The key diagnostic feature of CLL relies on a careful examination of the peripheral blood smear. In a typical case, there is a lymphocytosis of small, round, mature-appearing lymphocytes with scant amounts of cytoplasm and mature chromatin. Typically, the chromatin has a characteristic clumped appearance with absent nucleoli. Disrupted lymphocytes, known as smudge cells, are a common finding in CLL (Figure 22.1). A lym-phocytosis of 5 X 109 lymphocytes/L has been a mandatory part of the diagnostic criteria (see Chapter 23), although this will have to be reviewed in light of the description of CLUS.

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Figure 22.1 Typical peripheral blood smear in CLL showing small cells with clumped nuclear chromatin and occasional smudge cells

Figure 22.2 Bone marrow showing minimal nodular pattern of involvement

A small number of larger cells resembling prolymphocytes may be seen at diagnosis. Characteristically, these account for <10% of the WBC differential. In time the prolymphocytes can increase, leading to a variant form of CLL referred to as CLL/PL. This represents a type of progression of CLL. In most cases, prolymphocytes account for <55% of the total WBC. The morphology in these cases is characteristically dimorphic, a finding that is particularly helpful for diagnosis. An uncommon form of CLL may occur and is referred to as CLL of mixed cell type. Such cases demonstrate a spectrum of morphologies and thus differ from the typical dimorphic appearance of CLL with scattered prolymphocytes.

The bone marrow in CLL is virtually always involved, but a number of differing presentations may be encountered. These include a nodular pattern,/— interstitial, mixed, and diffuse (Figures 22.2 and 22.3).

Figure 22.3 Heavy, diffuse bone marrow involvement in CLL. A growth center can be identified in the biopsy

Some data suggest that these histologic patterns may have independent prognostic relevance in CLL. Occasionally, bone marrow biopsies may reveal the presence of growth centers, a characteristic histologic finding in the lymph nodes of patients with CLL. These represent scattered pale-staining areas where focal collections of prolymphocytes and so-called paraimmunoblasts reside. As the name indicates, this is where tumor growth is thought to occur and where one would typically encounter the otherwise uncommon mitotic figures.

A predominantly lymph-node-based form of the disease can occur, and is referred to as small lympho-cytic lymphoma (SLL). The lymph node histology, immunophenotype, and cytogenetic/molecular alterations are identical to classic CLL. Although this represents an uncommon diagnosis, some cases of SLL may never develop an absolute lymphocytosis. This fact alone lends credence to the suggestion that CLL and SLL are related, but unknown factors that distinguish a predominantly leukemic disease from a tissue-based illness are poorly understood. As noted above, the histology of CLL and SLL are identical. The infiltrates are diffuse, but the presence of growth centers imparts a pseudofollicular architecture that is diagnostic. This finding is the result of scattered growth centers that produce an alternating dark and light staining pattern (Figures 22.4 and 22.5). The lightly staining areas harbor prolymphocytes and paraimmunoblasts, larger cells with more vesicular chromatin and prominent nucleoli. Occasional cases may lack prominent growth centers and typically these same cells are scattered diffusely throughout the lymph node. This can lead to problems with the diagnosis if the typical cytological appearance of the CLL/SLL cells is not appreciated. In some cases, growth centers may begin to sheet-out, suggesting histologic transformation. Importantly, this finding is not tantamount to the so-called Richter's syndrome, but rather represents a form of disease progression. Immunohistochemical staining of

Figure 22.4 Low magnification image of a lymph node in CLL with "pseudo-follicular" pattern
Pseudofollicular Centers
Figure 22.5 Higher magnification of the same lymph node showing growth centers with increased prolymphocytes and paraimmunoblasts
Figure 22.6 Peripheral blood smear with "atypical" CLL. Cells have slightly less clumped chromatin and more flowing cytoplasm

sections of lymph nodes involved by CLL/SLL demonstrate weak expression of CD20 (stronger within the growth centers), expression of CD79a, coexpression of CD5 and CD23, and absence of cyclin D1.

CLL in most cases is easily diagnosed based on a combination of morphology and immunophenotypic findings. Rarely, cases are encountered where the distinction from other lymphoid leukemias or lymphomas is difficult, requiring ancillary studies such as cytogenetics, fluorescent in situ hybridization (FISH), and molecular genetics. In particular, the differential diagnosis of CLL includes a small group of other lymphoid malignancies with B cells coexpressing CD5. This list includes mantle cell lymphoma (MCL) and uncommon cases of marginal zone lymphoma (MZL) that may show CD5 expression. MCL typically has a distinct morphology, characterized by a cytologic spectrum rather than the typical dimorphic appearance of CLL. The peripheral blood may be involved at diagnosis in as many as one-third of cases. MCL in most cases reveals a small number of circulating blast cells, a feature that is never seen in CLL. However, rare cases exist that appear to overlap these two diseases, making accurate subclassification difficult. For these uncommon cases, other strategies can then be used to help distinguish between CLL and MCL. The immunophenotype of MCL is different from CLL in the majority of cases. The expression of CD20 is typically brighter than CLL, the cells express more sIg, they fail to express CD23, and virtually always express FMC7, an unusual epitope associated with the CD20 molecule. When a combination of morphology and immunophenotype do not allow a distinction between CLL and MCL, then FISH and/or standard cytogenetic studies are useful. MCL always shows the presence of a disease-defining translocation t(11;14)(q13;q32) involving CCND1 (cyclin D1) on chromosome 11. This translocation is never seen in CLL/SLL.

Lastly, infrequent cases of CLL are characterized by an atypical morphology (Figure 22.6). Such cases often show unusual morphologic features such as nuclear irregularity and more abundant, flowing cytoplasm. The cells may coexpress CD11c, a variable finding in typical CLL. These cases contain the subset of CLL in which the t(14;19)(q32;q13) involving BCL3 on chromosome 19q13 appears to be more common and tends to be associated with more aggressive clinical behavior. Chronic B-cell leukemias in which the cells lack CD5 coexpression should not be designated as CLL. Such cases frequently represent splenic MZL and may be associated with a slightly different morphology and the presence of some cells showing villous cytoplasmic projections. In the absence of other evidence to support a diagnosis of splenic MZL, based solely on the peripheral blood examination, such cases should be labeled as chronic B-cell leukemia, not otherwise specified.

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