Dr Samir Agrawal MB ChB, BSc, MRCP, FRCPath, PhD Consultant
Haematologist, St Bartholomew's Hospital (Barts), London .
Timothy Farren BSc(HONS) MIBMS, Clinical Scientist, St
Bartholomew’s Hospital (Barts), London.
The
following article has been written exclusively for the CLL Support
Association. It is aimed at patients and their carers and assumes
almost no prior medical knowledge. A printable copy can be obtained
by clicking this link.
Introduction
A few
words about chronic lymphocytic leukaemia (CLL) are necessary in
order to explain the diagnostic process. CLL is a malignancy of B
lymphocytes, one of several types of cells of the immune system.
Disorders of the other lymphocytes also occur – T cells and natural
killer (NK) cells – but are much rarer. While CLL is the commonest
adult leukaemia in the western world, there are many other types of
malignancy of B lymphocytes, globally referred to as B-cell
lymphoproliferative disorders (B-LPD).
As
suggested by the term ‘leukaemia’, CLL is a disease characterised by
an increase in the abnormal B-cells in the blood and bone marrow
(BM). Rarely, CLL cells may not be detected in the blood (or BM),
but only found in enlarged glands – lymph nodes (see below) – which
is a form of CLL localised to the tissues and often referred to as
small lymphocytic lymphoma (SLL). SLL is a subset of CLL and should
be treated as any other case of CLL.
An
increase in B lymphocytes in the blood – a ‘lymphocytosis’ –
indicates a B-LPD, however, infections may also lead to a
lymphocytosis, usually of T or NK-cells, but also of B-cells. Most
commonly, viral infections – which may or may not cause clinical
symptoms – are the cause of a lymphocytosis, which resolves
spontaneously with time.
Diagnosis
Clinical features
The
clinical presentation of CLL is entirely non-specific, with all the
findings also seen in other B-LPD, as well as other malignant and
non-malignant conditions. In fact, the commonest presentation of CLL
today is as an ‘incidental’ finding on a routine blood test (full
blood count) performed for some other reason, for example, prior to
an operation or as part of a health check. In other words, the
patients had no idea they were unwell! If patients do present
because of the CLL itself, this may include: enlarged glands, which
are called lymph nodes, in the neck, armpits, abdomen and groin (one
or more areas may be affected); recurrent infections (related to the
poorly functioning immune system in CLL); weight loss, fevers (not
related to infection) and drenching night sweats – globally referred
to as ‘B’ symptoms; excessive fatigue; a sensation of fullness in
the abdomen (usually due to an enlarged spleen)…
Full Blood Count
The full
blood count (FBC) is one of the key tests in the diagnostic process
and is the first step. The
widespread availability of FBC analysers explains the increasing
detection of CLL as an ‘incidental’ finding. The FBC reveals the
increase in the lymphocytes in the blood – but cannot tell whether
they are B-, T- or NK-cells. The other important information is the
level of the haemoglobin (Hb) and platelets, as if they are low,
this suggests bone marrow failure (usually due to the CLL) and is an
indication for treatment. From the FBC sample, a drop of blood is
spread on a glass slide, stained with dyes and examined under a
microscope. This allows the appearance of the cells to be determined
– CLL cells have a characteristic ‘clumped chromatin’ (which looks
like cracked mud!) pattern to the nucleus (the central dark part of
the cell) and from this a confident diagnosis of CLL can be made.
BUT, some cases of CLL do not have this typical picture and equally
other conditions can mimic CLL.
Immunophenotyping
Having
identified the lymphocytosis from the FBC, the next step is to
determine the nature of the cells – B-, T- or NK-cells – in the
blood. This is easily established by immunophenotyping. This test
uses reagents (antibodies) to label the cells only if they are
B-cells and emit light, which is then detected by a machine called a
flow cytometer. In addition to proving the cells are B-cells,
immunophenotyping produces a profile of the different molecules
expressed on the surface of the B-cells and establishes the typical
pattern seen in CLL. This requires a panel of reagents, as no single
marker can define a CLL cell, and the British Society of Haematology
has published guidelines on this (see website details). It should be
noted that different, but similar, panels may also be used to arrive
at the same final conclusion. To assist in the diagnostic process
with a panel of markers, Table 1 shows the five markers that
constitute the so-called ‘CLL score’. A high CLL score of 4 or 5 is
almost always proof of CLL. The diagnosis becomes less certain as
the CLL score decreases.
Table 1. Modified CLL scoring system
|
Antigen |
Expression |
Score |
Expression |
Score |
|
SmIgM |
Weak/Mod. |
+1 |
Mod/strong |
0 |
|
CD5 |
Positive |
+1 |
Negative |
0 |
|
CD23 |
Positive |
+1 |
Negative |
0 |
|
CD79b |
Neg /Weak |
+1 |
Moderate |
0 |
|
FMC7 |
Negative |
+1 |
Strong |
0 |
(A score
of 4 or 5/5 is strongly supportive of a diagnosis of CLL. Reference:
Moreau EJ, Matutes E, A’Hern RP, et al (1997) Improvement of the
chronic lymphocytic leukaemia scoring system with the monoclonal
antibody SD8 (CD79b). Am J of Clin Pathol; 108: 378-382)
Bone marrow
A bone
marrow test does not have any role in the diagnosis of CLL. In
general, a bone marrow biopsy is only performed if: treatment is to
be started – as a baseline to then assess response; the platelet
count is low and suggestive of idiopathic thrombocytopenia (ITP);
anaemia is present and the blood film and Coomb’s test (or DAT)
suggest autoimmune haemolytic anaemia (AIHA). Both ITP and AIHA are
phenomena where the body destroys its own platelets and red cells,
respectively, and such findings are relatively common in CLL.
Radiological imaging
Ultrasound and CT scanning allow more accurate documentation of the
enlarged lymph nodes, liver and spleen – all possible features of
CLL - than the physical examination. However, these tests do not
provide diagnostic information and are usually only necessary as
part of the work-up prior to instituting treatment.
Lymph node biopsy
A biopsy
of an enlarged lymph node is not routinely performed in CLL, as the
diagnosis is usually clear from analysis of the blood. In the
majority of cases, a definitive diagnosis of CLL can be made from
the FBC and immunophenotyping. However, if the cells in the blood
are not typical under the microscope and the CLL score is 3 or less,
looking at the cells in a biopsy specimen under a microscope can be
useful in definitively making a diagnosis – whether CLL or not.
Other tests at presentation
Other
tests that can be performed at diagnosis are usually for prognostic
purposes – see ‘Prognostic Factors’ also in this section on the
website. Cytogenetic analysis (looking at the chromosomes in the
cells) can also help in the diagnostic process in difficult cases. A
number of cytogenetic changes are commonly detected in CLL and if
present can support the diagnosis of CLL (as well as give prognostic
information). Perhaps the most important role of cytogenetics in
diagnosis is to specifically exclude mantle cell lymphoma (MCL) -
which is generally a more aggressive disease than CLL. There can be
significant diagnostic overlap between MCL and CLL, with either
disease looking like the other, both under the microscope and by
immunophenotyping!
Another
test used for prognosis – ZAP70 – can also provide diagnostic
information. At Barts and the London, we have been routinely
performing ZAP70 measurement for the last 5 years in all cases of
BLPD at diagnosis. If positive, our data indicates that this is
highly supportive of a diagnosis of CLL, as opposed to any other B-LPD.
Summary
In
general, the diagnosis of CLL is straightforward and can be made
confidently by a combination of the FBC, the appearances of blood
cells under the microscope and definitively established by
immunophenotyping. However, in difficult cases, a lymph node biopsy
and cytogenetic analysis of blood or BM cells can help establish a
definitive diagnosis. The commonest diagnostic confusion is with
Mantle Cell Lymphoma and it is important to be aware of the overlap
with CLL – with cytogenetics allowing separation of the two
conditions. Diagnostic accuracy is essential, as all the prognostic
markers available in CLL are only meaningful if the diagnosis really
is CLL!