Chronic lymphocytic leukemia (CLL) is a malignancy of B-lymphocytes characterized by accumulation of neoplastic cells with low proliferative capacity but a disrupted apoptotic pathway that hampers programmed cell death, resulting in their prolonged life span (1,2). As a consequence, many patients afflicted by CLL follow an indolent or slowly progressive course often, requiring no treatment (3). Because of this slow course and because CLL primarily affects the elderly [mean age at diagnosis, 60-65 (4)] most patients die with rather than of the disease or its complications. Indeed, many CLL patients with early-stage disease [Rai low risk (5) or Binet stage A (6)] have a normal life span (7). However, in a substantial number of patients, survival is shortened by the multifaceted pathological impact of progressive disease (8,9) or its treatment (10) and (to a much lesser extent) by clonal evolution to a more aggressive disease (11) or the development of second malignancies (12-16). This chapter examines the most recent literature on CLL clonal evolution, especially Richter's syndrome, and reviews Surveillance, Epidemiology, and End Results (SEER) data in order to quantify the risk for and types of second malignancies suffered by patients with CLL.
Hematological malignancies develop as second cancers in CLL with some frequency and include diffuse large cell lymphoma (DLCL), Hodgkin's disease (HD), and multiple myeloma (MM), with relative incidences of 3, 0.5, and 0.1, respectively. Of these, an aggressive and rapidly fatal form of DLCL described by Richter in 1928 is the best known second malignancy associated with CLL (17). The term Richter's syndrome was coined by Lortholary et al. (18), who reported four additional cases exhibiting the clinical and pathological syndrome. It includes the emergence of an aggressive DLCL occurring in a patient with pre-existing CLL, severe constitutional symptoms, and swift disease progression resulting in rapid clinical deterioration and death within 1 yr of onset. Given its low incidence, most reports on RS are anecdotal or are limited to only a few patients, and some have included rapidly progressive DLCL arising from low-grade lympho-proliferative disorders other than CLL (19,20). This review focuses on RS supervening in CLL, highlighting differences that relate to the primary underlying disorder, if other than CLL, especially when addressing its clonal origin.
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