The Principles of Clinical Cytogenetics - Extra Materials - Springer

408 Rizwan Naeem
have plentiful slightly basophilic cytoplasm, and have at least two nuclear lobes. With immunophenotyping,
H-RS cells are positive for CD30 in nearly all cases and for CD15 in the majority of cases
(232,255–257), are usually negative for CD45, and are consistently negative for Ig J chain, CD75, and
macrophage-specific markers such as the PG-M1 epitope of the CD68 molecule (258). Classical HL is
associated with overexpression and an abnormal pattern of cytokines and chemokines and/or receptors
in the H-RS cells, which contain monoclonal immunoglobulin gene rearrangements in greater than 98%
of cases and monoclonal T-cell receptor gene rearrangements in rare cases (259–261).
Somatic mutations in the variable region of the Ig heavy-chain genes are seen frequently. These
findings indicate a derivation of H-RS cells from germinal center B-cells or their progeny. Typically,
B-cells that have lost the capacity to express immunoglobulin rapidly undergo apoptosis. However,
H-RS cells that are incapable of producing immunoglobulins do not die, as the apoptotic pathway is
blocked in these cells.
Classical HL cases with abundant neoplastic cells might bear a resemblance to an anaplastic large
cell lymphoma (see above) and, in fact, many cases previously diagnosed as the lymphocyte-depleted
subtype have been shown to actually represent this type of non-Hodgkin lymphoma, prompting some
to doubt whether lymphocyte depleted HL is a true category at all.
Conventional cytogenetic and FISH studies show ploidy and hyperploidy consistent with
multinuclearity of the neoplastic cells. However, these techniques fail to demonstrate recurrent and
specific chromosomal changes in classical HL (262,263). Comparative genomic hybridization, however,
revealed recurrent gain of chromosomal subregions 2p, 9p, and 12q and distinct high-level
amplification on chromosome bands 4p16, 4q23-q24, and 9p23-p24 (264). t(14;18) and t(2;5) are
absent from H-RS cells and this can be of diagnostic significance (265,266).
IMMUNODEFICIENCY-ASSOCIATED LYMPHOPROLIFERATIVE
DISORDERS
The World Health Organization classifies this group of disorders into four major clinical subtypes:
• Primary immunodefiency syndromes and other primary immune disorders
• Infection with the human immunodefiency virus (HIV)
• Iatrogenic immunosuppression in patients with solid-organ or bone marrow allograft
• Iatrogenic immunosuppression associated with methotrexate treatment
Lymphoproliferative disorders (LPDs) associated with immunodefiency are a heterogenous group
and the nature of the immune defect is highly variable. For example, in cases of X-linked LPD, the
defect is in the immune surveillance, and in other cases it can be due to a defective DNA repair system
or defective apoptosis. Therefore, each primary immune disorder should be considered separately.
Lymphomas Associated with Infection by Human Immunodeficiency Virus
These heterogeneous disorders are predominately aggressive B-cell lymphomas in patients who
are immunocompromised; patients with HIV infections are prone to develop these lymphomas.
Lymphomas diagnosed in HIV-positive patients are monoclonal B-cell neoplasms, with evidence
of clonal proliferation of immunoglobulin genes detected by the Southern blot or PCR techniques
(267–269). Most cases also show somatic mutations involving immunoglobulin genes (270). There
are also T-cell cases, which have clonal rearrangement of T-cell genes (271,272). Cases of HIVassociated
Burkitt lymphoma, like other cases of Burkitt lymphoma, have genetic abnormalities
affecting 8q24.1, the chromosomal location of the MYC oncogene. In these cases, the typical
t(8;14),(q24;q23.2) or its variants affecting the light-chain genes at 2p11.2 and 22q11.2 have been
described. In addition to truncation within or around the MYC locus, point mutations in the first
intron/exon regulatory region are also present. Translocations of 8q24.1 are also detected in about
20% of diffuse large B-cell lymphomas (see above). In addition, a rearrangement of BCL6 (a proto-