High Grade B-cell Lymphoma

Question 1

What is the definition of High Grade B cell Lymphoma ?

Answer 1

• a group of aggressive, mature B cell lymphomas
• includes HGBCL with double and triple hit as well as HGBCL, NOS
  
  • Double or triple hit usually resemble DLBCL or have features of DLBCL and BL
  • HGBCL, NOS also can have intermediate features between both DLBCL and BL

Question 2

What is the definition of HGBCL with double or triple hit?

Answer 2

• aggressive mature B cell lymphoma
• harbors a MYC gene rearrangement along with BCL2 (18q21.3) and/or BCL6 (3q27.3)
  IMP:
  
  • lymphomas with only BCL2 or BCL6 rearrangements are not part of this category

Question 3

How should a grade 3B follicular lymphoma with double hit by molecular be classified ?

Answer 3

• if completely follicular in pattern (grade 3B) should be called Follicular lymphoma
• but the cytogenetic findings should be mentioned in a comment
• if there is a large B cell lymphoma associated with it then it becomes HGBCL arising from a Follicular lymphoma

Question 4

What should be mentioned in the report for all large B cell and HGBCL ?

Answer 4

• the morphology of the tumor cells

- should be put in the diagnostic line

Question 5

What lymphomas are NOT included in the HGBCL category?

Answer 5

• rare cases of B-ALL with MYC and BCL2 translocation

- these are just classified as B-ALL

Question 6

How are the rearrangements detected?

Answer 6

• FISH or cytogenetics
• Double-expressor is identified by IHC
• most double or triple hit are usually GCB

Question 7

What is the epidemiology of the HGBCL?

Answer 7

• most present in elderly patients
  
  • median age at diagnosis in 6-7th decade
  • but youngest reported patient low to mid 30s

Question 8

What is the etiology of HGBCL?

Answer 8

• must harbor at least 2 of the rearrangements
• also have complex cytogenetics in addition to those
• it is likely that the MYC rearrangement is a secondary event

Question 9

What is the disease localization ?

Answer 9

• more than 1/2 of patients present with widespread disease
• lymph node involvement also occurs
• involvement of more than 1 extranodal site is also frequently seen (including bone marrow and CNS disease)

Question 10

What are some of the clinical features of HGBCL ?

Answer 10

• most patients present with stage III or IV disease
• Double hit LBCL are enriched in patients with DLBCL who do not respond well to induction chemotherapy and CHOP or who have early relapses after complete remission

Question 11

What are the morphological findings of HGBCL ?

Answer 11

• variable morphologies are common
• state the appearance in the diagnostic line or comment
• ~50% of cases show DLBCL, NOS morphology
  
  • ~4-8% of DLBCL are actually double or triple hit
• ~50% have morphology similar to Burkitt lymphoma but with less basophilic cytoplasm
• blastoid morphology can also been seen
• usually have a diffuse growth pattern with starry sky (tingible body macrophages)
• proliferation rate can be variable and even low (does not exclude this entity)
• cytoplasm is usually more abundant than BL
• nuclei 3-4 x the size of normal lymphocyte

Question 12

What lymphoma that has blastoid morphology must be excluded in these cases?

Answer 12

• Blastoid variant of mantle cell lymphoma

- B acute lymphoblastic lymphoma/leukemia

Question 13

What is the immunophenotype of HGBCL ?

Answer 13

• positive for B cell markers and negative for TdT
• can lack surface immunoglobulin
• CD10 and BCL6 + in 75-90%
  
  • MUM1 in only about 20%

Question 14

What is the postulated normal counterpart of HGBCL ?

Answer 14

• limited investigation but felt to be mature germinal center B cells

Question 15

How should a lymphoma with MYC and CCND1 breakpoints be classified ?

Answer 15

• aggressive Mantle cell lymphoma with acquisition of MYC

Question 16

What other genetic abnormalities are frequently seen in HGBCL ?

Answer 16

• in addition to the rearrangements you see
  
  • TP53 mutations (often in MYC and BCL2 cases)
  • few MYD88 mutations
• hemizygous mutations of ID3 (different from Burkitt lymphoma ID3 mutations)

Question 17

What is the prognosis for patients with HGBCL ?

Answer 17

• complete response rate is relatively low and overall survival is short
  
  • median survival of 4-18 months

Question 18

What is the definition of HGBCL NOS ?

Answer 18

• waste basket diagnosis of cases that are not HGBCL with double/triple hit, BL or classic DLBCL
• morphology and IHC are non-specific in these cases
  IMP
  
  • these cases are rare and the diagnosis should not be made often

Question 19

IMPORTANT TO KNOW THIS

Answer 19

• cases of otherwise typical DLBCL, NOS with a MYC translocation should still be classified as DLBCL, NOS rather than a HGBCL NOS

Question 20

What is the morphology of HGBCL, NOS?

Answer 20

• can be variable but many have Burkitt like morphology
• blastoid lymphomas that lack TdT, MYC rearrangement with BCL2 or BCL6, and are not Mantle cell are also included in this category

Question 21

What is the immunophenotype of HGBCL, NOS?

Answer 21

• usually there is no specific immunophenotype but some general findings:
• all cases are CD20 mature B cell lymphomas
• BCL6 + with variable expression of CD10
• most cases lack IRF4/MUM1
• Ki67 is variable as is MYC expression by IHC (dependent on the rearrangement)

Question 22

What are some genetic findings in HGBCL, NOS?

Answer 22

• approximately 30% have a MYC gene rearrangement with or without copy number increases
• cases with BCL2 rearrangement and MYC copy number gains have also been reported

Question 23

What are prognostic and predictive factors ?

Answer 23

• poor outcome but in general it may be better than double or triple hit lymphomas
• cases with MYC amplification were found to have worse prognosis