Primary Mediastinal Bcell Lymphoma

Primary mediastinal B-cell lymphoma (PMBL) is a distinct subtype of diffuse large cell lymphoma originating from thymic B cells. It was first described nearly 25 years ago5960 and is now recognized as a unique entity based on clinical, immunophenotypic, and genotypic features. PMBL accounts for approximately 5% of all aggressive lymphomas and affects mainly young adults. The median age at presentation is in the third decade, with a slight female predilection. Most patients present with significant symptoms, including shortness of breath, superior vena cava syndrome, phrenic nerve palsy, cough, or chest pain, all due to local aggressiveness and invasion of other mediastinal and thoracic structures. Up to 80% of patients have disease limited to the thorax at presentation61; the bone marrow is only rarely involved. Despite their young age and apparently localized initial presentation, only a third of patients are alive at 5 years, and recurrences typically involve distant extranodal sites such as the kidney or CNS.

Histologic examination reveals a massive diffuse proliferation along with significant fibrosis. Similar to other DLBCLs, PMBL expresses CD19, CD20, and CD45 with variable expression of surface immunoglobulin and HLA molecules. Cytogenetic analysis shows several recurring abnormalities: gains of chromosome 9p in 50% of cases,62 trisomy 12q31 in 31% of cases, and trisomy 2p in occasional cases.63 Molecular features include amplification of the rel gene and overexpression of the mal gene, with absence of bcl-2, bcl-6, and myc expression. Recently, the gene expression pattern via microarray analysis of PMBL was shown to more closely resemble Hodgkin's lymphomas rather than NHLs.64 The clinical implications of this finding are yet to be defined, and PMBL continues to be treated similar to other DLBCLs.

In addition to unique epidemiologic and pathologic features, PMBL presents its own treatment challenges. Despite the initial supradiaphragmatic localization, there is difficulty in assigning patients a stage. Some consider PMBL to be stage II, whereas others feel that IVE is more appropriate due to invasion of mediastinal or intrathoracic structures.61 This could lead to heterogeneity when comparing patient populations between trials and published reports. Regardless of the staging, a full course of anthracycline-based treatment is initially offered, similar to advanced stage, aggressive lymphomas. However, up to a third of patients have primary refractory disease, and consolidative measures should therefore be considered. Mediastinal irradiation to the primary mass is commonly used. A report from the MD Anderson Cancer Center suggests that RT prevents local relapse,65 a finding supported by several European studies.6667 In a multicenter Italian study, patients remaining gallium avid after MACOP-B converted to gallium negative after consolidative RT and few patients relapsed. However, other authors have shown that RT adds little to disease control. Lazzarino and colleagues retrospectively reported on 99 evaluable patients and found that the relapse rate did not significantly differ between patients receiving RT and those who did not.61 Furthermore, 11 of 12 relapses in the RT group were intrathoracic. A French group reported that patients achieving only a PR to front-line chemotherapy did not further respond to RT.68 Highdose chemotherapy followed by autologous stem cell rescue in first remission has also been proposed, with very promising phase II data.63

At relapse, patients with PMBL are considered for autologous stem cell transplantation. In general, this population may do better as compared to the general group of aggressive lymphoma patients, partly due to their younger age and partly due to less common bone marrow involvement. Popat and colleagues69 report a series of patients with recurrent or refractory DLBCL treated with high-dose chemotherapy and found that having PMBL was a favorable prognostic feature. Sehn and colleagues70 also performed a retrospective analysis of 35 patients with PMBL treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) plus autologous bone marrow transplant (ABMT). Patients with primary refractory disease had 58% long-term disease-free survival and patients with relapsed disease had 27% long-term disease-free survival. The strongest predictor of PFS was chemotherapy responsiveness immediately before transplant. But even in chemo-therapy-refrac-tory patients, 33% long-term survival was observed.

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