PART ONE
General Cytology
driven by
Ig
or
TCR
enhancers. In the second mechanism, the
chromosomal breakpoints occur within the coding sequence
of each gene, such that the two broken genes are fused, lead-
ing to a chimeric gene translated into a new chimeric protein
with dysregulated function. The first mechanism accounts for
the majority of lymphoma diseases while the second molecular
event predominates in sarcoma.
There is an abundant literature demonstrating good cor-
relations between chromosomal abnormalities and different
lymphoma subtypes.12 Identification of specific genetic aber-
rations has several meaningful implications in non-Hodgkin
lymphoma's (NHL). First, it may help in accurately diagnos-
ing NHL. For example, identification of the t(11;14) translo-
cation makes it possible to distinguish mantle cell lymphoma
(MCL) from small lymphocytic lymphoma/chronic lymphoid
leukemia (SLL/CLL). The presence of the t(2;5) translocation
is the characteristic genetic feature of a subgroup of anaplastic
large cell lymphoma (ALCL). Second, demonstration of chro-
mosomal translocations may help in prognostic assessment of
NHL; marginal zone lymphoma of MALT type with a t(11;18) is
unlikely to respond to antibiotic therapy. By contrast, the MALT-
NHL negative for the t(11;18) is most often associated with
Helicobacter pylori
gastritis and more often responds to antibiotic
therapy. The presence of the t(2;5) translocation and its con-
secutive anaplastic lymphoma kinase
(ALK)
overexpression in
ALCL is associated with good prognosis. Third, identification of
genetic abnormalities in NHL may serve as markers for staging
assessment and for studies of minimal residual disease.
As Hodgkin's lymphoma does not exhibit any consistent or
specific genetic abnormality detectable by cytogenetics or FISH
analysis, the following topic will focus on non-Hodgkin's lym-
phoma. Within this last group, we will restrict our talk to NHL
subtypes exhibiting characteristic chromosomal aberrations
that can be used as diagnostic tools on a regular basis, and will
organize this section according to the REAL/WHO morphologi-
cal classification, hence from small cell lymphomas to large cell
lymphomas.
Follicular Lymphoma
Follicular lymphoma (FL) is characterized by the t(14;18)
(q32;q21) translocation (Fig. 2.8), which juxtaposes the B-cell
lymphoma/leukemia 2
(BCL2)
oncogene at 18q21 into the
heavy chain immunoglobulin (
IgH
) gene locus at 14q32, lead-
ing to upregulated expression of the BCL2 protein.17
BCL2
is an
antiapoptotic gene, and its overexpression leads to prolonged
cell survival that may make the cell more vulnerable to addi-
tional genetics events, leading to cell overgrowth and cancer. In a
minority of cases, variant translocations such as t(2;18)(p11,q21)
and t(18;22)(q21;q11), which relocate the
BCL2
oncogene to the
kappa light chain immunoglobulin
(IgL kappa)
gene locus and
lambda light chain immunoglobulin
(IgL lambda)
gene locus,
respectively, have also been observed.
This translocation t(14;18) and its variants are observed in
up to 85% of FL which are mainly represented by histological
grades 1, 2, and 3A. The remaining 15% cases do not exhibit a
t(14;18)(q32;q21) translocation and are essentially constituted
by FL grade 3B.18,19 Among them, a minority (~30%) exhibit
BCL2 overexpression on immunohistochemistry, resulting from
a non-Ig-related mechanism. The origin of this
BCL2
gene over-
expression is still unknown but could be due to duplication of
chromosome 18 as observed in some karyotypes, or could involve
other unknown mechanisms favoring
BCL2
overexpression.19
Fig. 2.8 Karyotype of follicular lymphoma
showing the balanced
t(14;18)(q32;q21) translocation (arrows). The gains for chromosomes 3, 12,
15, and X as well as deletion 13q are additional abnormalities associated with
clonal evolution.
The clinical outcome of this subgroup seems to be similar to
that of follicular lymphoma with t(14;18). The major subgroup
(~70%) does not show any
BCL2
overexpression but presents a
recurrent translocation of the 3q27 chromosomal region, result-
ing in a disruption of the B-cell lymphoma/leukemia 6
(BCL6)
oncogene located at this breakpoint. This abnormality is also
observed in diffuse large B-cell lymphomas (DLBCL), a feature
that will be discussed later. Of interest, these 3q27+ FL grade
3B show peculiar clinicopathologic features distinct from their
t(14;18)+ counterparts20: a stage III/IV disease as well as a bulky
mass are less frequently observed, and they usually disclose a
CD10- phenotype. Finally, this genetic subgroup seems to have a
better survival rate and have clinically more in common with de
novo 3q27+ DLBCL.19,20 These findings indicate that the search
for
BCL2
and
BCL6
rearrangement status by genetic analysis may
be clinically warranted for all cases of follicular lymphoma.
Although the t(14;18) translocation is an early event and is
critical for lymphomagenesis, it is by itself insufficient to pro-
duce FL. As said before, the prolonged cell survival provided by
BCL2
overexpression allows the acquisition of further genetic
events that contribute to the development of FL.21 These genetic
events occur as a series of chromosomal gains and losses that
can be detected at diagnosis as complex and heterogeneous
karyotypes. It is not the karyotypic complexity but rather the
type of abnormalities exhibited that underlies the varied clini-
cal outcome observed in FL. Recurrent cytogenetic aberrations
that have been noted to correlate with a more aggressive disease
include chromosomal gains such as +7, +12 or gain of 12q13-
14, +18 and chromosomal losses including del 6q, del(9)(p21),
and del(17)(p13), the two last aberrations corresponding to
loss of tumor suppressor genes
p16
and
p53.
Beside a complex
karyotype, 3q27/BCL6 translocations can subsequently occur in
t(14;18)+ FL, less frequently in low than in high grades, and
have been shown to correlate with a risk of transformation to
diffuse large B-cell lymphoma.22
Mantle Cell Lymphoma
According to the REAL/WHO classification, the diagnosis of mantle
cell lymphoma should be based on clinicomorphological but also
cytogenetic or molecular features.12 The genetic hallmark of MCL
is the t(11;14)(q13;q11) translocation (Fig. 2.9) that juxtaposes
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