What is the pathophysiology of primary mediastinal B-cell lymphoma (PMBCL)?

Updated: Sep 14, 2019
  • Author: Sonali M Smith, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Answer

The tumor cells resemble immunoblasts or centroblasts, and, in many cases, sclerosis and fibrosis can be identified. Flow cytometry studies identify a unique immunophenotype profile for primary mediastinal B-cell lymphoma (PMBCL). Malignant cells express B-cell antigens (CD20, CD19, CD22, and CD79a), and, in some patients, weak CD30 expression is noted. The weak CD30 expression can aid in differentiating PMBCL from anaplastic large cell lymphoma and classic Hodgkin lymphoma. This is critical, as Reed-Sternberg–like cells can be present in patients with PMBCL. Additionally, the malignant cells also lack CD15 expression but have frequent positivity of the transcriptional regulators BCL6, PAX5, and BOB1.

PMBCL is hypothesized to originate from the germinal or postgerminal centers; however, surface immunoglobulin expression is frequently absent.

Several studies have explored the underlying genetic and molecular features that lead to the evolution of primary mediastinal B-cell lymphoma (PMBCL). Gene expression profiling has clearly demonstrated that this disease entity is different from diffuse large B-cell lymphoma (DLBCL) and has identified several deregulated pathways involved in the pathogenesis of PMBCL. Steidl and Gascoyne eloquently summarized the recurrent gene alterations involved in the pathogenesis of PMBCL. [9]

Gene expression profiling has demonstrated overexpression of genes encoding the NF-kappa-B pathway, suggesting its involvement in the pathogenesis of PMBCL. Further, inhibiting I-kappa-B, which activates NF-kappa-B signaling, was shown to induce cell kill in vitro in PMBCL cell-lines.

Chromosomal gains and amplifications of the REL gene locus on band 2p16.1 have been found in 50% of cases. [9, 10, 11]  Other chromosomal aberrations that affect NF-kappa-B pathways include BCL-10 (1p22) and MALT-1 (18q21).

Song et al identified a tumor suppressor gene that encodes the A-20 protein, which acts as an inhibitor to the NF-kappa-B pathway downstream from the tumor necrosis factor (TNF) receptor. [12]  Mutations in that gene have been found in over 30% of PMBCL cases, but it has also been described in other lymphoid malignancies. [13, 14]  Another mutated tumor suppressor gene is SOCS1 (suppressor of cytokine signaling). SOCS1 usually acts as an inhibitor to the JAK-STAT6 pathway, preventing continued activation and proliferation. [15]  In fact, Mottok et al suggested that SOCS1 deletion mutations were present in 45% of 20 studied patients. [16]

More recent studies have also shown a role of immune deregulation in PMBCL pathogenesis. Specifically, the reduced expression of major histocompatibility II complex genes led to decreased infiltrating cytotoxic T-cells, and some investigators have suggested this can lead to inferior outcomes, arguing that more studies exploring the role of immune escape in PMBCL are warranted. Another mechanism by which PMBCL cells escape immune surveillance has been by overexpressing certain surface molecules such as PD-1 ligands and receptors, which, in turn, leads to inactivating infiltrating effector T cells. [17]


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