title: Pathobiology of primary mediastinal B-cell lymphoma.
abstract: Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H) gene crippling mutations.
authors.affiliation: Institute of Haematology Seràgnoli, Bologna University, Policinico S. Orsola, via Massarenti 9, 40138, Bologna, Italy. pileri@med.unibo.it
authors.forename: Stefano A
authors.initials: SA
authors.lastname: Pileri
authors.forename: Pier L
authors.initials: PL
authors.lastname: Zinzani
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Elena
authors.initials: E
authors.lastname: Sabattini
authors.forename: Stefano
authors.initials: S
authors.lastname: Ascani
authors.forename: Maura
authors.initials: M
authors.lastname: Rossi
authors.forename: Franco
authors.initials: F
authors.lastname: Cavalli
mesh_terms: D003937:Diagnosis, Differential; D015321:Gene Rearrangement; D006801:Humans; D016130:Immunophenotyping; D016393:Lymphoma, B-Cell / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D008479:Mediastinal Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D000090063:Proto-Oncogene Mas
chemical_list: C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas