BCL-2

by Jan Klos

Background

Protein is coded on chromosome 18 and localized on outer membranes in mitochondria, nuclei and smooth endoplasmic reticulum- The main function is preventing apoptosis by inhibiting pro-apoptotic proteins. Bcl-2 regulates also mitochondrial dynamics being involved in the regulation of mitochondrial fusion and fission. It is also involved in controlling metabolic activity and insulin secretion in pancreatic beta-cells.

Staining in normal tissues

Protein is expressed by a variety of cell types both in normal conditions and neoplasia. In lymphoid tissue, Bcl-2 is normally expressed in T-cells, pre-B cells and mature B-cells. It is downregulated in germinal center B-cells where activated apoptosis eliminates the cells which are not capable to produce antibodies with high avidity.

Staining in tumors

  • In cases of follicular lymphoma the neoplastic germinal centers are positive (percentage of positivity is related to the grade of follicular lymphoma)
  • In neoplastic lesions the upregulation of Bcl-2 may act by suppression of programmed cell death and extension of the tumor cell life span
  • Bcl-2 overexpression contributes to increased resistance to chemotherapy
  • The prognostic value of Bcl-2 overexpression is depending on the tumor type
  • Altered expression of the proteins may lead to either premature cell death or contribute to increased cell survival promoting neoplastic growth

Staining pattern

Staining pattern is cytoplasmic only sometimes with some granularity.

Control tissue

Lymphoid tissue of tonsil or appendix.

Application

  • Highly sensitive marker differentiating follicular lymphoma (usually strongly positive reaction in follicles) from follicular hyperplasia (negative follicles)
  • Positive staining of follicular lymphoma varies according to the differentiation grade (positive in grade 1 > 95%, grade 2 in ~80% and grade 3 in ~75%)
  • Primary cutaneous and pediatric variants of follicular lymphoma are negative.
  • Negative staining in otherwise typical follicular lymphomas with translocation (t14;18) may sometimes depend also on applied antibody clone (Masir N et al) since some somatic mutations of the translocated BCL2 gene may prevent epitope recognition by BCL2 antibodies, and hence cause false negative expression using the standard antibody.
  • Useful marker for distinguishing reactive monocytoid B-cell hyperplasia (negative) from marginal zone lymphoma (positive)
  • Negative staining in classic Burkitt lymphoma is a standard but staining may be positive in ~ 15% of B-cell lymphoma with intermediate features between DLBCL and Burkitt lymphoma
  • May be useful in differentiating between malignant mesothelioma (negative in >90% of non-sarcomatous and ~80% of sarcomatous subtypes) and solitary fibrous tumor or synovial sarcoma (both are positive in ~90%)

Selected references

  1. Adam P, Baumann R, Schmidt J et al. The BCL2 E17 and SP66 antibodies discriminate 2 immunophenotypically and genetically distinct subgroups of conventionally BCL2-“negative” grade 1/2 follicular lymphomas. Hum Pathol. 2013 Sep;44(9):1817-26. doi: 10.1016/j.humpath.2013.02.004. Epub 2013 May 2. PMID: 23642737
  2. Cory S, Huang DC, Adams JM. TheBcl-2 family: roles in cell survivaland oncogenesis. Oncogene. 2003 Nov 24;22(53):8590-607. Review. PMID: 14634621
  3. https://en.wikipedia.org/wiki/Bcl-2
  4. https://www.nordiqc.org/
  5. Lai R, Arber DA, Chang KL et al. Frequency of bcl-2 expression in non-Hodgkin’s lymphoma: a study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-cell hyperplasia. Modern Pathology 1998; 11:864-869.
  6. Masir N1, Campbell LJ, Jones M et al. Pseudonegative BCL2 protein expression in a t(14;18) translocation positive lymphoma cell line: a need for an alternative BCL2 antibody. Pathology. 2010 Apr;42(3):212-6. doi: 10.3109/00313021003631296.
  7. Pernick N. BCL2. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsbcl2.html. Accessed May 12th, 2020.