Haematological Malignancies
New Developments in Chronic Lymphocytic Leukaemia Diagnosis
Julio Delgado, Rodrigo Santacruz, Tycho Baumann, and Emili Montserrat
Department of Hematology, Institute of Hematology and Oncology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
Abstract Chronic lymphocytic leukaemia (CLL) is the most prevalent leukaemia in the developed world, with a remarkable racial and sex diversity.
The diagnosis of CLL is based on the presence in blood of more than 5,000 monoclonal B cells/µl, with a distinctive immunophenotype
(CD5+, SmIg dim , CD20 dim , CD19, CD23), which persists for more than 3 months. Newer monoclonal antibodies, such as anti-CD43, anti-CD200
or anti-ROR1, may provide further information in differentiating CLL from other chronic lymphoproliferative disorders. CLL lacks a specific
genetic signature regarding chromosomic aberrations, but in cases of uncertain diagnosis molecular genetics including fluorescent in situ
hybridisation may be useful. Next-generation sequencing techniques are unfolding the molecular heterogeneity of CLL.
Keywords Chronic lymphocytic leukaemia, small lymphocytic lymphoma, Richter's Syndrome, inmunophenotyping, prognosis, monoclonal
B-cell lymphocytosis
Disclosure: The authors have no conflicts of interest to declare.
Received: 14 June 2013 Accepted: 27 July 2013 Citation: European Oncology & Haematology, 2013;9(2):114–8
Correspondence: Emili Montserrat, Department of Hematology, Institute of Hematology and Oncology, Hospital Clínic, IDIBAPS, University of Barcelona,
C/ Villarroel, 170, 08036 Barcelona, Spain. E: emontse@clinic.ub.es
Chronic lymphoproliferative disorders (CLPD) comprise several disorders
that arise from a monoclonal proliferation of mature B or T cells. Among
these entities, there are many that frequently involve the blood and
are usually detected in routine blood analyses, the most frequent
being chronic lymphocytic leukaemia (CLL). Before the advent of
immunophenotyping, most CPLD were diagnosed as CLL, but advances
in the morphological evaluation of peripheral blood and lymphoid tissues,
immunohistochemistry, flow cytometry and molecular genetics have
facilitated their differential diagnosis. Moreover, these new techniques
are allowing to identify distinct clinico-biologic forms of CLL. 1–3
Epidemiology CLL is the most prevalent form of leukaemia. In the US it is estimated
that approximately 16,000 cases/year are diagnosed with CLL. The age-
adjusted incidence rate is 4.2 cases per 100,000 per year, with a clear
difference between men (5.8 cases/year) and women (3.0 cases/year). 4
In Europe, the incidence rate is similar (4.9 cases/year), with a similar
sex distribution (5.9 for males and 4.0 for females). 5 The incidence of CLL
dramatically increases with age, reaching >20 cases/year in individuals
older than 70, and even >30 cases/year in patients aged 80 or older.
On the contrary, CLL is infrequent in persons under the age of 40 (0.2
cases/year). 4 One of the most notorious epidemiological characteristics
of CLL is its racial diversity. Within the US, the incidence rate is highest in
Caucasian males (6.2 cases/year) and females (3.2 cases/year) compared
with African Americans (4.3 and 2.0 cases/year for males and females,
respectively), while Asian Americans and Pacific Islanders had the lowest
incidence (1.3 and 0.7 cases/year for males and females, respectively). 4
Incidence rates are even lower in the Far East, and countries such as
Japan have an age-adjusted incidence of 0.48 cases/year, which is even
lower than that of mantle-cell lymphoma (MCL) in that region. 6
114 Furthermore, the clinical outcome of patients with CLL is also different
across various ethnic groups. In the US, African American patients with
CLL present at a younger age and with more frequent advanced disease,
extranodal involvement and B symptoms compared with Caucasian
patients. Consequently, African American patients had a significantly
shorter event-free and overall survival, an effect that was found to
be independent from other prognostic factors in a multivariable
analysis. 7 By contrast, in a recent series or Japanese patients, most
cases had favourable prognostic markers and an excellent clinical
outcome. 8 It is important to note, however, that rather than diversity
in the characteristics of the disease, these differences could reflect
disparities in access to medical care. 7
Diagnosis The hallmark of the disease is an increased white blood cell count with
a high percentage of small, mature-looking lymphocytes. In patients
diagnosed on routine analysis, anaemia is found in less than 10 % of
the patients. Importantly, anaemia is not always due to the infiltration
of the bone marrow by the disease; other causes such as autoimmunity,
iron, folic acid or vitamin B12 deficiency may account for the presence of
anaemia and should be discarded when these comorbidities are under
consideration. 9,10 Likewise, a marked thrombocytopenia (e.g. <20,000/
µl) should raise the possibility of an immune origin, particularly in the
absence of anaemia. Hypogammaglobulinaemia is frequent (30 % of
patients) and tends to worsen over the course of the disease. 11 Serum
immunofixation can demonstrate an M component (usually of the
immunoglobulin M [IgM] type) in around 10–15 % of patients. A positive
direct antiglobulin test is observed in around 5 % of the patients at
the time of diagnosis, with clinically apparent autoimmune haemolytic
anaemia being less frequent. 12 The lymph nodes show involvement by
© Touc h ME d ic a l ME d ia 2013