Proteins of the Bcl-2 family are regulators of apoptosis (programmed cell death) localized to membranes of primarily mitochondria, but also to smooth endoplasmic reticulum and nucleolemma. The fine balance between pro- and anti-apoptotic Bcl-2 family members regulates the cell fate in response to many signalling pathways. Altered expression of the proteins may lead to either premature cell death or to inappropriate cell survival promoting neoplastic growth. Bcl-2, Bax and Bcl-X are the most well known proteins in this family. Bcl-2 ("B-cell lymphoma/leukaemia-2"), which acts as an inhibitor of apoptosis, was originally discovered as a proto-oncogene in low-grade B-cell lymphomas.
In the adult organism Bcl-2 expression is generally confined to cells that are rapidly dividing and differentiating. In lymphocytes, Bcl-2 is highly expressed in T-cells, pro-B cells and mature B-cells (where lifespan is extended) while downregulated in germinal centre B-cells (where apoptosis forms part of the developmental pathway in order to select only cells producing antibodies with high avidity).
In neoplastic lesions Bcl-2 upregulation may act by suppression of programmed cell death and extension of the tumour cell life span. Bcl-2 overexpression contributes to increased resistance to chemotherapy. However, the prognostic value of Bcl-2 overexpression is dependent on the tumour type, and in some types BCl-2 may even have a tumour suppressor effect.
Overexpression of Bcl-2 is common in many types of cancer, including non-Hodgkin's lymphoma and leukaemias, adenocarcinomas (e.g., prostate, colorectum, stomach, and lung), squamous cell carcinoma, small cell carcinoma, neuroblastoma and various sarcomas. Among the latter, strong Bcl-2 positivity has particularly been demonstrated in gastrointestinal stromal tumor, solitary fibrous tumor, and synovial sarcoma, while fibromatosis and "malignant fibrous histiocytoma" are usually negative.
Among malignant lymphomas, Bcl-2 protein overexpression is often caused by chromosomal translocation (14;18) with Bcl-2 gene rearrangement. This is especially seen in follicular lymphoma. bcl-2 is expressed in almost 100% of the grade I lymphomas, in >80% of the grade II and in 75% of the grade III lymphomas. Follicular lymphoma of the skin is often bcl-2 negative.
Bcl-2 is helpful in distinguishing follicular lymphoma from reactive follicular hyperplasia. Bcl-2 staining can not be used for differential diagnosis between follicular lymphoma and other types of low-grade B-cell lymphomas since most of the latter also express bcl-2.
Monocytoid B-cell hyperplasia contrasts with bcl-2 negativity against positive reaction in 80% of the marginal zone lymphomas.
Possibly, Bcl-2 may aid in the differential diagnosis of sarcomas (see above).
Tonsil is an appropriate control: An at least weak but distinct cytoplasmic reaction must be seen in the majority of the basal squamous epithelial cells, while the germinal centre B-cells should be negative.
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