymphadenopathy or splenomegaly.
  • Flow cytometry on the blood shows 6.4 × 10³/µL clonal B cells: CD19 positive, CD20 dim positive, CD23 positive, aberrant CD5 positive, with dim surface immunoglobulin and kappa light-chain restriction.
  • A repeat CBC and flow panel 4 months later show the same clonal B-cell count and phenotype.
TestResultPreviousReference intervalFlag
WBC12.8 × 10³/µL High1 year ago: 7.1 × 10³/µL7.1 × 10³/µL1 year ago4.5–11.0 × 10³/µL4.5–11.0High
Absolute lymphocytes8.9 × 10³/µL High1 year ago: 2.4 × 10³/µL2.4 × 10³/µL1 year ago1.0–4.8 × 10³/µL1.0–4.8High
Hemoglobin14.2 g/dL1 year ago: 14.5 g/dL14.5 g/dL1 year ago13.5–17.5 g/dL13.5–17.5
Platelets245 × 10³/µL1 year ago: 260 × 10³/µL260 × 10³/µL1 year ago150–400 × 10³/µL150–400

Specimen: H 2, L 5, I 1. EDTA whole blood, drawn at the routine visit

Decision 1 of 3

The film shows small mature lymphocytes with frequent smudge cells. What does this pattern call for?

Smudge cells and an absolute lymphocytosis are compatible with CLL. They are not specific for it, and flow cytometry establishes clonality.

Treated smudge cells as specific for CLL

Smudge cells are fragile lymphocytes broken during film preparation. They are common in CLL and also occur in other lymphocytoses. CLL needs a sustained clonal B-cell count of at least 5 × 10³/µL with the characteristic phenotype, so smudge cells support referral for flow cytometry.

Small mature lymphocytes with smudge cells and an absolute lymphocytosis are the compatible pattern. Flow cytometry gives the clonal count and phenotype needed for classification.

The absence of symptoms matters for classifying MBL or CLL once the clonal count is known. It does not replace the flow result.

Review Chronic lymphocytic leukemia

Decision 2 of 3

Are the clonal B-cell count and phenotype enough to establish CLL here?

The phenotype identifies the type of clone. The clonal B-cell count and its persistence over time distinguish CLL from MBL, and the phenotype cannot make that distinction.

6.4 × 10³/µL clonal B cells is above the 5 × 10³/µL iwCLL threshold, and the repeat panel at 4 months confirms it is sustained. Lymphadenopathy, organomegaly, or cytopenia is not needed when the blood threshold is met.

A sustained clonal B-cell count of 5 × 10³/µL or more meets the iwCLL threshold. Lymphadenopathy or organomegaly is not required for this criterion.

Review Chronic lymphocytic leukemia

Decision 3 of 3

What do you report for this patient?

The sustained clonal B-cell count of 6.4 × 10³/µL is above the iwCLL threshold. MBL applies to a lower clonal count with no qualifying findings.

A clonal B-cell count of 6.4 × 10³/µL with the characteristic phenotype, sustained on a repeat panel at 4 months, meets the iwCLL threshold for CLL.

The blood clonal count and its persistence already meet the iwCLL threshold. A marrow biopsy is not required to establish CLL by this criterion.

Review Chronic lymphocytic leukemia

The sustained clonal B-cell count of 6.4 × 10³/µL with the CLL phenotype, confirmed on a repeat panel 4 months later, is above the 5 × 10³/µL iwCLL threshold. CLL is reported without lymphadenopathy, organomegaly, or a cytopenia.

For reference

Sources checked