Primary Mediastinal Large B-Cell Lymphoma: incidence, survival, immunophenotype, and molecular characteristics

On 14^th January 2017, Ferreri and Martelli published a review article on Primary Mediastinal Large B-Cell Lymphoma (PMBCL) in Critical Reviews in Oncology and Hematology.¹

PMBCL is an uncommon, but not rare, lymphoma that occurs worldwide. It makes up 2–3% of all NHLs and 6–10% of DLBCLs, and in the 2001 WHO classification, PMBCL as listed as a separate entity. So far, no specific risk factors have been identified for PMBCL.

This lymphoma is characterized by diffuse proliferation of medium to large B-cells, and is associated with sclerosis and some level of compartmentalization. It normally presents as a progressive, bulky (>10cm in 70–80% patients) tumor in the anterior mediastinum, resulting in compressive symptoms such as early dyspnea, dysphagia cough, and compromised airway and/or great vessels causing a superior vena cava syndrome. PMBCL has relatively early presentation, and so at diagnosis approximately 80% patients have stage I/II disease. Currently, the complete staging work-up for PMBCL is the same as for nodal NHL and includes a physical examination, complete hematological and biochemical examinations, total-body computerized tomography, and bone marrow biopsy and aspiration.

Key Highlights

Incidence, survival and risk factors

Currently, only one large population based study has estimated PMBCL incidence, using US SEER database data in 400 patients diagnosed between 2000 and 2012.²

• Annual incidence rate = 0.4 per million
• In the Caucasian population, females have a significantly higher incidence than males (ratio 1.5)
• Five-year survival = 85%; survival is lower (70%) in “other populations” which include Asian, Hispanic, American Indian, and Alaska natives
• Prognosis decreases with increasing age; multivariate analysis found a 3.5 higher risk of patients aged >60 compared to patients aged 18–39yrs
• Pts with stage III/IV disease had an 80% higher risk compared to pts with stage I/II disease

Immunophenotype and molecular characteristics

• Cells generally do not express cytoplasmic or surface immunoglobulin
• Cells express B-cell-related antigens, for example CD19, CD20, CD22, CD79a, PAX5, and CD45
• Around 80% cases are CD30+, although weaker and less homogeneous than cHL and ALCL cases
• Cells are commonly positive for BCL2 (55–80%) and CD23 (70%), negative for CD10 (8–32%), and variable for BCL6 (45–100%)
• Approximately 70% cases are MAL+, whereas DLBCL and cHL are rarely MAL+
• The GEP transcriptional signature of PMBCL is closer to a typical cHL signature
  • Recurrent amplification of JAK2 on chromosome band 9p24 observed in 50–70% cases
  • Translocation involving CIITA seen in around 40% cases
  • PDL1 and PDL2 overexpression and MHC-II down-modulation are key to PMBCL survival in the thymus
  • 2p16 gain results in REL proto-oncogene duplication, encoding a transcription factor of NFkB family

Ferreri and Martelli noted that the population based study using SEER data found that there was an increasing trend in incidence rate of PMBCL from 2001 to 2012 in all ages, races, and both sexes. The authors of the review stated that this trend is partly explained by the increased recognition for this lymphoma subtype.

The authors of the review also state that the reasons for the complex demographics observed in patients of different ethnic groups are currently unclear, and suggest that further study in this area is required especially to determine the roles of genetic factors, gene-environment interactions, and gender factors. They also recommend that studies are needed to identify markers for monitoring MRD status in PMBCL, as currently there are none.

Lastly, Ferreri and Martelli state that constitutive activity of JAK-STAT and NFkB pathways are molecular hallmarks of PMBCL, and that PMBCL and HL are molecularly similar. They also suggest that components of the NFkB and JAK-STAT signalling pathways, in addition to PD1/PDL1, present as novel therapeutic targets.

Currently, a phase II trial is ongoing (NCT02038933) for nivolumab (a fully humanized IgG-4 monoclonal antibody specific for PD-1) in patients with R/R DLBCL including PMBCL who are ineligible for transplant.³

Abstract:

Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct clinical and biological disease from other types of DLBCL. It is more frequent in young female and constitutes 6%-10% of all DLBCL. PMLBCL is characterized by a diffuse proliferation of medium to large B-cells associated with sclerosis. Molecular analysis shows it to be a distinct entity from other DLBCL. Rituximab CHOP/MACOP-B-like regimens followed by with mediastinal radiotherapy (RT) were associated with a 5-years PFS of 75%-85%. More intensive regimens, as DA-EPOCH-R without mediastinal RT, have shown very promising results, but this therapeutic advance needs to be confirmed in further prospective trials. The role of consolidative mediastinal RT should be still better assess in prospective comparative studies. PET-CT scan is a powerful tool to define the real quality of response and it is hoped that future prospective trials may allow its role in the de-escalation of mediastinal RT.