Matutes_EU Haematology 03/03/2010 13:17 Page 66
Haematological Malignancies Lymphoproliferative Disorders
Figure 1: Circulating Lymphocytes Displaying an monoclonal gammopathy of undetermined significance (MGUS) for
Eccentric Nucleus and Abundant, Mildly Basophilic
myeloma or monoclonal B-cell lymphocytosis (MBL) for chronic
Cytoplasm with Coarse Granules – Typical Features of
Large Granular Lymphocytes
lymphocytic leukaemia (CLL). Symptomatic patients manifest with
fever, infections or mouth ulcers, arthralgias and/or tiredness, the
latter not attributable to the anaemia. Few patients manifest with
immune thrombocytopenia and pulmonary artery hypertension.
10,18
Up
to half of patients have splenomegaly, approximately 20% have skin
lesions and a minority have hepatomegaly; lymphadenopathy is rare.
In some cases, the spleen is shown to be enlarged only by imaging
studies. Patients with the CD4
+
CD8±dim phenotype rarely present
with cytopenias, while its association with neoplasms is frequent.
19
Patients with CLD of NK cells, in contrast to aggressive NK-cell
neoplasms, are often asymptomatic and organ involvement is rare.
The leukocyte count may be normal or slightly raised, but most
patients have an increase in circulating LGL even without having
an absolute lymphocytosis; many develop lymphocytosis after
splenectomy. Cytopenias are more common in T-cell LGL leukaemia
than in CLD of NK cells. The most frequent cytopenia is neutropenia
and it is unrelated to marrow infiltration or hypersplenism. Anaemia
and thrombocytopenia are less frequent and are present in around
one-third of patients. A few patients may present with a picture of red-
Figure 2: Haematoxylin-cosin-stained Spleen Section
from a Case of Large Granular Lymphocyte Leukaemia
cell aplasia. Liver function tests may be impaired and the autoimmune
Showing Red-pulp Involvement by Mature Lymphocytes
screen reveals abnormalities such as the presence of rheumatoid
factor, antinuclear antibodies, circulating immunocomplexes and
polyclonal hypergammaglobulinaemia; a few patients with T-cell LGL
leukaemia have hypogammaglobulinaemia that relates to the
suppressor function of the LGL on the B lymphocytes.
Diagnosis
Although the diagnosis of T-cell LGL leukaemia or CLD of NK cells can
be suspected in patients with a persistent increase in LGL (greater
than six months and with >2,000/µl circulating LGL), it usually requires
the integration of morphology with immunophenotyping and, in T-cell
LGL leukaemia, T-cell receptor (TCR) rearrangement studies by
Southern blot or polymerase chain reaction (PCR). Suggested criteria
for diagnosis comprise first, persistent and sustained expansions of
LGL, second, demonstration of a characteristic immunophenotype,
third, confirmation of clonality by molecular studies and fourth,
integration of all these data with clinical features. Updated criteria by
patients with rheumatoid arthritis, and has been documented in T-cell Semenzato et al. stress the fact that not all of these criteria may be
LGL leukaemia with higher frequency than in the normal population. This present in some patients with low LGL counts in whom an expansion
suggests a similar immunogenetic basis for these two conditions.
13
of an LGL clone is detected by molecular analysis.
16
Diagnostic criteria
Similarly, CLD of NK cells may be associated with autoimmune diseases. for CLD of NK cells are not well established. Diagnosis may be
A genetic susceptibility to develop CLD of NK cells has been suggested problematic due to the difficulties in demonstrating clonality.
to be related to a distinct killer immunoglobulin receptor (KIR) repertoire However, persistence of the NK-cell expansion in the blood greater
that contains a high number of activating KIRs.
14,15
In contrast to than six months and a pattern of bone-marrow infiltration by these
aggressive NK-cell neoplasms, EBV is exceedingly rare. cells as seen in T-cell LGL leukaemia support the diagnosis.
Clinical Features Circulating T and NK LGLs have a nucleus with condensed chromatin, no
T-cell LGL leukaemia preferentially affects adult patients and is visible nucleoli and abundant cytoplasm that contains coarse granules
infrequent in childhood. It is more common in eastern than in western (see Figure 1). Bone marrow involvement by LGL is variable and may be
countries. One-third of patients are asymptomatic and the diagnosis subtle with a good haemopoietic reserve despite cytopenias. The
comprises a routine blood count that shows lymphocytosis, mild trephine biopsy shows interstitial and/or intrasinusoidal lymphoid
neutropenia or both.
1,16
Asymptomatic patients may have other infiltration. Lymphoid nodules may be present, but these are shown to
concomitant conditions such as myelofibrosis, eosinophilia of be reactive by immunohistochemistry and composed by CD20
+
B cells
uncertain origin, monoclonal gammopathy, etc. The term T-cell and CD4
+
non-neoplastic T-cells.
20
Immunohistochemistry allows a
clonopathy of unknown significance (TLUS) has been coined to better estimate of the degree of involvement by highlighting the
designate those asymptomatic patients who represent the benign end infiltrates and parallel findings of flow cytometry in the blood and
of the clonal T-cell LGL proliferations,
17
a scenario similar to marrow aspirates. Spleen histology shows red-pulp involvement with
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