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Small mature lymphocytes, CLL and MBL

14 min

  • Recognize a small mature lymphocytosis that needs flow cytometry for clonality
  • Name the flow cytometry result that separates CLL from monoclonal B-cell lymphocytosis

Read the full reference

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)?

The next section explains it.

Right. The next section explains why.

The next section explains it.

The next section explains it.

Get the idea

A compatible film awaits a count

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 The film pattern is compatible with CLL, and it calls for flow cytometry to settle the question.

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.1 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 call MBL as CLL.

Two prognostic markers

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 variable read alongside it.1 These markers guide risk assessment and treatment planning once the diagnosis is settled. They play no part in separating CLL from MBL, which rests on the clonal B-cell count, its persistence, and any qualifying lymphadenopathy, organomegaly, or cytopenia.1,2

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

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. Read the flow result: 4.1 × 10³/µL clonal B cells is the number that matters here, apart from the 6.2 × 10³/µL total lymphocyte count.

    The iwCLL threshold measures the clonal B-cell count, and 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 those findings: none are present.

    Lymphadenopathy, organomegaly, or a disease-related cytopenia can establish CLL even below the blood threshold.

  4. Report the pattern as 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, is the definition of MBL.

Report monoclonal B-cell lymphocytosis: the clonal B-cell count of 4.1 × 10³/µL is below the 5 × 10³/µL iwCLL threshold, and no lymphadenopathy, organomegaly, or cytopenia is present to establish CLL at a lower count.

Your turn

Problem 1 of 3

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, and their absence on one preparation does not remove the compatible pattern the lymphocytes themselves show.

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 read from the lymphocytes themselves. A preparation that happens to show fewer smudge cells still carries a CLL-compatible film.

Hint
  1. Smudge cells are a preparation artifact. The film does not require them.
  2. The chromatin pattern and cell size are what define a CLL-compatible film, along with the lymphocytosis itself.

Review Chronic lymphocytic leukemia

Problem 2 of 3

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 decides 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 alongside the count.
  3. A count below the threshold, with no qualifying findings, has its own name.

Review Chronic lymphocytic leukemia

Problem 3 of 3

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

Review Chronic lymphocytic leukemia

Use 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/µL7.1 × 10³/µL1 year ago4.5–11.0 × 10³/µLHigh
Absolute lymphocytes8.9 × 10³/µL2.4 × 10³/µL1 year ago1.0–4.8 × 10³/µLHigh
Hemoglobin14.2 g/dL14.5 g/dL1 year ago13.5–17.5 g/dL
Platelets245 × 10³/µL260 × 10³/µL1 year ago150–400 × 10³/µL

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 is what 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 supplies the clonal count and phenotype needed to go further.

The absence of symptoms bears on whether MBL or CLL applies once the clonal count is known. It does not stand in for the flow result.

Review Chronic lymphocytic leukemia

Decision 2 of 3

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

The phenotype identifies the type of clone. The clonal B-cell count and its persistence over time are what separate CLL from MBL, and the phenotype alone 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. No lymphadenopathy, organomegaly, or cytopenia is needed when the blood threshold itself is met.

A sustained clonal B-cell count of 5 × 10³/µL or more meets the iwCLL threshold on its own. Lymphadenopathy or organomegaly is not required when this route is met.

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 through this route.

Review Chronic lymphocytic leukemia

The clue that settles this case is the clonal B-cell count read on its own, twice: 6.4 × 10³/µL with the CLL phenotype, confirmed sustained on a repeat panel 4 months later. That count clears the 5 × 10³/µL iwCLL threshold by itself, so CLL is reported without needing lymphadenopathy, organomegaly, or a cytopenia.

Keep

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