Chronic Lymphocytic Leukemia

CLL represents a monoclonal proliferation of mature-appearing B lymphocytes, although approximately 5 percent of patients have a T-cell variant.152-155 Patients with B-cell CLL present with generalized lymphadenopathy, splenomegaly, and/or slowly progressive lymphocytosis. Although lymphocyte counts in patients with CLL may exceed 200,000/p.l, in contrast to the "sticky" myeloblasts in AML, leukostatic syndromes (cerebral or lung involvement) are rare.156 An absolute lymphocyte count of greater than 10,000/p.l is required for the diagnosis of CLL. However, it may be possible to suggest the diagnosis of CLL in patients with lower lymphocyte counts, if immuno-phenotypic analysis documents the presence of cells that have a characteristic surface marker profile.157 Such immunopheno-typic characteristics detailed in Chapter 6 include the presence of B-cell markers, including weak surface immunoglobulin expression with co-expression of the T1 or CD5 nominal T-cell antigen.158 Fairly specific for the diagnosis of CLL, CD5 expression is also seen on cells from patients with intermediate lymphoma (mantle cell lymphoma). Mantle cell lymphoma is typ-

Table 3-5. WHO Classification System

B-cell neoplasms Precursor B-Cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lympoblastic leukemia) Mature (peripheral) B-cell neoplasmsa B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocyte leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma ( + /- villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of MALT type Nodal marginal zone B-cell lymphoma ( + /- monocytoid

B cells) Follicular lymphoma Mantle-cell lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma Burkitt's lymphoma/Burkitt cell lymphoma T-cell and NK-cell neoplasms Precursor T-cell neoplasm Precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia) Mature (peripheral) T-cell neoplasmsa T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-cell lymphoma Adult T-cell lymphoma/leukemia (HTLV1+) Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sezary syndrome Anaplastic large cell lymphoma, T/null cell, primary cutaneous type Peripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, T/null cell, primary systemic type

Abbreviations: HTLV1+, human T-cell leukemia virus; MALT, mucosa-associated lymphoid tissue; NK, natural killer.

Note: Only major categories are included. Subtypes and variants will be discussed in the WHO book2 and are listed in Tables 7 through 16. Common entities are shown in boldface type.

a B- and T-/NK-cell neoplasms are grouped according to major clinical presentations (predominantly disseminated/leukemic, primary extranodal, predominantly nodal).

ically CD23 negative, which is positive in CLL. The lack of expression of CD79b and CD22 also distinguishes CLL from other indolent ß-cell neoplasms.159

Cytogenetic abnormalities, usually trisomy 12, occur in 40 percent of patients with CLL.160 Patients whose cells carry additional chromosomal abnormalities have a worse prognosis than those who have trisomy 12 as the sole cytogenetic abnormal-ity.161>162 Atypical morphology and p53 mutations also augur for a worse prognosis.152 The low proliferative index character istic of CLL cells reduces the rate of successful metaphase spreads required for cytogenetic analysis. However, the technique of FISH allows detection of cytogenetic abnormalities in cells from approximately twice as many CLL patients as noted by cytogenetic studies.163,164 Loss of the 11q23 region (including the ataxia telangiectasia gene) is noted in 20 percent by FISH analysis.165 Lymphocytes from 50 percent of CLL patients fail to express the tumor suppressor gene, retinoblastoma,166 which may correlate with 13q14 abnormalities,167 a common genetic abnormality in CLL. Neoangiogenesis in marrow from CLL may also play a pathophysiological role.168

The bone marrow is involved in virtually all patients with CLL. Such involvement varies from focal lymphocytic infiltration to extensive marrow replacement in advanced disease (Plate 3-2A-C). Some investigators have suggested a correlation between specific bone marrow patterns169 and clinical outcome, whereas others have not found such an association. Patients with diffuse involvement of the bone marrow by neo-plastic lymphocytes are more likely to have a worse prognosis than those who present with nodular involvement. Those with a mixture of diffuse and nodular infiltration have an intermediate prognosis. These patterns of bone marrow involvement in CLL may add prognostic information to the commonly used clinical staging systems.170,171 However, pathogenic and clinical staging are not independent in that those with higher stage involvement have a greater degree of marrow involvement compared with those with lower stage involvement.

Most lymphoid cells infiltrating the marrows of patients with CLL are small lymphocytes, but occasionally large and immature lymphocytes may be present as well. Neoplastic lym-phocytic infiltrates may be confused with normal lymphoid follicles, which are generally located adjacent to bone trabeculae and are especially common in elderly patients. Marrow fibrosis is quite rare.172 Reed-Sternberg-like cells (perhaps activated B cells) have been occasionally noted.173,174

Approximately 25 percent of those with CLL will experience an autoimmune hemolytic anemia at some point during their clinical course.154,175 In such patients, erythroid hyperplasia may be a prominent histological finding on bone marrow examination.

Peripheral blood findings include the presence of numerous small lymphocytes with clumped nuclear chromatin. Smudge cells (lymphocytes damaged during smear preparation) may be evident, as well as occasional medium-size atypical lymphoid cells and rare blastlike cells. Although most of the small lymphocytes appear morphologically normal, occasional cytoplas-mic clear spaces, granules, or inclusions (thought to represent endoplasmic reticulum) may be noted.176 The nuclear envelopes and cisternae of the rough endoplasmic reticulum may contain monoclonal immunoglobulin molecules.177

The most common physical finding in patients with CLL is lymphadenopathy, which may include extensive involvement in one or more lymph node sites. The lymph nodes tend to be soft, painless, discrete, and rubbery; however, as the disease progresses, coalescence and attachment to surrounding tissues may result in large fixed masses. Despite the size of such prominent tumors, they arise solely from lymphocytic infiltration within the capsule. The normal lymph node architecture is diffusely replaced by leukemic lymphocytes (Plate 3-2D). The invasive cells in patients with small lymphocytic lymphoma are immunologically and morphologically identical to CLL cells.178 A variable number of large, more immature-appearing cells may be mixed with the predominant population of small mature cells in lymph nodes.179 Only about 10 percent of patients can be shown to have marked numbers of immature or blastic lymphoid cells in involved lymph nodes: It is possible that clonal evolution of these immature cells may result in acute leukemia or lymphomatous transformation of CLL into a more aggressive entity.

The spleen, occasionally weighing more than 1 kg in advanced cases, is almost always enlarged in patients with CLL. In contrast to CML, splenic infarction is rarely noted. Microscopic findings in the spleen in patients with CLL are similar to those present in lymph nodes. Normal architecture is replaced by a monotonous infiltrate of small lymphocytes. Iron pigment may be prominent because of chronic hemolysis. The liver may be slightly enlarged as a result of lymphocytic infiltration of periportal tracts and occasional nodular masses that encroach on the parenchyma. Unlike CML, hepatic sinusoids are rarely infiltrated. Almost any other organ or site (particularly the gastrointestinal tract or kidney)180 may be infiltrated by lymphocytes although diffuse involvement is uncommon. Central nervous system (CNS) involvement,181 including lep-tomeningeal spireal,182 is rare. Exaggerated reactions to insect bites have been reported in patients with CLL; however, clinical pathological examination of such alledged lesions typically reveals no evidence of a bite.183

That there are rare cases of "true" T-cell CLL that behave in an indolent fashion similar to their B-cell counterparts is debatable. In fact, the WHO system (Table 3-5) does not include T-cell CLL but rather several T-cell neoplasms that may be confused with CLL, including adult T-cell leukemia or lymphoma (ATCLL), which occurs in those infected with the HTLV-1 retrovirus (endemic in the southern Japanese island of Kyushu and in the Caribbean).184,185 Patients with ATCLL tend to present with lymphadenopathy, hypercalcemia, and leukocytosis. Lymph node biopsies and examination of the peripheral blood smear reveals pleomorphic large cells that have immunopheno-typic characteristics of the CD8 T-cell subset. Skin lesions, a predilection for CNS involvement, neutropenia, and marrow involvement are also common in this aggressive disease. Morphologically, peripheral T cells from such patients may have a convoluted cerebriform nuclear appearance and scant cytoplasm (Plate 3-2E, F).185 Occasional cells have a more immature nucleus with a nucleolus and basophilic cytoplasm, resembling prolymphocytes.

Other T-cell chronic leukemias include T-cell granular lym-phocytic leukemia, formerly called T-cell lymphocytosis and cytopenia, characterized by an indolent clinical course in most patients, granulocyte or erythrocyte aplasia in the marrow, and a strong association with rheumatoid arthritis.186-190 The lymphocytes display a characteristic immunophenotype: CD8 (suppressor cell) positive; weak (or no) positivity for CD5, Leu-7, and Fc receptors. Importantly, such patients also have CD56

positivity, which is associated with the natural killer (NK) cell phenotype. The morphological hallmark of cells from patients with this disorder are their large size and the presence of acid phosphatase positive azurophilic granules.187,188 Marrow findings may include nonparatrabecular lymphoid infiltrates, lym-phadenopathy is rare, and red pulp cord and sinus infiltrates in the spleen.191 This so-called large granular lymphocytic leukemia (LGL) has been defined as a T-cell neoplasm.192 Most patients with this entity have a relatively benign clinical course, although fatal blastic transformation has been described.193 The CD8+ entity, which is an indolent proliferative process, is generally readily distinguished from an aggressive rapidly fatal disease, termed NK-cell leukemia.193,194

Patients with CLL may develop (or "transform" to) a more aggressive clinical entity. Transformation of CLL to a malignant large cell lymphoma,195,196 called Richter's syndrome, is discussed in Chapter 6. Development of prolymphocytic leukemia during the course of CLL has also been reported (see below). Rarely, CLL may transform into an acute leukemia, with one case of simultaneous CLL and AML having been reported.197 Moreover, it is also possible for the CLL cells to clonally evolve into a disease resembling ALL.

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