The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Hematologic Neoplasms 395
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma is a neoplasm of monomorphic
small round B-lymphocytes in the peripheral blood, bone marrow, and lymph nodes. These cells
are mixed with prolymphocytes and paraimmunoblasts (pseudofollicles), and usually express CD5
and CD23. The term “small cell lymphoma” (SCL) is consistent with CLL that is restricted to cases
where the tissue morphology and immunophenotype are that of CLL, but that are nonleukemic and
present in nodal and extranodal sites.
There are many names for this group of neoplasms, including well-differentiated lymphocytic
diffuse leukemia, CLL, immunocytoma, lymphoplasmacytoid type, small lymphocyte B-CLL, small
lymphocytic leukemia, consistent with CLL, and B-cell chronic lymphocytic leukemia.
Chronic lymphocytic leukemia comprises about 90% of chronic lymphoid leukemias in the United
States and Europe. According to a recent study, it constitutes about 6.7% of non-Hodgkin’s lymphoma
(107). The majority of patients are greater than 50 years old and the median age is 65, with
male-to-female ratio of 2 : 1.
Patients with CLL are usually asymptomatic at presentation; however, some show fatigue, autoimmune
hemolytic anemia, infections, splenomegaly, hepatomegaly, lymphadenopathy, or extranodal
infiltrates (110,111). They might show involvement of bone marrow and peripheral blood at the time
of diagnosis, with a total lymphocyte count in excess of 10 10 cells/L. Lymph nodes, liver, and spleen
are typically infiltrated with leukemic cells. Lymph node morphology shows nodal enlargement and
invasion of the architecture with a pseudofollicular pattern of regularly distributed pale areas containing
larger cells in a dark background of small cells (112,113). Mitotic activity is typically very
low. Pseudofollicles, also known as proliferation centers or growth centers, with a continuum of
small, medium, and large cells, are present. Bone marrow morphology shows small lymphocytes
with clumped chromatin, and scant, clear to lightly basophilic cytoplasm and with a regular outline
are seen. Smudge or basket cells are typically seen in blood smears.
In many cases of CLL, Ig heavy- and light-chains genes are rearranged. There is recent evidence
that there are two distinct types of CLL, defined by somatic mutational analysis of immunoglobulin
genes. Forty to fifty percent of patients show no somatic mutation of the variable region gene, consistent
with naïve B-cells, whereas 50–60% have somatic mutations consistent with a derivation from
both germinal center and B-lineage cells (114).
About 80% of cases exhibit abnormalities when examined by cytogenetics and FISH analysis
(115). Trisomy 12 is present in about 20% of patients, and deletion of chromosome 13q14 is seen in
up to 50% of cases (115,116). Cases with trisomy 12 predominately have nonmutated immunoglobulin
variable-region genes, whereas those with 13q14 abnormalities more often have mutations in this
region.
Deletions of 11q22–23 are found in about 20% of cases, and somatic mutations have also been found
in the homologous allele in this group of cases (117). Deletions of 6q21 or 17p13 (the P53 locus) are
seen in 5% and 10% of cases, respectively (118). t(11;14) and other BCL1 gene rearrangements have
been reported, but most of these cases might be examples of leukemic mantle cell lymphoma (115).
Cytogenetic analysis of bone marrow from CLL patients has always been a difficult task. Many
laboratories use B-cell mitogens, which results in proliferation of B-cells. Trisomy 12 has been
reported at much higher rates in such cases, as compared to cases without B-cell stimulation. Whether
this represents true in vivo status or is a tissue culture artifact is not yet known.
Recent advances in molecular cytogenetics (FISH) have changed the cytogenetic look of CLL (see
Chapter 17, Fig. 11). Deletions of 13q, involving the RB1 gene, have been found in about 50% of
cases studied by FISH. Interestingly, these deletions are sometimes also present in a homozygous
state, in which both copies of chromosome 13 are deleted (see Fig. 2w,x).
Deletion and mutation of P53 have been associated with the resistance to treatment and represent
an independent marker for poor survival. Deletions of 11q have been associated with extensive nodal