Clinical diagnosis of chronic lymphocytic leukaemia is defined by absolute lymphocytosis of at least 5×109/L mature-appearing lymphocytes and an appropriate immunophenotype (figure).  These characteristics distinguish chronic lymphocytic leukaemia from mantle-cell lymphoma and splenic marginal-zone lymphoma, the diseases that most frequently mimic chronic lymphocytic leukaemia.  In a few individuals, tumour is confined to lymph nodes or other tissues without blood or bone marrow involvement. In these people, the disorder is known as small lymphocytic lymphoma: histological findings and immunophenotype are identical to chronic lymphocytic leukaemia and management should be the same. Individuals without involvement of lymph nodes or other tissues, who have a population of small lymphocytes immunophenotypically similar to chronic lymphocytic leukaemia cells in blood or bone marrow below the threshold necessary for diagnosis of chronic lymphocytic leukaemia, are designated as having monoclonal B-cell lymphocytosis. Molecular and cellular markers have been identified that could predict disease progression. In particular, the mutational profile of immunoglobulin genes and  and some cytogenetic abnormalities  show strong prognostic value. However, these biological differences do not separate chronic lymphocytic leukaemia into two different disorders; it remains one disease with heterogeneous features. 
Despite the ready availability of tumour cells in chronic lymphocytic leukaemia, up to now, very little has been known about the pathophysiology of the disease. The cells themselves are remarkably inert in vitro. Most, if not all, cell lines attributed to chronic lymphocytic leukaemia are either from patients with mantle-cell lymphoma masquerading as chronic lymphocytic leukaemia or B-cell lymphoblastoid lines from contaminating normal lymphocytes.  Until the past few years, no animal model had existed for chronic lymphocytic leukaemia. The TCL1 transgenic mouse develops a CD5+ B-cell lymphoproliferative disease that serves as a model for aggressive forms of chronic lymphocytic leukaemia but not for the frequent indolent form. 
The discovery that the mutational status of IGHV genes affects profoundly the prognosis of chronic lymphocytic leukaemia has acted as such a spur to our understanding of the disease's pathology, but full review of this topic is not possible within the space confines of this Seminar. Instead, we will concentrate on three topics: the B-cell receptor; genetic abnormalities revealed by interphase cytogenetics; and the balance between proliferation and apoptosis.
13 JL Binet, F Caligaris-Cappio and D Catovsky et al., Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia, Blood 107 (2006), pp. 859–861.
14 E Matutes, K Owusu-Ankomah and R Morilla et al., The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL, Leukemia 8 (1994), pp. 1640–1645.
15 HK Muller-Hermelink, E Montserrat, D Catovsky and NL Harris, Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: ES Jaffe, NL Harris, H Stein and JW Vardiman, Editors, World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues, IARC Press, Lyon (2001), pp. 127–130.
16 GE Marti, AC Rawstron and P Ghia et al., Diagnostic criteria for monoclonal B-cell lymphocytosis, Br J Haematol 130 (2005), pp. 325–332.
17 TJ Hamblin, Z Davis, A Gardiner, DG Oscier and FK Stevenson, Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia, Blood 94 (1999), pp. 1848–1854.
18 RN Damle, T Wasil and F Fais et al., Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia, Blood 94 (1999), pp. 1840–1847.
19 H Döhner, S Stilgenbauer and A Benner et al., Genomic aberrations and survival in chronic lymphocytic leukemia, N Engl J Med 343 (2000), pp. 1910–1916.
20 T Hamblin, Chronic lymphocytic leukaemia: one disease or two?, Ann Hematol 81 (2002), pp. 299–303.
21 HG Drexler, WG Dirks, Y Matsuo and RA MacLeod, False leukemia-lymphoma cell lines: an update on over 500 cell lines, Leukemia 17 (2003), pp. 416–426.
22 R Bichi, SA Shinton and ES Martin et al., Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression, Proc Natl Acad Sci USA 99 (2002), pp. 6955–6960.