P. M. Kluin

Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study.

PURPOSE We studied the prognostic significance of bcl2 and p53 protein expression in relation to clinical and pathologic characteristics in patients with diffuse large B-cell lymphoma (LCL). PATIENTS AND METHODS Three hundred seventy-two patients with LCL were retrieved from a population-based registry for non-Hodgkins lymphoma (NHL). bcl2 and p53 protein expression was studied on paraffin-embedded tumor tissue by immunohistochemistry in relation to clinical factors. Response to therapy and survival were analyzed in 165 patients who were uniformly staged and treated and for whom all prognostic data were available according to the International Prognostic Index (IPI). RESULTS Forty-five percent of tumors showed strong expression of the bcl2 protein (bcl2++), with a higher frequency in patients with primary nodal involvement. Disease-free survival (DFS) was significantly better in bcl2-negative/intermediate (bcl2-/+) cases as compared with bcl2++ cases (P = .0011). At 5 years, bcl2-/+ patients showed a DFS rate of 74%, in contrast to bcl2++ patients with a DFS rate of 41% (P = .002). Bcl2 was the strongest independent prognostic value in a multivariate analysis, with a relative risk (RR) of 3.0 in comparison to p53 expression and the clinical factors of the IPI. Overall survival (OS) was not significantly influenced by bcl2 protein expression. p53 protein expression was found in 13% of cases, with a higher frequency in patients with extensive disease. p53 expression did not influence the chance to achieve complete remission (CR) and survival. CONCLUSION bcl2 protein is frequently expressed in LCL and is a strong independent prognostic factor for DFS. p53 expression is related with high tumor burden, but is not an independent risk factor for CR and survival.

Mantle-cell lymphoma: a population-based clinical study.

PURPOSE From a population-based non-Hodgkins lymphoma (NHL) registry, 41 patients with mantle cell lymphoma (MCL) -- a recently defined distinct B-cell NHL -- were selected and compared with patients with low- or intermediate-grade NHL from the same registry. PATIENTS AND METHODS The incidence and behavior of MCL in the area of the Comprehensive Cancer Center West (CCCW) from 1981 to 1989 were analyzed. Age, performance, tumor bulk, extranodal localization, stage, response to therapy, and survival were registered. Expression of cyclin D1 protein and Ki-67 were measured in 29 patients. RESULTS MCL made up 3.7% of NHLs. The median age was 68 years, and the male-to-female ratio was 1.6:1. Seventy-eight percent presented with stage IV, with the majority having bone marrow involvement. The complete response (CR) rate was 32% (13 of 41), with a median duration of 25 months. The median overall survival time was 31.5 months. The International Prognostic Index identified five patients with a low-risk score and a median survival time of 93+ months. In 23 of 29 patients, cyclin D1 overexpression was present, without any relation to overall or disease-free survival. In contrast, a proliferative index less than 10% was significantly related to a better overall survival time (50 v 24 months). CONCLUSION MCL is a disease of the elderly, who present with widespread disease and with a poor response to therapy. Although it harbors features of an indolent NHL, it behaves clinically as an aggressive NHL with a short overall survival time.

Primary non-Hodgkin's lymphoma of bone: a clinicopathological investigation of 60 cases

A retrospective analysis of patients presenting with primary lymphoma of bone (PLB) was performed to determine clinical factors affecting prognosis in relation to histological subtype and treatment outcome. Data from 106 patients, presenting with a PLB between 1943 and 1996, were retrieved from the files of the Netherlands Committee on Bone Tumours and Leiden University Medical Centre. The lymphomas were reclassified according to the REAL and updated Kiel classification. The clinical presentation, survival and prognostic factors were investigated. Sixty patients had sufficient clinical information and adequate follow-up to be included in the study. All 33 PLB that could be immunophenotyped were of B cell origin. According to the REAL classification, most PLB were large (B) cell lymphomas (92%) and according to the Kiel classification 45% of the tumours were centroblastic multilobated. PLB presented most often in the long bones (48%), with Ann Arbor stage I (46%), II (16%), IV (16%) and unknown (20%). Stage IV disease was exclusively caused by the presence of multiple bone lesions. Notwithstanding the heterogeneous treatment, the 5-year overall survival was 61%; 46% of patients were progression free at 5 years. Patients at presentation older than 60 had a worse overall survival (76% vs 37%, P = 0.0002) and a worse progression-free period (58% vs 28%, P = 0.0073). Patients with the immunoblastic subtype had a worse survival than the centroblastic mono/polymorphic subtype or the centroblastic multilobated subtype (P = 0.015). Primary lymphoma of bone represents an uncommon bone tumour with a relatively homogeneous morphology and clinical behaviour. Compared to other aggressive lymphomas, PLB have a favourable prognosis.

Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15–64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50–116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.

Successful outcome with a "quintuple approach" of posttransplant lymphoproliferative disorder.

Background. The treatment of posttransplant lymphoproliferative disorder (PTLD) remains empirical. We review our treatment of seven cases of PTLD consisting of five interventions: 1) reduction of immunosuppression; 2) antiviral drugs; 3) interferon-&agr;; 4) gamma-globulins; and 5) anti-CD19 monoclonal antibodies. Methods and Results. Seven consecutive patients who had undergone a simultaneous pancreas-kidney, liver, heart, or kidney transplantation were treated. One patient acquired a primary EBV infection with an oligoclonal immunoblastic lymphoma early after pancreas-kidney transplantation; all others developed a monoclonal polymorphic or immunoblastic lymphoma 2 to 123 months after transplantation. In all patients extranodal sites were involved, in three the graft was also involved. Five patients received the full quintuple approach and all rapidly obtained a complete remission (CR) with a median follow-up of 31 months (7-74 months). Of the two patients who did not receive interferon-&agr; for fear of graft rejection one responded slowly with a CR after 7 months, and the other obtained a rapid CR followed by a relapse at 4 months. All three patients with a liver or heart transplant could keep their graft. All patients are still alive with a median follow-up of 31 months (7-74 months). Conclusion. This combined approach resulted in a favorable outcome in patients with high risk monoclonal PTLD after solid organ transplantation.

Lymphomatoid papulosis with a natural killer-cell phenotype

Lymphomatoid papulosis (LyP) is defined as a recurrent self‐healing papulonodular eruption with the histological features of a (CD30+) cutaneous T‐cell lymphoma. The atypical cells usually have a CD3+/–, CD4+/–, CD8–, CD30+, CD56– T‐cell phenotype. We report an unusual case of LyP, in which the atypical cells expressed a CD3–, CD4–, CD8–, CD30+, CD56+ phenotype. Detailed phenotypic and genotypic analysis confirmed that these cells had a natural killer (NK)‐cell phenotype. Lymphomas with an NK‐cell phenotype usually have a poor prognosis. However, the waxing and waning of papular lesions for more than 20 years and the excellent response to low‐dose oral methotrexate in this patient suggest similar clinical behaviour to LyP cases with a T‐cell phenotype.

Somatic changes in B-lymphoproliferative disorders (B-LPD) detected by DNA-fingerprinting.

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The molecular biology of B-cell lymphoma: Clinicopathologic implications

SummaryNonrandom chromosomal translocations like the t(14;18), t(8;14), and t(11;14) are found in distinct types of B-cell malignancies. Recent molecular studies concerning their structure and origin showed that many translocations occur in early precursor B cells and may be interpreted as aberrant immunoglobulin gene rearrangements. The available data from in vitro experiments, transgenic mice, and normal human individuals indicate that these translocations are essential but insufficient for full tumorigenesis. The consequent “multi-hit” concept might have important implications for the detection of minimal residual disease using the polymerase chain reaction for these translocations. The strong associations with specific types of lymphomas underline their differences in histogenetic origin. Thus, based on differences inbcl-1 andbcl-2 rearrangements, molecular analysis may help to distinguish follicular lymphoma from diffuse centrocytic lymphoma and chronic lymphocytic leukemia. Furthermore, based on differences inbcl-2 and c-myc rearrangements, subtypes of de novo centroblastic lymphoma can be distinguished that have striking differences in biological behavior, especially nodal versus extranodal presentation. Therefore, future studies will show an increasing clinical relevance of molecular analysis in B-cell neoplasia.

Subcellular Localization of bcl-2 Protein

The bcl-2 oncogene is normally transiently expressed both in lymphoid and myeloid cells as well as in various epithelia (Hockenbery et al. 1991). It may have a function in the transition of dividing (precursor) cells to mitotically inactive and relatively longliving daughter cells (Vaux et al., 1988, Nunez et al. 1991). The protein acts through protection against programmed cell death (apoptosis). Deregulation by the t(14; 18) translocation in lymphoid malignancies induces inappropriate cell survival and serves as one of the steps towards a fully malignant behaviour.

Reactive hemophagocytic syndrome as a presenting feature of Hodgkin's disease

Abstract We report the case of a 60-year-old man with febris of unknown origin, severe pancytopenia, and rapidly developing splenomegaly due to reactive hemophagocytic syndrome and Hodgkins disease. Reactive hemophagocytic syndrome is often rapidly fatal and, once this diagnosis is considered, an underlying infection or malignancy should be treated promptly. An extensive search of the literature revealed only two other cases of reactive hemophagocytic syndrome and Hodgkins disease. This is the only reported patient who survived after being diagnosed as having reactive hemophagocytic syndrome and Hodgkins disease.