B-Cell Chronic Lymphoid Leukemias

In healthy adults and older children, the majority of circulating lymphocytes in the blood are T cells (approximately 70% of lymphocytes) with fewer B cells (25%) and natural killer (NK) cells (5%). However, at birth this proportion is reversed, with B cells outnumbering T cells by a ratio of 2:1. The normal absolute lymphocyte count and normal relative percentage of lymphocytes also vary with age. In adults the lymphocyte count is typically 1.0–4.0 × 10 9 /L, whereas children often have much higher absolute lymphocyte counts. For example, the normal lymphocyte count for infants younger than 6 months ranges from approximately 2.0–17.0 × 10 9 /L. In healthy adults, lymphocytes typically comprise approximately 35% of all leukocytes, whereas children between the ages of 1 month and 1 year commonly exhibit a much higher relative percentage, with lymphocytes normally comprising approximately 60% of leukocytes.

Lymphocytosis is defined as an absolute lymphocyte count that exceeds the upper limit of the age-appropriate reference range, usually >4.0 × 10 9 /L for adults, and may be due to either reactive or neoplastic conditions. Reliable distinction between reactive and neoplastic etiologies can often be achieved by carefully reviewing a blood smear to evaluate the appearance of the lymphocytes in the context of the clinical findings and other laboratory data. If a neoplastic etiology is suspected, then additional techniques, most commonly flow cytometry (FC), are often used.

Normal lymphocytes are generally small cells with round nuclei, condensed (mature) chromatin, and scant cytoplasm ( Fig. 10.1 ). In contrast, reactive lymphocytosis (e.g., due to a viral infection) is typically characterized by a wide range of cell morphologies within a given blood smear, with a proportion of the lymphocytes appearing large owing to the presence of abundant cytoplasm, often with increased cytoplasmic basophilia, particularly where the cytoplasm contacts adjacent red blood cells ( Fig. 10.2 ). Some cells may appear plasmacytoid, with moderately abundant cytoplasm and an eccentrically located nucleus ( Fig. 10.3 ). Reactive lymphocytes may occasionally exhibit significant nuclear atypia, which may raise concern for a neoplastic process ( Fig. 10.4 ). Neoplastic lymphocytes often show abnormal morphologic features, particularly nuclear abnormalities. In contrast to the wide range of morphologic variability characteristic of a reactive lymphocytosis, neoplastic lymphoid cells usually appear distinctly monomorphic ( Fig. 10.5 ). Table 10.1 summarizes the morphologic features of normal, reactive, and neoplastic lymphocytes.

Fig. 10.1

Normal lymphocytes. All of these lymphocytes were photographed from the same blood smear in a healthy individual with a normal complete blood cell count. Normal lymphocytes have round nuclei, condensed chromatin, and scant cytoplasm, although some normal lymphocytes exhibit mildly irregular nuclear contours or slightly more abundant cytoplasm.

Fig 10.2

Reactive lymphocytes in (A), a patient with infectious mononucleosis, and (B), a patient with an acute viral infection of unknown type. The most characteristic feature of a reactive lymphocytosis is the wide variety of lymphocyte morphologic appearances within a given blood smear. Occasional lymphocytes appear normal, whereas others are larger and have some degree of nuclear irregularity, less condensed chromatin, and/or more abundant cytoplasm. Note the accentuated cytoplasmic basophilia where the cytoplasm contacts adjacent red blood cells, a feature commonly seen in reactive lymphocytes.

Fig. 10.3

Plasmacytoid reactive lymphocyte (same patient as in Fig. 10.2B) showing moderately abundant, basophilic cytoplasm, a pale paranuclear Golgi region, and an eccentrically located nucleus, similar to the appearance of a normal plasma cell.

Fig. 10.4

Reactive lymphocytes in a patient with acute human immunodeficiency virus infection. Occasionally, reactive lymphocytes may show significant nuclear irregularity that may raise concern for a leukemia or lymphoma. These cases require careful correlation with the clinical impression and may necessitate further evaluation, such as by flow cytometry.

Fig. 10.5

Neoplastic lymphocytosis (circulating Sézary cells in a patient with mycosis fungoides). In contrast to a reactive lymphocytosis, neoplastic lymphocytes characteristically exhibit a monomorphic appearance in which all of the lymphocytes show similar atypical morphologic features.

Table 10.1

Morphologic Features of Normal, Reactive, and Neoplastic Lymphocytes

Morphology Normal Lymphocytes Reactive Lymphocytes Neoplastic Lymphocytes
General features Limited spectrum of cell shapes and sizes Marked variability in size and shape of cells; occasional immunoblasts or plasmacytoid forms may be seen Often a monomorphic population showing similar atypical morphologic features from cell to cell
Cell size 7–15 μm 10–25 μm 8–30 μm
Nuclear-to-cytoplasmic ratio 5:1 to 2:1 3:1 to 1:2 7:1 to 3:1
Nucleus Dense chromatin; no distinct nucleoli (subtle chromocenters may be seen) Variably condensed chromatin; occasional cells have nucleoli (e.g., immunoblasts) Nuclei may be cleaved or have irregular contours; chromatin varies from dense to fine and reticulated; nucleoli are variably prominent
Cytoplasm Scant, pale blue Abundant, pale blue; often stains darker blue at contact points with adjacent red blood cells Often scant, but sometimes moderately abundant; some leukemia types have cytoplasmic projections; some high-grade lymphomas have deeply basophilic cytoplasm with vacuoles

The remainder of this chapter provides an overview of the B-cell chronic leukemias, including some B-cell lymphoproliferative disorders that precede overt B-cell chronic leukemias ( Box 10.1 ). Chronic leukemias of T-cell or NK-cell type are discussed in Chapter 13 .

Box 10.1

2017 World Health Organization Classification of B-cell Chronic Leukemias and Related Lymphoproliferative Disorders (Abbreviated List)

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma

    • Monoclonal B-cell lymphocytosis

  • B-cell prolymphocytic leukemia

  • Splenic marginal zone lymphoma

  • Hairy cell leukemia

  • Splenic B-cell lymphoma/leukemia, unclassifiable

    • Splenic diffuse red pulp small B-cell lymphoma

    • Hairy cell leukemia variant

  • Lymphoplasmacytic lymphoma

  • Plasma cell neoplasms

  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

  • Nodal marginal zone lymphoma

  • Follicular lymphoma

  • Mantle cell lymphoma

  • Diffuse large B-cell lymphoma and related subtypes

  • Burkitt lymphoma

  • High grade B-cell lymphoma

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in Western countries. The incidence rate ranges from 5 to 20 cases per 100,000 population, with higher rates in individuals older than 70 years. The median age at diagnosis is 72 years, and there is a male predominance (male-to-female ratio of approximately 2:1). CLL has the highest genetic predisposition among all hematologic malignancies; 5% to 10% of patients have a family history of CLL at the time of diagnosis.

CLL is morphologically and phenotypically indistinguishable from small lymphocytic lymphoma (SLL), differing only in the degree of peripheral blood lymphocytosis and involvement of secondary lymphoid tissues. CLL is diagnosed when there is a peripheral blood clonal lymphocyte count of 5.0 × 10 9 /L or higher with a CLL-like phenotype demonstrated by FC. SLL is diagnosed when there is evidence of nodal, splenic, or extramedullary involvement and the clonal, CLL-like lymphocyte count in the blood is less than 5.0 × 10 9 /L. Patients present as either CLL or CLL/SLL in 80% to 90% of cases. Only 10% to 20% of patients lack significant blood involvement and are classified as SLL. Clonal, CLL-like proliferations less than 5.0 × 10 9 /L without lymphadenopathy, organomegaly, or other features of a B-cell lymphoproliferative disorder are classified as monoclonal B-cell lymphocytosis (MBL) ( Fig. 10.6 ).

Fig. 10.6

Diagnostic criteria for disease classification as either chronic lymphocytic leukemia ( CLL ), small lymphocytic lymphoma ( SLL ), combined CLL/SLL, or monoclonal B-cell lymphocytosis ( MBL ).

Patients with CLL are often asymptomatic and the disease is identified incidentally when a complete blood cell count is performed for an unrelated reason. Some patients present with lymphadenopathy or splenomegaly, leading to a diagnosis of CLL/SLL or SLL. Uncommonly, the disease is identified during evaluation for an immune-mediated cytopenia such as a hemolytic anemia or immune thrombocytopenia. A small paraprotein, usually of the immunoglobulin M(IgM) type, can be identified in approximately 10% of patients.

The lymphocytes of CLL/SLL are generally small and have round nuclei, condensed chromatin, and scant cytoplasm. Individual CLL cells may be difficult to distinguish from normal lymphocytes. Morphologic clues suggestive of CLL include a marked lymphocytosis, the presence of many smudge cells, and subtle cytologic abnormalities such as a cracked appearance to the chromatin ( Fig. 10.7A ). A smudge cell represents a disrupted lymphocyte nucleus that has been stripped of cytoplasm and occurs as an artifact of blood smear preparation owing to the fragility of the CLL cells. Smudge cells can be reduced by adding a drop of serum albumin to four or five drops of blood before making the blood smear ( Fig. 10.7B ). Note that smudge cells are not specific to CLL/SLL and may be seen in other lymphoproliferative disorders or in reactive lymphocytes.

Fig. 10.7

Chronic lymphocytic leukemia (CLL) in peripheral blood. Neoplastic lymphocytes in CLL are typically small and have scant cytoplasm and condensed chromatin, often with cracks (so-called cracked earth or soccer ball chromatin). (A) Frequent smudge cells are common in CLL and arise as an artifact of slide preparation owing to the fragility of the neoplastic lymphocytes. (B) This blood smear is from the same patient but was prepared after adding a drop of albumin to the blood, which stabilizes the cell membranes and greatly reduces the number of smudge cells.

Some cases of CLL/SLL show atypical morphologic features such as larger cell size or a greater degree of nuclear atypia ( Fig. 10.8 ). Prolymphocytes, which are larger lymphoid cells with more dispersed chromatin and a characteristic prominent nucleolus, are often present in low numbers in cases of CLL/SLL (often <5% of lymphocytes). CLL/SLL cases with more than 15% prolymphocytes suggest disease progression and may be associated with worsening clinical symptomatology ( Fig. 10.9 ).

Fig. 10.8

Chronic lymphocytic leukemia (CLL) with atypical morphologic features. (A) CLL cells exhibit mild to moderate nuclear irregularity, have larger cell size, and/or have more abundant cytoplasm. (B) CLL cells show significant nuclear irregularity. Two prolymphocytes with prominent pale nucleoli are also present. Occasional prolymphocytes are common in CLL but when increased (e.g., >15% of leukocytes) are associated with more aggressive clinical behavior.

Fig. 10.9

Chronic lymphocytic leukemia (CLL) with increased prolymphocytes. This image demonstrates small lymphocytes and several smudge cells typical of CLL, but it also shows three larger prolymphocytes with more dispersed chromatin and a prominent central nucleolus. One cell at the left side of the image shows features intermediate between a typical CLL cell and a prolymphocyte and is difficult to classify.

Bone marrow (BM) involvement is present in the vast majority of CLL cases and usually occurs in an interstitial (nonparatrabecular) distribution. The lymphoid infiltrate may appear diffuse, nodular, or as a combination of these patterns ( Fig. 10.10 ).

Fig. 10.10

Chronic lymphocytic leukemia/small lymphocytic lymphoma in bone marrow with (A) diffuse interstitial involvement by small lymphocytes, and (B) nodular involvement of the marrow interstitium.

Lymph node involvement in SLL or CLL/SLL is characterized by effacement of the normal nodal architecture by a diffuse infiltrate of small lymphocytes. At low power, there are characteristic subtle pale areas referred to as proliferation centers that contain increased numbers of larger lymphoid cells and impart a pseudo-nodular appearance ( Fig. 10.11 ). Larger lymphoid cells in the proliferation centers include prolymphocytes and slightly larger paraimmunoblasts ( Fig. 10.12A ). Transformation to diffuse large B-cell lymphoma, referred to as Richter transformation, occurs in 2% to 8% of patients with CLL/SLL and portends a very poor prognosis ( Fig. 10.12B ).

Fig. 10.11

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in a lymph node. The normal lymph node architecture is completely effaced. This low-power image shows multiple pale pseudonodules that impart a “cloudy sky” appearance characteristic of CLL/SLL. The pale clouds are referred to as proliferation centers and, when viewed at high power, are found to contain a number of admixed larger lymphoid cells (prolymphocytes and paraimmunoblasts).

Fig. 10.12

Chronic lymphocytic leukemia/small lymphocytic lymphoma in a lymph node. (A) This high-power view of a proliferation center shows many small lymphocytes with dark, compact chromatin as well as frequent larger cells with vesicular chromatin and prominent nucleoli (prolymphocytes and paraimmunoblasts). (B) Other areas of this lymph node show sheets of large lymphoid cells with vesicular chromatin, consistent with transformation to diffuse large B-cell lymphoma (Richter transformation).

FC is essential for the diagnosis of CLL/SLL because the disease has a characteristic phenotype ( Table 10.2 ). CLL/SLL cells express pan–B-cell antigens such as CD19 and CD20, with CD20 expression often dimmer than normal B cells. The vast majority of cases express CD5, CD23, and CD200 and show dim monotypic κ or λ surface light chain expression. Approximately 80% to 90% of cases have cytogenetic abnormalities detectable by fluorescence in situ hybridization (FISH). Particular cytogenetic abnormalities, as well as molecular assays and other established prognostic features such as ZAP70 and CD38, are useful in determining an individual’s prognosis and can help guide therapy ( Table 10.3 , Fig. 10.13 ).

Table 10.2

Typical Flow Cytometry Phenotypes of B-cell Lymphomas/Leukemias

Disease CD5 CD10 CD11c CD20 CD22 CD23 CD25 CD103 CD123 CD200 FMC7
CLL/SLL + −/+ +(d) + + +
B-PLL −/+ + + −/+ −/+ +
HCL +(b) +(b) +(b) + + + +(b) +
HCL-v + +(b) + v + −/+ +
SMZL +/− + + −/+ +/− +
LPL + + −/+ +/− +/− +
FL + + + −/+ +
MCL + + + +

+, positive; −, negative; -/+, often negative; +/-, often positive; b, bright; B-PLL, B-cell prolymphocytic leukemia; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; d, dim; FL, follicular lymphoma; HCL, hairy cell leukemia; HCL-v, HCL variant; LPL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; SMZL, splenic marginal zone lymphoma; v, variable.

Table 10.3

Prognostic Factors in CLL/SLL

Type of Testing Abnormality Frequency Better Prognosis Worse Prognosis
FISH No FISH abnormality 10%–20% +
del(13q14) 50% +
+12 20% +
del(11q22-23) ATM , BIRC3 10%–15% +
del(17p) TP53 5%–10% +
del(6q21) MYB 5% +
Molecular Mutated IGHV genes 50%–70% +
Unmutated IGHV genes 30%–50% +
TP53 mutation 5%–10% +
Flow cytometry ZAP70 + 25%–45% +
CD38 + 30%–40% +

CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; FISH, fluorescence in situ hybridization.

Fig. 10.13

Fluorescence in situ hybridization showing del(17p) in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). A normal cell (upper right) contains two green signals for the centromere of chromosome 17 and two red signals for the 17p13.1 locus. The cell in the lower left contains only one red signal, indicating del(17p). This deletion involves loss of the TP53 gene and is associated with a poor prognosis in CLL/SLL.

Image courtesy Debra Saxe, PhD.

For many years, clinical staging has been based on either the Rai or Binet system, and these systems are still widely used ( Table 10.4 ). In 2016, an international prognostic index for CLL/SLL was published, which includes the Rai or Binet stage but also incorporates the powerful negative prognostic impact of certain molecular genetic abnormalities, particularly del(17p) or TP53 mutation ( Table 10.5 ).

Table 10.4

Rai and Binet Staging Systems for Classification of Chronic Lymphocytic Leukemia

From Genentech. New disease perspectives and goals of therapy in CLL. Available at: https://docplayer.net/15673631-New-disease-perspectives-and-goals-of-therapy-in-cll.html.

System Stage Definition Median Survival
Rai staging system 0 (low risk) Lymphocytosis only 11.5 years
I (intermediate risk) Lymphocytosis and lymphadenopathy 11.0 years
II (intermediate risk) Lymphocytosis in blood and marrow with splenomegaly and/or hepatomegaly (with or without lymphadenopathy) 7.8 years
III (high risk) Lymphocytosis and anemia (hemoglobin <11 g/dL or hematocrit <33%) 5.3 years
IV (high risk) Lymphocytosis and thrombocytopenia (platelet count <100,000/mm 3 ) 7.0 years
Binet staging system A Enlargement of <3 lymphoid areas (cervical, axillary, inguinal, spleen, liver); no anemia or thrombocytopenia 11.5 years
B Enlargement of ≥3 lymphoid areas 8.6 years
C Anemia (hemoglobin <10 g/dL or thrombocytopenia platelet count <100,000/mm 3 ), or both 7.0 years

Table 10.5

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma International Prognostic Index

Prognostic Feature Adverse Factor Grade
Age >65 years 1
Clinical stage Rai I–V or Binet B–C 1
β 2 -microglobulin level >3.5 mg/L 2
IGHV mutation status Unmutated (>98% homology with germline) 2
Del(17p) and/or TP53 mutation Present 4

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Apr 3, 2021 | Posted by in HEMATOLOGY | Comments Off on B-Cell Chronic Lymphoid Leukemias

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