The Principles of Clinical Cytogenetics - Extra Materials - Springer

406 Rizwan Naeem
ALK encodes a tyrosine kinase receptor belonging to the insulin receptor superfamily, which is
normally silent in lymphoid cells. With t(2;5), the nucleophosmin housekeeping gene fuses with ALK
to produce a chimeric protein (238,239), in which the N-terminal portion from NPM1 is linked to the
intracytoplasmic portion of ALK. The particular cytoplasmic and nuclear staining seen in these cases
can be explained by the formation of dimers between wild-type nucleophosmin and the NPM1/ALK
fusion protein.
Many variant translocations involving ALK and other partner genes on chromosomes X, 1, 2, 3,
17, 19, and 22 have also been reported. Some ALK-positive ALCLs are associated with the presence
of t(1;2)(q25;p23). This translocation involves TPM3 gene on chromosome 1, which encodes a nonmuscular
tropomyosin α-chain. In cases with t(1;2) that express the TPM3/ALK fusion protein, ALK
staining is restricted to the cytoplasm of malignant cells and in virtually all cases is strongest near the
cell membrane.
Other genes can fuse with ALK; examples include two variant rearrangements; t(2;3)(p23;q35)
and inv(2)(p23q35). Two different fusion proteins, TFG/ALK short and TFG/ALK long, are associated
with the rare t(2;3)(p23;q35), which involves the TFG (tropomyosin receptor kinase-fused) gene
on chromosome 3. inv(2)(p23q25) involves the ATIC gene (also known as PURH) on 2q, which
encodes 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase
(240,241). This gene plays a key role in de novo purine biosynthesis (242).
For prognosis, ALK expression correlates with the expression of other markers, such as epithelial
membrane antigen (EMA) and a cytotoxic phenotype and is strongly associated with younger age
groups, lower international prognostic index (IPI) risk groups, and a good prognosis. ALK-negative
ALCL, however, shows a more heterogeneous immunophenotype and clinical behavior. Genetic studies
of ALK-negative cases have not been performed in detail, but might be of future use in determining
whether ALK-positive and ALK-negative ALCL are part of the same disease entity.
RT-PCR is one of the methods commonly use for detecting the (2;5) translocation, but cases with
variant translocations will not be amplified/identified by standard RT-PCR using primers that are specific
for ALK and NPM1. Therefore, at present, cytogenetic studies should always be part of the workup.
Also, the (2;5) translocation leads to positive staining for ALK in both the nucleus and cytoplasm, but
with the variant translocations, often only cytoplasmic staining will be observed. Therefore, immunohistochemistry
has largely supplemented molecular analysis for the diagnosis of ALCL.
Recent microarray-based CGH analysis (see Chapter 17) of a few cases revealed genomic imbalances
(GI) in all cases studied. This includes oncogene copy number gains of FGFR1 (8p11.1-p11.2)
in three cases and NRAS (1p13.2), MYCN (2p24.1), RAF1 (3p25), CTSB (8p22), FES (15q26.1), and
CBFA2 (21q22.3) in two cases. Real-time PCR analysis of nine DNA samples from eight cases with
cytogenetic and genomic imbalances detected amplifications of CTSB and RAF1 in seven cases
(88%), of REL (2p12p-13) and JUNB (19p13.2) in six cases (75%), and of MYCN and YES1 (18p11.3)
in four cases (50%) (243). Prognostic parameters associated with such changes are still not very well
defined and are definitely needed to determine treatment strategies in individual patients (244).
HODGKIN LYMPHOMA
Thomas Hodgkin is widely attributed with the first description of human lymphoma, originally
known as Hodgkin’s disease. The disease was also referred to as lymphogranulomatosis, but this
term is no longer used. This disorder accounts for approximately 30% of all lymphomas.
With minor modifications, the Revised European American Lymphoma (REAL) classification
has been adopted by the World Health Organization, resulting in the REAL/WHO classification, now
the most widely used system for classification of Hodgkin lymphoma (HL). HL is comprised of two
distinct entities, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classical
Hodgkin lymphoma. The latter is further divided into four subtypes: lymphocyte rich, nodular sclerosing,
mixed cellularity, and lymphocyte depleted