Hairy Cell Leukemia

HCL was initially described in 1958 under the term "leukemic reticulosis" (59). Because of the unique morphologic features of the leukemic B-cells, with their highly characteristic "hairy" cytoplasmic projections, the term hairy cell leukemia was finally accepted in 1966 (60). HCL

Table 4

Immunophenotypic Patterns of the Most Common Leukemic B-Cell Chronic Lymphoproliferative Disorders Other Than CLL

CD19 CD22 CD20/FMC7 CD5 CD10 CD23 CD79b sIg CD103 CD11c CD43 CD24 HC2 CD25 CD38

Primary leukemias

PLL

+

+

+

-/+

-

-

+

HCL

++

++

++

-

-

-

+

HCLv

++

++

++

-

-

-

+

Primary lymphomas

LPL

+

+

+

-/+(weak)

-/+(weak)

-

-/+

MCL

+

+

+

+

-/+

-

+

FL

+

+

+

-

++

-/+

+

SMZL

+

+

+

-

-

-

+

LCL

+

+

+

-/+

-/+

-/+

-/+

PLL, prolymphocytic leukemia; HCL, hairy cell leukemia; HCLv, HCL variant; LPL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; FL, follicular lymphoma; SMZL, splenic marginal zone B-cell lymphoma, LCL, large B-cell lymphoma; -, negative; +(weak), weakly positive; +, positive; ++, strongly positive.

presentation is different from that of other chronic B-cell leukemias: patients have cytopenias and splenomegaly, villous large lymphocytes in a PB smear and a dry BM aspirate (61-64).

To the best of our knowledge, the potential normal counterpart of hairy cells has not been identified so far, in either PB or BM or in lymphoid tissues such as the spleen. From the phenotypic point of view, typical hairy cells show unique features, which include coexpression of CD103, CD25, and HC2 and strong reactivity for CD11c (8,45,47,53,61-65) (Table 4). In addition, overexpression of several pan-B antigens such as CD19 and CD22 together with CD20/FMC7 is also a frequent finding (3,46,65,66). Most cases are CD5-, CD23-, and CD24- and show sIg expression of the IgG and/or the IgA isotypes, with strong reativity for CD79b (17,44,48). Based on their flow cytometry light scatter properties—forward (FSC) and sideward light scatter (SSC)—hairy cells are larger than normal B-cells from both PB and BM (3,4,25,26).

A variant form of HCL has been reported (61-64). Like classical HCL, variant cases frequently display splenomegaly, anemia, and thrombocytopenia but in association with leukocytosis and in the absence of monocytopenia (61-64). In these patients, leukocytosis is at the expense of atypical hairy cells that, together with the characteristic "hairy" cytoplasmic projections, may show a prominent nucleoli (61-64). Phenotypically, these B-cells are similar to typical hairy cells, except that they are usually CD25- and HC2- (46,47).

3.2.3. Follicular Lymphoma

Of all the primary lymphomas displaying PB involvement, FL is the most frequently observed. Although the overall incidence of PB involvement in FL has been estimated to be around 10-40% of all cases (68), the use of sensitive techniques [such as multiparameter antigen stainings analyzed by flow cytometry and the polymerase chain reaction (PCR)], shows that neoplastic B-cells are already detectable in PB at diagnosis, or they will appear later in the evolution of the disease, in a substantially higher proportion of FL cases (68,69). From the morphological point of view, these patients, in contrast to CLL cases, frequently show the presence of small lymphocytes with a cleaved nuclei or a certain degree of polymorphism with both small and large lymphocytes in the absence of smudged cells (68). Phenotypic analysis of clonal B-cells (Table 4) shows strong sIg, CD22, and CD20/FMC7 expression, together with reactivity for CD38; CD79b is usually expressed at levels intermediate between CLL and HCL (4,8,45,47,53). In addition, these cells are typically CD10+ (52) and negative for CD11c, CD23, CD5, CD43, CD103, and HC2 (4,8,25,45,47,53). It should be noted that different patterns of reactivity for the CD10 antigen have been reported, not only in FL (1,25,70) but also in multiple myeloma (71,72), such variability probably being associated with the use of different monoclonal antibody clones and fluorochrome conjugates (72). In this sense, for assessment of CD10 expression in FL either the J5 or the 5-1B4 monoclonal antibody clones conjugated to the most sensitive fluorochromes—phycoeryth-rin (PE) or PE/cyanin 5—should be used as the reference reagents (72,73).

From the genetic point of view, a high proportion (60-80%) of patients with FL have the t(14;18) translocation (68), in which the bcl2 gene from chromosome 18 is translocated into chromosome 14, close to the region where the Ig heavy chain gene is located (68,74); this translates into a very high cytoplasmic expression of the bcl2 protein (75).

Overall, the existence of neoplastic B-cells in the PB of patients with FL does not seem to influence disease outcome, except if it is associated with high white blood cell counts (> 50 x 109/L) (68). Even so, clearance of PB B-cells after treatment has been associated with a better clinical outcome in FL (76).

3.2.4. Mantle Cell Lymphoma

Around one-third of all MCLs show PB and/or BM infiltration the latter usually consisting of either a paratrabecular or a diffuse pattern (77). In these cases, differential diagnosis with B-CLL represents a major challenge. MCL is usually morphologically associated with small lymphocytes, but, in contrast to typical CLL cases, these cells show an irregular nuclei contour, with even some cleaved nuclei and nucleoli, in the absence of Gumprecht's shadows (77). Even though in both entities clonal B-cells are CD5+, CD24+, CD22+(weak), and CD11c-/+(weak) (1,8,50,4548), different patterns of expression are found in MCL compared with CLL for other phenotypic markers. Accordingly, MCL B-cells are characteristically CD23- and show high expression of sIgM+ (with or without sIgD+), CD79b, and FMC7/CD20 together with variable reactivity for CD38 and CD43 (1,2,25,50,52) (Table 4). In addition, CD54 and CD18 expression has been suggested to be particularly useful in the differential diagnosis between MCL and atypical CLL, the reactivity for both markers being higher in MCL (50). In the blastic variant of MCL (1,77), B-cells show FSC and SSC values higher than those of normal B-cells, and they are usually associated with a greater proliferative rate (77). Typically, in both the classical and variant forms of MCL, B-cells carry the t(11;14) (q13;q32) translocation, which involves the bcll and IgH genes (77) and translates into overexpression of the PRAD1/cyclin D1 protein (77,78). Although overexpression of cyclin D1 represents a characteristic phenotypic feature of MCL, until now, no reliable technique has been reported that would allow its assessment by conventional flow cytometry (79).

In MCL, the presence of neoplastic B-cells in the PB has been suggested to be associated with a worse clinical outcome (77).

3.2.5. Marginal Zone Splenic Lymphoma

MZSL has been extensively studied from both the clinical and the phenotypic point of view (80,81). MZSL frequently affects adult patients around the fifth decade of life who show a large splenomegaly in the absence of lymph node involvement (81,82); in PB, lymphocytes larger than those found in CLL patients with round nuclei, sometimes with nucleoli, basophilic cytoplasm, and characteristic "hairy" cytoplasmic projections shorter than those observed in HCL, are frequently found (81). Leukocytosis is usually moderate (between 10 and 30 x 109/L), and mild anemia and thrombocytopenia are detected in up to 20-30% of all cases, owing to hypersplenism (81). Up to 50% of SZML cases have been reported to have a serum monoclonal component typically of the IgM isotype, which is sometimes associated with the presence of Ig light chains in the urine (81).

From the phenotypic point of view, MZSL probably represents one of the most heterogeneous B-CLPD (2,80). Typically these cells show strong sIg and CD79b expression, together with reactivity for pan-B cell markers such as CD19 and CD22; in contrast to HCL, SMZL is usually CD24+ (8,45-48,53,83,84). In addition, clonal SMZL B-cells are FMC7+/CD20+ but negative or weakly positive (<25% of the cases) for CD38, CD43, and CD25 (52,80-82). Surface antigens characteristic of other B-CLPD such as CD5, CD10, CD23, CD103, and HC2 are frequently absent in MZSL (<20% positive cases) (2,80-82). In contrast, CD54 is expressed at similar levels as in MCL and FL (50).

3.2.6. Lymphoplasmacytic Lymphoma

LPL frequently shows BM involvement, with the presence of clonal B-cells in PB being less common (8,45-48,53). In PB, low to moderate numbers of clonal small B-lymphocytes fre quently coexist with typical lymphoplasmacytes or even with plasma cells (8,45-48,53). A serum monoclonal component is detected in most cases, although the use of sensitive methods such as immunofixation is frequently required for its detection (1,2,85). From the phenotypic point of view, the most characteristic features of clonal PB B-cells from patients with LPL include the absence or weak expression of CD5 and CD10 together with reactivity for pan-B-markers— CD79a+, CD19+, CD22+, and FMC7/CD20+—and CD38, associated with the presence of cytoplasmic IgM and high CD54 expression (2,8,50,45-48) (Table 4). Around half of all LPL patients have been reported to carry the t(9;14)(p13;q32) translocation (86), which involves the PAX5 gene (86) and might be of help for the differential diagnosis between this and other variants of non-Hodgkin's lymphomas (NHL).

3.2.7. Large Cell Lymphoma

Only a small proportion of all B-large cell lymphomas (<5%) show PB involvement at diagnosis (68). Typically, large immunoblasts and/or centroblasts in the PB are present that display high light scatter characteristics (FSC and SSC) and show strong reactivity for pan-B-markers such as CD19—overexpressed in immunoblastic lymphomas (87), FMC7/CD20, CD22, CD79b, and sIg (2,45-47,53); in up to 50% of the cases, neoplastic B-cells are CD10+ (52). Although most patients have a CD5-, CD23- phenotype, cases have been reported in which clonal B-cells show variable expression for these antigens (1,2) (Table 4). Some LCL cases display DNA aneuploidy by flow cytometry (88), and they typically show intermediate to high proliferative rates (88,89), which helps in the differential diagnosis with other leukemic B-CLPD. Because of the morphological appearance of the large leukemic B-cells, in some cases the myeloid (monocytic/dendritic cell) origin of the neoplastic cells has to be ruled out.

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