The Principles of Clinical Cytogenetics - Extra Materials - Springer

396 Rizwan Naeem
involvement, rapid disease progression, and short survival time (118). In one study, deletion of chromosome
bands 11q22–23 was seen by cytogenetics in 6% of cases, but when the same cases were
studied with FISH utilizing specific probes, the incidence of 11q deletions was found to be about
20% and was the second most frequent aberration following deletion of 13q14. Interestingly, 13q and
11q deletions are more frequent than the highly recognized trisomy 12.
A study by the first International World Congress on Cytogenetics of CLL (IWCCLL) showed a
correlation between karyotypic finding and overall survival in 391 patients with B-CLL. Patients
whose leukemic cells had a normal karyotype had a better survival (median 15 years) than those
whose cells had clonal cytogenetic aberrations (median: 7.7 years). In addition, patients with complex
chromosomal abnormalities had a worse outcome than those with single aberrations (119).
Chronic lymphocytic leukemia represents a good example of how the use of molecular cytogenetic
and molecular genetic techniques have led to the identification of two new independent prognostic
markers, deletion of the TP53 tumor suppressor gene, and deletion of genomic region 11q22.3
to q23.1. This should be evaluated further prospectively in large clinical trials.
The clinical course in CLL is indolent, but the disease is not usually considered to be curable with
available therapy. The overall 5-year actual survival of CLL patients in recent studies was 51%, with a
failure-free survival (no markers of relapse) rate of 25% (107). Trisomy 12 correlates with atypical
morphology and an aggressive clinical course (115,120), whereas abnormalities of chromosome 13q14
are associated with long-term survival and good prognosis. Patients whose tumors have mutations in Ig
gene variable regions have a better prognosis than those with germline VH region mutations. In addition,
patients with tumor cells that express CD38 appear to have a worse prognosis than those that do
not express it (114,121). Cases with 13q22–23 deletions have extensive lymphadenopathy and poor
survival. Cases with TP53 abnormalities have also been associated with a poor prognosis.
Transformation of CLL to high-grade lymphoma occurs in approximately 3.5% of cases. These
are usually diffuse large B-cell lymphomas (see below).
Splenic Marginal Zone Lymphoma
Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm comprised of small lymphocytes
that surround and replace the splenic white bulk germinal centers. The lymphoma cells can be found
in peripheral blood as villous lymphocytes. This is a rare disorder, representing less than 1% of
lymphoid neoplasms, but it might account for most cases of otherwise unclassified chronic lymphoid
leukemia that are CD5 negative. The tumor mainly involves the spleen and the splenic hyler lymph
nodes, bone marrow, and, often, peripheral blood. The usual presentation is splenomegaly, occasionally
accompanied by autoimmune thrombocytopenia or anemia, and variable presence of peripheral
blood villous lymphocytes (122,123).
Tumor cells have surface IgM and IgD and are CD20 positive, CD79a positive, CD5 negative,
CD10 negative, CD23 negative, CD43 negative, and CD103 negative (124,125). The absence of CD5
and CD43 is useful in excluding CLL and mantle cell lymphoma, the absence of CD103 excludes
hairy cell leukemia, and the absence of CD10 excludes follicular lymphoma. Immunoglobulin heavy
and light genes are rearranged in SMZL, and most cases have somatic mutations. In addition,
intraclonal variations have been detected, suggesting ongoing mutation (126).
Cytogenetically, allelic loss of chromosome 7q21-q32 has been described in up to 40% of small
marginal zone lymphomas (127). Dysregulation of the CDK6 gene located at 7q21, resulting from
translocations involving this chromosomal region, has been reported in several cases of splenic lymphoma
with villous lymphocytes (SLVL) (128). Trisomy 3 and t(11;18), common in extranodal marginal
zone lymphoma, are not uncommon in SMZL, where trisomy 3 has been described in 17% of
cases (129). BCL2 gene rearrangements, notably t(14;18)(q32;q21), have not been described in this
category.
The clinical course of SMZL is indolent, even with bone marrow involvement (130). Response to
chemotherapy of the type that is typically effective in other chronic lymphoid leukemias is often