BCL-6

Synonyms: B-cell lymphoma 6 protein, Bcl6

by Assia Bassarova

Background

The BCL-6 (B-cell lymphoma 6) gene spans 24 kb on chromosome 3q27. In lymphoid tissue the BCL-6 expression is mostly restricted to the germinal center (GC) B cells. BCL-6 prevents premature activation and differentiation of GC B cells and provides an environment tolerant to the DNA breaks associated with immunoglobulin gene remodeling mechanisms involved in the production of high-affinity antibodies of different isotypes.

Staining in normal tissues

  • In lymphoid tissues, BCL-6 protein is expressed in germinal-center B cells in secondary follicles in both the dark (centroblast-rich) and light (centrocyte-rich) zones
  • It is also detectable in CD4-positive T cells, both in the germinal centers, in interfollicular areas, as well as in perifollicular CD30+ lymphoid cells
  • In addition, BCL-6 protein is expressed in thymocytes, mainly in the cortex of thymus
  • Outside the hematopoietic system, the expression of BCL-6 has also been observed in various tissues including both squamous and transitional epithelia

Staining in tumors

  • All cases of follicular lymphoma and in Burkitt lymphoma
  • DLBCL shows positivity in 60-80% of cases (in virtue of BCL-6 involvement in chromosomal translocations affecting band 3q27)
  • T-cell lymphoma cases with CD4+phenotype (including primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma and follicular variant of peripheral T-cell lymphoma) often show usually weaker than B-cell lymphomas nuclear positivity in around 80% of cases
  • Varying, usually low percentage of other lymphomas is reported positive while marginal zone lymphomas and mantle cell lymphomas are negative as a rule
  • Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) shows positive staining in around 50%
  • Some other tumors including squamous cell carcinoma (NOS), urothelial carcinoma and around 20% breast carcinoma also show BCL-6 expression often correlated to prognosis
  • BCL-6 expression in neuroblastoma (60%) is associated with low-risk disease and better clinical outcomes
  • BCL-6 is also positive in around 60% sarcomas with BCOR-CCNB3– fusion

Staining pattern

Strong nuclear staining.

Control tissue

Appendix / tonsil with strong nuclear staining in virtually all germinal center cells of secondary lymphoid follicles. The squamous epithelium of the tonsil as well as the crypt epithelium of the appendix show weak to moderate nuclear reactivity.

Application

  • Sensitive, but not specific marker of follicle center B-cells, along with CD10
  • Useful in discriminating follicular lymphomas (positive for both BCL-6 and CD10) from other low-grade B-cell lymphomas, which may have nodular (follicular) growth pattern, particularly mantle cell lymphoma and marginal zone lymphoma
  • Used in sub-classifying DLBCL into GCB and ABC subtype, which has both prognostic and therapeutic significance
  • Together with BCL-2 used to distinguish neoplastic (BCL-2 positive) from hyperplastic (BCL-2 negative) follicles
  • Can be helpful distinguishing nodular lymphocyte predominant Hodgkin lymphoma (positive in NLPHL 100%) from classical Hodgkin lymphoma (positive only in 15-30%)
  • Double staining of CD3 and BCL-6 identifies phenotype of follicular T helper cells (useful in subtyping T-cell lymphomas)
  • Recommended to use in panel since positive staining is not equivalent of lymphoid origin and may cause a potential interpretation pitfall when used alone

Selected references

  1. Dalla-Favera R, Ye BH, Lo Coco F, et al. BCL-6 and the molecular pathogenesis of B-cell lymphoma. Cold Spring Harb Symp Quant Biol. 1994; 59:117-23. doi: 10.1101/sqb.1994.059.01.015. PMID: 7587061.
  2. Dent AL, Vasanwala FH, Toney LM. Regulation of gene expression by the proto-oncogene BCL-6. Crit Rev Oncol Hematol. 2002 Jan;41(1):1-9. doi: 10.1016/s1040-8428(01)00164-0. PMID: 11796228.
  3. Falini B, Fizzotti M, Pileri S, et al. Bcl-6 protein expression in normal and neoplastic lymphoid tissues. Ann Oncol. 1997;8 Suppl 2:101-4. PMID: 9209651.
  4. Niu H. The proto-oncogene BCL-6 in normal and malignant B cell development. Hematol Oncol. 2002 Dec; 20(4):155-66. doi: 10.1002/hon.689. PMID: 12469325.
  5. Pinilla SMR1, Roncador G, Rodríguez-Peralto JL, et al. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol. 2009 Jan; 33(1):81-90.  doi: 10.1097/PAS.0b013e31818e52fe. PMID: 18987541
  6. Qi H, Liu D, Ma W, Wang Y, Yan H. Bcl-6 controlled TFH polarization and memory: the known unknowns. Curr Opin Immunol. 2014 Jun; 28:34-41. doi: 10.1016/j.coi.2014.01.016. Epub 2014 Feb 28. PMID: 24583637.
  7. Zhan H-Q 1, Xiao-Qiu Li X-Q, Zhu X-Z, et al. Expression of follicular helper T cell markers in nodal peripheral T cell lymphomas: a tissue microarray analysis of 162 cases. J Clin Pathol. 2011 Apr; 64(4):319-24.  doi: 10.1136/jcp.2010.084459. Epub 2011 Feb 17. PMID: 21330314 DOI: 10.1136/jcp.2010.084459