Primary mediastinal (thyme) large B cell lymphoma

Question 1

What is the definition of primary mediastinal

large B cell lymphoma ?

Answer 1

• primray to the mediastinum
  
  • cases arising outside of this location may occur but are probably very rare
• mature, aggressive B cell lymphoma

Question 2

What is the epidemiology of this large

B cell lymphoma ?

Answer 2

• uncommon, 2-3% of NHLs
• usually presents in young adults (~35 age)
• preferentially occurs in young women

Question 3

What is the location of this lymphoma (PMBL) ?

Answer 3

• localized to the anterior/superior medistinum
  
  • location of the thymus
• usually very bulky disease (>10 cm in most patients)
• invades adjacent structures
• regional involvement of supraclavicular and cervical LN can occur
• with progression, dissemination of disease is often seen
  
  • liver, adrenals, kidneys and CNS
  • bone marrow involvement is usually absent
  • leukemia is not observed

Question 4

What are the clinical features of this disease?

Answer 4

• symptoms are related to the mass in the mediastinum
  
  • often present with SVC syndrome
• B symptoms may be present
• IMP
  
  • must rule out distant LN and bone marrow involvement to exclude a systemic large B involving the mediastinum

Question 5

What are key microscopic features in PMBL?

Answer 5

• there is a wide morphologic specrum from case to case
• growth pattern is diffuse
  
  • often have compartmentalizing alveolar fibrosis
  • cells are intermediate to large with abundant pale cytoplasm and oval round nuclei
  • IMP some cases the lymphoma cells can be pleomorphic and/or multilobulated
  • RARE
    
    • Grey-Zone Lymphoma
    • features in between primary mediastinal large B and Hodgkin
    • these are designated as B cell lymphoma unclassifiable
    • two lymphomas can occur together (reported) or preceed one another

Question 6

What is the immunophenotype of PMBL ?

Answer 6

• expresses B cell lineage antigens
  
  • CD19, CD20, CD22, and CD79a
  • BUT often lacks Ig despite a functional Ig gene rearrangement
    
    • but it does have expression of other transcription factors including: Pax5, BOB1, OCT2, and PU1
• CD30 is expressed in >80% of cases but more heterogeneous and weak compared to CHL
• CD15 can be positive in a minority of cases
• EBV is almost always absent
• MUM1- usually present (~75% of cases)
• Other variably expressed but usually present markers: BCL2, BCL6
• CD10 is less commonly seen in up to 30% of cases

Question 7

What immunophenotypic markers are usually seen in

PMBL and not in typical DLBCL ?

Answer 7

• CD23
• MAL antigen
• PDL1 and PDL2
• CD54
• FAS (aka CD95)

IMP: usually lacks HLA I/II class antigens

Note: MYC can be expressed

Question 8

What is the postulated counterpart

of PMLB ?

Answer 8

• Thymic, medullary asteroid activeated cytidine deaminase-positive B cell

Question 9

What is the genetic profile of PMBL

in regards to antigen receptor genes ?

Answer 9

• Immunoglobulin genes are rearranged and may be class switched
• high load of somatic mutations without ongoing mutation activity

Question 10

What is typical of PMBL by gene expression profiling ?

Answer 10

• distinct expression profile from other LBCLs
• shares similarities with CHL

Question 11

What are the cytogenetic abnormalities of PMBL ?

Answer 11

• rearrangements of MYC, BCL2 and BCL6 are rare
• the downregulation of MHC class II molecules
  
  • leads to an immune priveleged phenotype
• multiple possible aberrations in the PDL locus cause the typical over-expression of PDL1 and PDL2
  
  • CIITA alterations and copy-number gains and high level amplifications of the locus seem to exclusively occur in PMBL.

Question 12

What are the typical findings of the genomic

profile for PMBL ?

Answer 12

• gains in chromosome 2p16.1 (~50% of cases)
• gains involving chromosomes Xp11.4-21, Xq24-26, 7q22, 12q31, and 9q34 are seen in 1/3 of cases
• constituitively activated NF-KappaB pathway
• constituitively activated JAK/STAT pathway
  
  • this is also seen in CHL

Question 13

What are the prognostic and predictive factors

for PMBL ?

Answer 13

• IMP: variations in microscopic findings do not predict differences in survival
• IMP: should differetiate from “Grey-Zone” Lymphoma, which is more aggressive
• Response to intensive chemotherapy with or without radiotherapy is usually good
• Better prognosis as compared to GCB and ABC lymphomas, with higher cure rates

Question 14

What predicts poor outcome and survival in PMBL ?

Answer 14

• Poor outcome predictors
  
  • extension into adjacent organs or pleura
  • pleural or pericardial effusion
  • poor performance status
• FDG-PET
  
  • predicts survival after chemotherapy