Richter's transformation in chronic lymphocytic leukemia.
ABSTRACT Richter's syndrome (RS) is the development of high-grade non-Hodgkin's lymphoma (NHL) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. This process may be triggered by viral infections (eg, Epstein-Barr virus infection), which are common in immunosuppressed patients. The large cells of RS either arise through a transformation of the original CLL clone or, less frequently, represent a new or secondary neoplasm. Karyotypic changes, including trisomy 12, chromosome 11 abnormalities, and multiple cell-cycle regulator disruptions, have been found in patients with RS. Although these genetic defects are believed to cause CLL cells to proliferate and, by facilitating the acquisition of new genetic abnormalities, to transform into RS cells, none appears predominantly responsible for the transformation. The prognosis is generally poor, and most patients do not have long-term (durable) responses to therapy. Rituximab and cytotoxic combination therapy followed by stem cell transplantation is associated with improved clinical outcome. Curative treatment strategies are needed.
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ABSTRACT: The development of diffuse “histiocytic” lymphoma in patients with chronic lymphocytic leukemia (CLL), Richter's syndrome, occurs infrequently, but it is a distinct clinicopathologic phenomenon. In this report we describe five new cases of Richter's syndrome and summarize data on an additional 41 patients. Information from three separate series suggests a 3 to 10 per cent incidence of diffuse histiocytic lymphoma in patients with CLL. There were no features of CLL in these 46 patients in whom diffuse histiocytic lymphoma subsequently developed which would have distinguished them from patients with typical CLL in whom diffuse histiocytic lymphoma never developed. The median interval between the diagnosis of CLL and the recognition of diffuse histiocytic lymphoma in these 46 patients was 24 months (range, less than one month to 156 months). Fever (65 per cent), increasing lymphadenopathy (46 per cent), weight loss (29 per cent) and abdominal pain (26 per cent) were the clinical features which characterized the development of diffuse histiocytic lymphoma. Median durations of survival from the diagnosis of CLL and diffuse histiocytic lymphoma were 28 months and four months, respectively. Thirty-four per cent of the patients had received no treatment for CLL prior to the diagnosis of diffuse histiocytic lymphoma. Cytotoxic therapy for diffuse histiocytic lymphoma was generally unsuccessful in patients with Richter's syndrome (14 per cent complete remission rate). Clinical features of diffuse histiocytic lymphoma, which have been associated with poor response to combination chemotherapy (bulky lymph node masses, gastrointestinal or bone involvement and previous exposure to cytotoxic drugs), were common in these patients and may have contributed to the poor therapeutic response. Morphologic and immunologic studies suggest that the diffuse histiocytic lymphoma seen in patients with CLL arises as a proliferation and “dedifferentiation” of the lymphocytes of the preexisting CLL. Absolute proof that diffuse histiocytic lymphoma arises as a clonal progression of CLL cells is lacking, however, and further study of the genesis of diffuse histiocytic lymphoma in CLL is required.The American Journal of Medicine 05/1980; 68(4):539-48. · 4.77 Impact Factor
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ABSTRACT: In order to define better the cytological and clinical features of atypical B-cell chronic lymphocytic leukaemia (B-CLL) with t(ll;14)(ql3;q32), sequential morphologic immunological and cytogenetic studies were performed in seven patients belonging to a series of 72 consecutive cases presenting with a diagnosis of CLL or atypical CLL according to the FAB criteria.Cytologic diagnosis in these seven patients with t(ll;14) was typical CLL in two cases presenting with < 10% large lymphocytes (LL) and prolymphocytes (PL) and atypical CLL in five cases in which LL and PL comprised between 10% and 55%. The diagnosis was supported by histologic findings on bone marrow biopsy (five cases) or splenectomy specimens (two cases). A progressive increase of peripheral LL and PL was observed, resulting in a switch of FAB diagnosis over a 6-60-month period from typical CLL into atypical CLL in two cases and from atypical CLL into prolymphocytic leukaemia in five cases.Immunophenotyping showed a mature B-cell phenotype with CD19, CD22, CD24 positivity and CD10 negativity in all patients. A bright-staining pattern for surface immunoglobulins (SIg) was detected in 6/7 cases, CD5 positivity in 6/7 cases, and CD23 positivity in 1/7 cases. The FMC-7 monoclonal antibody was positive in >40% cells in 5/6 cases.Chromosome changes in addition to t(11; 14) were seen in five cases; in two cases unbalanced translocations involving the 3q21 chromosome region, resulting in partial trisomy for the long arm of chromosome 3, were detected early in the course of the disease. Karyotype evolution that was associated with disease progression occurred in 3/6 assessable patients.Comparison of these findings with similar data from 65 B-CLL patients without t(ll;14) showed that atypical morphology, switch of FAB diagnosis during the course of the disease, and karyotype evolution were more frequently seen in cases with t(ll;14) (5/7 v 15/65 cases, P = (V015, 7/7 v 7/65 cases, P < 0-0001, and 3/6 v 5/45 assessable cases, P= 0-04, respectively). The frequency of positivity for CD2 3 and bright SIg staining differed significantly in the two groups.It is concluded that t(ll;14) identifies a cytologically atypical subset of B-CLL, characterized by frequent cytologic and cytogenetic evolution and by a distinct immunological profile, sharing some biological features with mantle cell lymphoma.British Journal of Haematology 03/2008; 90(2):409 - 416. · 4.94 Impact Factor
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ABSTRACT: Chronic lymphocytic leukemia (CLL) may convert to a diffuse large cell lymphoma (Richter's syndrome) over time. In occasional cases of Richter's transformation, Epstein-Barr virus (EBV) has been identified in the lymphoma cells. To evaluate the association of EBV infection with Richter's syndrome, the biopsy specimens and clinical records of 25 patients who were seen at the Mayo Clinic between 1984-1996 were retrospectively evaluated for the presence of EBV by immunoperoxidase staining for expression of EBV latent membrane protein (LMP), as well as the expression of EBV RNA and DNA in the cells by in situ hybridization. Four of the 25 patients showed evidence of EBV in the diffuse large cell lymphoma cells-three patients with a B-cell phenotype were positive for LMP, EBV DNA, and RNA; and one patient with a T-cell phenotype had positive EBV RNA in the large cell lymphoma cells. The Richter's syndrome was treated with combination chemotherapy in 15 patients, three received radiotherapy, three were followed without further therapy after a splenectomy, two died before treatment could be started, and one patient had insufficient follow-up. One patient with evidence of EBV in large cell lymphoma cells was treated with acyclovir as initial therapy. The median survival of EBV-positive patients was three months compared with nine months for EBV-negative patients, but this difference was not statistically significant (P = 0.385). Evidence for EBV infection related to Richter's transformation was present in 16% of the patients in this study and may be associated with a poorer outcome. Primary therapy with acyclovir in one patient did not seem to be beneficial and other therapeutic modalities in patients with EBV-positive Richter's transformation need to be explored.American Journal of Hematology 03/1999; 60(2):99-104. · 4.00 Impact Factor