Lymphoma and plasma cell neoplasms
Mature B cell neoplasms
High grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements


Topic Completed: 11 February 2019

Revised: 18 February 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: High grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements [title]


Genevieve M. Crane, M.D., Ph.D.
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Cite this page: Tashakori M, Crane G. High grade B cell lymphoma with MYC and BCL2 or BCL6 rearrangements. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomabunclassburkitt.html. Accessed July 21st, 2019.
Definition / general
  • Aggressive mature B cell lymphoma
  • Category of high grade B cell lymphoma newly defined in the revised 2016 WHO (Blood 2016;127:2375, Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 2017)
  • All B cell lymphomas harboring a MYC rearrangement (chromosome 8q24.2) and a rearrangement in BCL2 (18q21.3) or in BCL6 (3q27.3) with some exceptions
    • Exceptions: Grade 3B follicular lymphomas with retained follicular architecture and B lymphoblastic leukemia / lymphoma with MYC and BCL2 translocations (may also arise out of follicular lymphoma) (Hum Pathol 2015;46:260)
  • Large B cell lymphoma with double hit arising out of a follicular lymphoma should still be designated as high grade B cell lymphoma
Essential features
  • Aggressive, mature B cell lymphoma
  • Presence of MYC rearrangement at chromosome 8q24.2 and a rearrangement in BCL2 (at chromosome 18q21.3) or in BCL6 (at chromosome 3q27.3)
  • Should be distinguished from diffuse large B cell lymphoma (DLBCL), NOS and Burkitt lymphoma for both biological and clinical reasons (Curr Opin Hematol 2012;19:299)
Terminology

Note:
  • Lymphomas with pre-existing or co-existing indolent lymphoma should be diagnosed as such (example: high grade B cell lymphoma with MYC and BCL2 rearrangements, transformed from follicular lymphoma)
  • Incorporates some cases of old terminology "B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma" (2008 WHO classification, no longer used)
  • Often called double hit lymphoma if two rearrangements are present (MYC and BCL2 or MYC and BCL6) or triple hit lymphoma if all three rearrangements are present (MYC, BCL2 and BCL6) (Hematology Am Soc Hematol Educ Program 2014;2014:9)
  • MYC translocation is required
  • Most double hit lymphomas with MYC and BCL2 translocations are double expressers (> 40% of cells Myc+; > 50% of cells BCL2+ by IHC) but these are not synonymous and this protein expression is not required
  • Most double expresser DLBCL, NOS are not double hit lymphomas and this cannot be used as a surrogate for cytogenetic testing
ICD coding
  • ICD-0: 9680/3 - B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma
Epidemiology
  • Mostly elderly patients
  • Median age sixth or seventh decade
  • Slight male predominance
Sites
  • Mainly lymph node
  • Frequently involve more than 1 extranodal site (bone marrow, CNS)
  • > 50% of patients present with widespread disease
Etiology
  • MYC, BCL2 double hit thought to arise from mature germinal center B cells; MYC, BCL6 more variable cell of origin
  • MYC translocation appears to be a secondary event, although this has been best established in cases arising out of follicular lymphoma (Blood Rev 2017;31:37)
  • Many additional cytogenetic abnormalities generally found
Diagrams / tables

Images hosted on other servers:

Diagnostic approach

Clinical features
  • More than half present with advanced disease (stage IV according to the Lugano Staging system, updated from the former Ann Arbor classification) (J Clin Oncol 2014;32:3059)
  • More than one extranodal localization, bone marrow and CNS may be involved (Curr Opin Hematol 2012;19:299, Blood 2014;124:2354)
  • High international prognostic index (IPI)
  • Elevated lactate dehydrogenase (LDH)
Diagnosis
  • Rearrangements of MYC, BCL2 and BCL6 should be detected by classic cytogenetics, FISH or other molecular / genetic tests (Blood 2016;127:2375)

Note:
  • Increased copy number, amplification or mutations are insufficient to qualify for this category in the absence of mentioned rearrangements; however, a complex karyotype is frequently seen
Prognostic factors
  • Relatively low response rate with R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone, plus the monoclonal antibody rituximab) with short overall survival (4.5 - 18.5 months), prompting investigation of alternative therapeutic approaches (J Clin Oncol 2010;28:3360, Blood 2015;126:2466)
  • MYC partner: MYC / IG translocation may have a worse outcome compared to non-IG partner in some studies although this remains an area of investigation (Blood 2015;126:2466, Haematologica 2014;99:726)
  • Tumor morphology (may warrant further study, per WHO): majority of double hit lymphomas have DLBCL morphology and can be indistinguishable morphologically
  • Extent of the disease
  • International prognostic index (IPI) score (N Engl J Med 1993;329:987)
  • CD30 expression in > 20% of tumor cells has been associated with a better prognosis in DLBCL; however, this study found that 0/46 cases with MYC aberrations (rearrangement or amplification) were positive for CD30 at this level, excluding double / triple hit lymphomas from group (Blood 2013;121:2715)
Case reports
Treatment
  • R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone, plus the monoclonal antibody rituximab)
  • Complete response is relatively low (Hematology Am Soc Hematol Educ Program 2014;2014:107)
  • Overall survival is short (median survival of 4.5 - 18.5 months with R-CHOP)
Microscopic (histologic) description
  • Variable morphology
  • Subset (~50%) with morphology of DLBCL, NOS (Histopathology 2016;68:1090)
    • Diffuse growth pattern
    • Relatively few small lymphocytes
    • Some fibrosis
    • Starry sky macrophages may be present
    • Variable degree of mitosis and apoptosis
    • Nuclei with variable size and contour, some 3 - 4 times the size of normal lymphocytes (larger than Burkitt lymphoma cells)
    • Cytoplasm more abundant and less basophilic than in Burkitt lymphoma
  • Subset (~50%) with morphology of Burkitt lymphoma or has features intermediate between DLBCL and Burkitt lymphoma (Blood 2011;117:2319):
    • Diffuse proliferation
    • Medium to large nuclei
    • Very few admixed small lymphocytes
    • No stromal reaction or fibrosis
    • Starry sky macrophages generally present
    • High mitotic rate and apoptosis
    • Some relatively monomorphic (similar to Burkitt lymphoma) and more variation in nuclear and nucleolar features
    • Cytoplasm less basophilic than in Burkitt lymphoma
  • Other cases may have blastoid cytomorphology (Histopathology 2012;61:945)
    • Tumor cells are mature B cells positive for CD10 and BCL6 and negative for TdT
    • Medium sized cells resembling small centroblasts
    • Nuclei with finely granular chromatin and inconspicuous nucleoli
    • Small rim of cytoplasm
Microscopic (histologic) images

Contributed by Genevieve M. Crane, M.D., Ph.D.
   

H&E, 40X of
high grade B cell lymphoma
with MYC and BCL2
translocations

BCL2

Myc



Images hosted on other servers:

H&E

Positive stains

Note:
Negative stains
Flow cytometry description
  • Some cases lack sIg (multiple IG loci involved by translocations)
Flow cytometry images

Lack of sIg

Molecular / cytogenetics description
  • MYC (8q24.2) rearrangement:
    • IG partners (usually IGH, less frequently IGK or IGL): 65%
    • Non-IG partners
  • BCL2 (18q21.3) rearrangement
  • BCL6 (3q27.3) rearrangement

Note:
  • In current classification, a combination of a chromosomal rearrangement of one gene and copy number increase or amplification of other genes is not sufficient to classify a case as a double hit high grade B cell lymphoma
Molecular / cytogenetics images

Images hosted on other servers:

Karyotype

Differential diagnosis
Board review question #1
Which of the following is confirmation of double hit lymphoma?

  1. High MYC and Ki67 expression on IHC
  2. MYC and BCL2 expression on IHC, each 40% expression
  3. MYC and BCL6 gene rearrangement on FISH
  4. MYC and CCND1 expression on IHC
  5. MYC and CCND1 gene rearrangement on FISH
Board review answer #1
C.
Board review question #2
Evaluation of CD30 expression in double hit lymphoma is recommended because it

  1. Can be suggestive of further FISH studies
  2. Can be used for targeted therapy
  3. Defies a new subclass of double hit lymphoma
  4. Is mainly associated with BCL6 gene rearrangement rather than BCL2 gene rearrangement
  5. Is a prognostic factor
Board review answer #2
B.
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