Analysis of microsatellite instability in chronic lymphoproliferative disorders

Microsatellite instability (MSI) represents one specific pattern of genomic instability and is one of the genetic lesions most frequently detected in human neoplasia. Although MSI has been found to be associated with a wide variety of solid cancers, its involvement in lymphoid malignancies is virtually unexplored. In this study, we have investigated the presence of MSI in chronic lymphoproliferative disorders by comparing the pattern of nine microsatellite repeats (two tetranucleotides, two trinucleotides, and five dinucleotides) on autologous germline and tumor DNA of 23 patients, including 17 with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL), four with hairy cell leukemia, one with lymphoplasmacytoid lymphoma, and one with T-cell chronic lymphocytic leukemia. All samples at diagnosis displayed a germline pattern of the microsatellites examined, thus suggesting that MSI is not involved in the pathogenesis of these lymphoproliferations. Also, no microsatellite alterations were observed in consecutive samples of B-CLL/SLL obtained from the same patient at various stages of the disease both before and after chemotherapy. Conversely, alterations in 3/9 microsatellite repeats were detected in one case of Richter's syndrome which had evolved from a pre-existent B-CLL/SLL phase. Overall, the low frequency of MSI among chronic lymphoproliferative disorders adds further weight to the common view that the mechanisms and patterns of genomic instability in lymphoid neoplasia differ markedly from those commonly observed in solid cancers.     

Richter's Syndrome Showing Pronounced Lymphadenopathy in Response to Administration of Granulocyte Colony-Stimulating Factor

A patient with Richter's syndrome developed rapid generalized lymph node enlargement with a decrease of peripheral blood lymphocytes after recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy for neutropenia induced by chemotherapy. The lymphadenopathy subsided spontaneously following discontinuation of rhG-CSF medication. Reinstitution of rhG-CSF therapy was followed by the same response as during initial therapy. Histopathologically, the lesions were characteristic of diffuse large cell lymphoma (DLL) with no evidence of myeloid cell involvement. No spontaneous contraction of enlarged lymph nodes followed withdrawal of the second course, but the enlargement subsided with chemotherapy. The patient died of myocardial infarction. All residual tumors examined post mortem presented microscopic features of small lymphocytic lymphoma (SLL), and G-CSF receptor was demonstrated on these neoplastic cells by Northern blot hybridization analysis. This observation indicates that some B cell malignancies may retain G-CSF receptor and respond to G-CSF.     

Skin lesions in chronic lymphocytic leukemia

Cutaneous lesions occur in up to 25% of patients with chronic lymphocytic leukemia (CLL). These can be caused by either cutaneous seeding by leukemic cells (leukemia cutis, LC) and other malignant diseases or nonmalignant disorders. Skin infiltration with B-lymphocyte CLL manifests as solitary, grouped, or generalized papules, plaques, nodules, or large tumors. Prognosis in CLL patients with LC is rather good and many authors claim that it does not significantly affect patients' survival. However, prognosis is poor in patients in whom LC shows blastic transformation (Richter's syndrome) and when leukemic infiltrations in the skin appear after the diagnosis of CLL. Secondary cutaneous malignancies are also frequent complications in patients with CLL. A higher risk was seen in skin cancer, for which eightfold higher occurrence has been stated. There are some suggestions that alkylating agents and purine analogs may be associated with an increased incidence of secondary malignancies in CLL. Nonspecific, secondary cutaneous lesions are frequently observed in CLL patients. The most common secondary cutaneous changes seen in CLL are those of infectious or hemorrhagic origin. Other secondary lesions present as vasculitis, purpura, generalized pruritus, exfoliative erythroderma, and paraneoplastic pemphigus. An exaggerated reaction to an insect bite and insect bite-like reactions have been also observed.     

Hodgkin's disease variant of Richter's syndrome in chronic lymphocytic leukaemia patients previously treated with fludarabine

The transformation of chronic lymphocytic leukaemia (CLL) into large-cell lymphoma (Richter's syndrome, RS) is a well-documented phenomenon. Only rarely does CLL transform into Hodgkin's lymphoma (HL). To further analyse the clinico-pathological and genetic findings in the HL variant of RS, we performed a single-institution study in four patients, who developed HL within a mean of 107 months after diagnosis of CLL. All were treated with fludarabine. Three cases were Epstein-Barr virus (EBV)-associated mixed cellularity (MC) HL, the fourth was nodular sclerosis (NS) HL without EBV association. The sites involved by HL included supra- and infradiaphragmal lymph nodes and the tonsils; stage IV disease was also documented. All patients presented with CLL treatment-resistant lymphadenopathies and B-symptoms. In two of the MC cases, molecular analysis performed on CLL samples and microdissected Hodgkin and Reed-Sternberg cells (HRSC) suggested a clonal relationship, while in NS no indication of a clonal relationship was detected. In summary, HL can occur in CLL patients at any site, up to 17 years after initial diagnosis, especially after treatment with fludarabine. The majority present with B-symptoms and CLL treatment-resistant lymphadenopathy, are of the MC type, clonally related to CLL and might be triggered by an EBV infection.     

Large‐cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine–rituximab‐containing regimens: natural history‐ or therapy‐related complication?

Novel therapeutic regimens containing purine analogs and monoclonal antibodies have led to significant improvement in the course of indolent lymphoproliferative diseases (LPD). Complete clinical and even molecular remissions have been achieved in an increasing proportion of patients. In parallel to their tumor cytotoxic effect, these agents are inevitably associated with prolonged immunosuppression inherent to their mechanism of antilymphocytic activity. Until now, attention has been paid mainly to opportunistic infection occurring as a result of the above drug-induced immunosuppression and less to other possible complications, such as malignancy or tumor progression in the immunocompromised host. Here we briefly report nine patients with previously treated indolent LPD in whom the onset of large-cell transformation occurred during or shortly after the initiation of regimens containing these agents before transformation occurred. One patient had received rituximab alone, three fludarabine-containing regimens and five received sequential regimens containing both agents. This     

J-chain-producing immunoblastic lymphoma in a case of Richter's syndrome

Summary A 66-year old male with Richter's syndrome died 52 month after diagnosis of chronic lymphocytic leukaemia (CLL). The clinical course was characterized by a marked IgM hypoglobulinaemia which paralleled a chronically relapsing Herpes simplex infection. Autopsy showed a large retroperitoneal and intraabdominal tumour mass and well defined supradiaphragmatic lymphomas. Histological examination revealed a composite tumour consisting of CLL B-cell type (B-CLL) and immunoblastic malignant lymphoma of B-cell type (B-IbL). The lymphocytes bear -chains on their surface and to a lesser extend within their cytoplasm, the obviously defective immunoblasts produce J chains exclusively. Flow cytophotometric data seem to indicate an identical diploid stem line of the two tumours. The majority of the cells are in G_0/1 phase. The CLL rarely produces mitoses, however, the IbL has a mitotic rate of 7% and a considerable proportion (33%) of cells in the phase of DNA-synthesis. This is the fourth malignant lymphoma and the second immunoblastic lymphoma to be reported that produces J chain in the absence of immunoglobulin.     

Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus

A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus–positive B-cell lymphoproliferative disorders. These Epstein-Barr virus–B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma–like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus–B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder.     

Diffuse large B-cell lymphoma arising independently to lymphoplasmacytic lymphoma: a case of two lymphomas

Richter's syndrome occurs in 5-10% of patients with chronic lymphocytic leukemia, either by transformation of the primary neoplastic lymphocyte, or as a distinct B-cell neoplasm. We report a Japanese patient with lymphoplasmacytic lymphoma in whom a diffuse large B-cell lymphoma developed after treatment with rituximab. Molecular examination on immunoglobulin VH genes revealed that the lymphomas had arisen in two separate clones. We reviewed clinical case reports in literature, and found 30-40% of cases with Richter's syndrome and composite lymphoma had a second B-cell lymphoma of a different origin.     

Secondary follicular lymphoma of the bone, transformed into large cell lymphoma, in a patient with chronic lymphocytic leukaemia: an uncommon manifestation of Richter's syndrome

Patients with chronic lymphocytic leukemia (CLL) are at a significantly increased risk of developing a second malignant neoplasm in the course of their disease. The occurrence of large cell lymphoma [Richter's syndrome (RS)] has been described in approximately 3-5% of CLL patients. Other types of secondary lymphoid malignancies are extremely rare. Here we describe a patient, heavily pretreated, with long history of CLL who developed a secondary follicular lymphoma, transformed into a diffuse large cell lymphoma (LCL), with isolated manifestation in the bone, a very rare manifestation of RS. CLL and LCL cells were of distinct clonal origin, as documented by DNA sequencing of the CDR3 regions. Twelve months after the completion of chemo- and local radiotherapy, the patient is still in remission.