Clinical Information

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization (WHO) classification and accounts for approximately 2% to 3% of all non-Hodgkin lymphomas (NHL).(1) Currently, diagnosis relies on consensus of histopathology, clinical variables, and presentation (as it can present outside the mediastinum), giving rise to diagnostic inaccuracy in routine practice. This is complicated by recent studies that identified lymphomas sharing molecular and morphological features with PMBCL, yet without involvement in the mediastinum.(2) Since classification can impact therapeutic approach, the need has arisen for a more robust method to identify PMBCL vs diffuse large B-cell lymphoma (DLBCL).

Gene expression profiling studies have demonstrated that PMBCL can be distinguished from subtypes of DLBCL based on gene expression signatures in fresh/frozen tissues,(3,4) which are often difficult to obtain in conventional clinic settings. Members of the Lymphoma/Leukemia Molecular Profiling Project have developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in clinically-available FFPE tissue,(5) which has been subsequently validated against this published data in the Molecular Diagnostics Arizona Lab.

Research suggests that novel therapeutic approaches might have preferential benefit in PMBCL as compared to DLBCL.(6,7,8,9)

The Lymph3Cx assay builds upon the previously described and validated Lymph2Cx assay.(4,10) The Lymph3Cx assay is a qualitative assay utilizing a 58-gene signature (45 endogenous targets and 13 housekeeping genes), reporting calculated scores to distinguish PMBCL from DLBCL.(5) After determination of PMBCL vs DLBCL status, the built-in Lymph2Cx assay then provides the cell-of-origin (COO) for samples determined to be DLBCL as previously described.

DLBCL is the most common form of NHL, accounting for up to 30% of newly diagnosed cases in the United States. DLBCL is an aggressive (fast-growing) lymphoma caused by the uncontrollable growth and proliferation of B lymphocytes. It can arise in lymph nodes or outside of the lymphatic system in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Although DLBCL is the most common form of NHL, there are distinct subtypes that may affect prognosis (how well patients will do with standard treatment) and treatment options. Since 2008, WHO classification of lymphoid neoplasms has recognized 2 distinct molecular subgroups of DLBCL: a germinal center B-cell (GCB) type, an activated B-cell (ABC) type, as well as a third group of cases that do not belong to either (unclassifiable). These were all originally grouped together based on shared morphology but can be distinctly separated based on their biology, particularly their gene expression pattern. According to a review of the 2016 revision of the WHO guidelines,(1) a better understanding of the molecular pathogenesis of these 2 subgroups has led to the investigation of more specific therapeutic strategies based on COO classification. Current data suggests that the ABC subtype of DLBCL has a poorer prognosis compared to the GCB subtype or unclassifiable cases; and that the ABC subtype may differentially respond to specific therapies.(11,12,13)