The Principles of Clinical Cytogenetics - Extra Materials - Springer

394 Rizwan Naeem
Cytogenetic abnormalities in T-ALL and T-LBL are observed less frequently than in B-ALL. In
contrast to B-ALL, for the T-ALL/LBL, such changes are not useful at this point for risk assessment
or prognosis. In about one-third of T-ALL/LBL, chromosomal translocations involve the T-cell
receptor α-locus at 14q11.2 [often via inv(14)(q11.2q32); see Fig. 2bbb], the β-locus at 7q35, and
the γ-locus at 7p14–15, with a variety of partner genes (113). These include the transcription factor
MYC at 8q24.1 (see Fig. 1p), TAL1 at 1p32, RBTN1 at 11p15, RBTN2 at 11pl3, HOX11 at 10q24, and
the cytoplasmic tyrosine kinase LCK at 1p34.3–35. In most cases, these translocations lead to the
dysregulation of transcription of the partner genes by juxtaposition with a regulatory region of one of
T-cell receptor loci. In about 25% of cases of T-cell ALL, the TAL1 locus is dysregulated by microscopic
deletions in its 5' regulatory region rather than by translocation. Loss of heterozygosity of the
tumor suppressor gene CDKN2A (an inhibitor of cyclin-dependent kinase 4 [CDK4]) at 9p21 occurs
more frequently than visible deletions; only about 30% of these cases are cytogenetically abnormal.
Prior to the advent of current therapeutic protocols, the prognosis of childhood T-ALL/LBL was
unfavorable, but with current treatments regimes, survival is compatible to B-ALL. A recent oncology
group study described the 5-year event-free survivals by karyotype group: 51% of those with an
abnormal karyotype versus 62% of those with a normal karyotype (4% statistical error). These data
should be viewed as promising, but require confirmation from another series before the associations
are considered definitive (105,106).
MATURE B-CELL NEOPLASMS
Mature B-cell neoplasms comprise about 90% of lymphoid neoplasms. The two most common types
are large-cell lymphoma and follicular lymphoma, which comprise about 50% of all non-Hodgkin’s
lymphomas. They represent approximately 4% of new cancers each year around the world (107,108).
Mature B-cell neoplasms resemble normal stages of B-cell differentiation and typically have
distinctive morphology and immunophenotypes that allows them to be readily classified according
to their cells of origin. The major known risk factor for mature B-cell neoplasia appears to be an
abnormality of the immune system, either an immunodeficiency or autoimmune disease. Infectious
agents have also been shown to contribute in the development of several types of mature B-cell
lymphomas (109).
In the WHO classification, the mature B-cell lymphomas are listed according their major clinical
presentations. These are predominately disseminated leukemic types, primary extranodal lymphomas,
and predominately nodal lymphomas, which might involve extranodal sites as well.
Several mature B-cell neoplasms have characteristic genetic abnormalities that are important in
determining their biologic features and are very useful in differential diagnoses. These aberrations
include t(11;14)(q13;q32) in mantle cell lymphoma (see Fig. 1v), t(14;18)(q32;q21) in follicular
lymphoma (see Fig. 1y), t(8;14)(q24;q32) in Burkitt lymphoma (see Fig. 1q), and t(11;18)(q21;q21)
in MALT lymphoma. The first three translocations place cell locus oncogenes under the control of
the immunoglobulin heavy-chain gene on the long arm of chromosome 14, resulting in constitutive
activation of the oncogenes, whereas the (11;18) translocation results in a chimeric fusion protein
involving BIRC3 (API2) on chromosome 11 and MALT1 on chromosome 18. In follicular lymphoma
and MALT lymphoma, these translocations result in overexpression of an apoptosis inhibitor gene
(BCL2 or API2, respectively), whereas in Burkitt lymphoma and mantle cell lymphoma, the translocations
results in overexpression of genes associated with proliferation (CCND1, also called BCL1,
and MYC, respectively).
In general, these neoplasms are extremely heterogeneous, and knowledge of the correct diagnosis
is essential to predict the outcome and direct therapy. More precise subclassifications of these neoplasms
have led to more innovative therapies, including localized radiation therapy for eradication of
MALT lymphoma and humanized anti-CD20 as an adjunct to therapy for all types of CD20-positive
B-cell lymphomas.