The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Hematologic Neoplasms 399
Immunoglobulin heavy chains and light chains are rearranged in follicular lymphoma. Variable
region genes show extensive somatic mutations, with intraclonal heterogeneity consistent with a
derivation from follicular center cells (155,156).
Almost all cases of follicular lymphoma have cytogenetic anomalies (157). The most common
is t(14;18)(q32;q21) (see Fig. 1y), in which the BCL2 gene is juxtaposed with the Ig heavy-chain
locus and is seen in about 70–95% of cases (158,159). This translocation is not associated with
either a better or worse prognosis. Also, a rarely seen translocation [t(2;18)(p12;q21)] fuses BCL2
with the Ig κ light-chain gene on chromosome 2. Other cytogenetic abnormalities include gain of
chromosome 7, gain of chromosome 18, and involvement of chromosomes 3q27-q28, 6q23-q36,
and 17p. In addition to the BCL2 gene rearrangement, BCL6 mutations are also seen. Deletions and
other alteration of chromosome 9p involving the CDKN2B and CDKN2A gene loci have been reported
in cases of follicular lymphoma that transforms to diffuse large B-cell lymphoma (DLBCL
or B-cell DLCL; see below).
Mantle Cell Lymphoma
This is a neoplasm of B-cell origin; cell morphology is composed of monomorphic small- to
medium-sized lymphoid cells with asymmetrical nuclei. These cells morphologically closely resemble
centrocytes/cleaved follicular center cells (FCCs; see the subsection Follicular Lymphoma) but frequently
have slightly less irregular nuclear contours (160,161). Mantle cell lymphoma (MCL) comprises
approximately 3–10% of non-Hodgkin’s lymphoma (107). It occurs in middle-aged to older
individuals, with a median age of about 60. Lymph nodes are the most commonly involved site.
Spleen and bone marrow, with or without blood involvement, are other frequent sites of disease
presentation (162,163).
Under the microscope, MCL demonstrates architectural obliteration via monomorphic lymphoid
proliferation, with a vaguely nodular, diffuse growth pattern (164,165). A true follicular node pattern
is very rarely present. The majority of cases have immunoglobulin heavy-chain and light-chain gene
rearrangements, but variable-region genes are not mutated in most cases. This is consistent with a
pregerminal center B-cell origin, but a small portion of cases also shows somatic mutations suggestive
of postfollicular phenotype (166–168).
Conventional cytogenetic analysis demonstrates a translocation between the immunoglobulin
heavy-chain and cyclin D1 (CCND1, BCL1, PRAD1) genes, t(11;14)(q13;q32) (see Fig. 1v) in 70–75%
of cases (169–171). However, almost all cases demonstrate this gene rearrangement using FISH
probes specific to these regions (172,173). In addition, almost all cases show overexpression of
cyclin D1 mRNA by Northern blot techniques (174). A minority of cases, especially those of
blastoid and other more aggressive types, have additional mutations, deletions, or other abnormalities
in genes for negative cell-cycle-regulating proteins such as TP53, P16 (CDKN2A), and P18
(CDKN2C) (175,176). BCL2 and MYC rearrangements are usually absent. Many cases have point
mutation and/or deletion of the ATM (ataxia telangiectasia-mutated) gene at 11q22.3-q23.1 (164).
A recent study using oligonucleotide microarray analysis reported 12 of 28 MCL patients (43%)
with such mutations (177).
In addition to t(11;14), there are other relatively frequent cytogenetic abnormalities seen in MCL,
some of which are also common in CLL. These include 13q14 deletions, total or partial trisomy 12,
and 17p deletions, among others. The pleomorphic blastoid variant of MCL has a high incidence of
tetraploidy.
Mantle cell lymphoma has a median survival of 3–5 years, but the vast majority of patients cannot
be cured. Adverse prognostic indicators include trisomy 12, unbalanced cytogenetic abnormalities,
and complex karyotype. TP53 mutation/overexpression and a variety of other clinical parameters are
also poor prognostic indicators. The presence of a karyotype with t(11;14) as the sole anomaly predicts
an intermediate clinical outcome, whereas cases with normal karyotypes are associated with a
better prognosis (178).