bcl-2, B-cell leukemia/lymphoma 2 gene

The gene for bcl-2 is located on chromosome 18. The gene product is an inner mitochondrial membrane protein which inhibits apoptosis, so extending cell survivial. The bcl-2 gene is transcribed into three mRNA variants, which translate to give two proteins: bcl-2 alpha consists of 239 amino acids while bcl-2 beta of 205 amino acid is identical except for the C-terminal17. Most t(14;18) translocation breakpoints cluster within a narrow region of a 5.4 kb exon that contains an untranslated region of the bcl-2 mRNA. The t(14;18) translocation results in a hybrid bcl-2/immunoglobulin heavy chain transcript consisting of the 5' half of the bcl-2 mRNA fused to a "decapitated" immunoglobulin heavy chain mRNA. Nucleotide sequence analyses confirmed that the hybrid transcripts continue to encode a normal bcl-2 protein18.

Immunohistochemical expression

Soft tissue tumours:

 

bcl-2 positivity

solitary fibrous tumours

95%

synovial sarcoma

93% (141/151)

leiomyoma

6/242,5

epithelioid leiomyoma

4/42

leiomyosarcoma

20% (17/86)5

rhabdomyosarcoma

7/72

neurofibroma

12/155

schwannoma

31/325

malignant peripheral nerve sheath tumours

16/465

haemangiopericytoma

19/245

spindle cell lipoma

16/185

fibromatosis

0/235

dermatofibroma

0/105

dermatofibrosarcoma protuberans

22/385

DFSP with fibrosarcomatous transformation

9/105

malignant fibrous histiocytoma

32/995

low grade myxofibrosarcoma

7/105

Kaposi's sarcoma

56/615

fibrosarcoma

9/435

fibroadenoma and phyllodes tumour of the breast

some stromal cells positive6

pseudoangiomatous hyperplasia of the breast

strongly positive (5/5)6

invasive carcinoma of breast

68% (97/142)8

nasopharyngeal carcinoma

89% (50/56)9

squamous cell carcinoma of lung

17/2513

adenocarcinoma of lung

15/4613

adenosquamous carcinoma of lung

1/313

large cell carcinoma of lung

6/1113

gastric carcinoma

36/8011

cholangiocarcinoma

0/2810

 

Diagnostic utility

 

bcl-2

follicular hyperplasia

 0/4015

follicular lymphoma

36/3715

 

n

MIB1

bcl-2

p16

cervical glandular intraepithelial neoplasia

21

86% of cases stained >10% of cells

negative or focal

all strong diffuse positivity

tubo-endometrial metaplasia

13

negative to <10% of cells

12/13 diffusely positive

62% focally positive

microglandular hyperplasia

14

negative to <10% of cells

negative (note reserve cells positive)

all negative

References

1 Hirakawa N, Naka T, Yamamoto I, Fukada T, Tsuneyoshi M. Overexpression of bcl-2 protein in synovial sarcomas.   Human Pathology 1996; 27: 1060-1065

2 Soini Y, Paakko P bcl-2 is preferentially expressed in tumours of muscle origin but is not related to p53 expression.   Histopathology 1996; 28:141-145.

3 Poniecka, A. W., Alexis, J. B. An immunohistochemical study of basal cell carcinoma and trichoepithelioma. Am J Dermatopathol 1999; 21:332-6

4 Battifora H. Immunohistochemistry in tumour prognosis. In Immunohistochemistry Long Course, Nice, October 18-23, 1998.

5 Ordonez NG. Localized (solitary) fibrous tumor of the pleura. Adv Anat Pathol 2000;7:327-340.

6 T Moore and AHS Lee. Expression of CD34 and bcl-2 in phyllodes tumours, fibroadenomas and spindle cell lesion of the breast. Histopathology 2001; 38-62-67.

7 Verghese et al. Mitotic rate, ER and bcl-2 expression in short term Tamoxifen treated breast cancer. J Pathol 2001:193(suppl):31A.

8 Nakopoulou, L., Michalopoulou, A., Giannopoulou, I., Tzonou, A., Keramopoulos, A., Lazaris, A. C., Davaris, P. bcl-2 protein expression is associated with a prognostically favourable phenotype in breast cancer irrespective of p53 immunostaining. Histopathology 1999;34:310-319.

9 Murono, S., Yoshizaki, T., Park, C. S., Furukawa, M. Association of Epstein-Barr virus infection with p53 protein accumulation but not bcl-2 protein in nasopharyngeal carcinoma. Histopathology 1999;34:432-8.

10 Arora, D. S., Ramsdale, J., Lodge, J. P., Wyatt, J. I. p53 but not bcl-2 is expressed by most cholangiocarcinomas: a study of 28 casesHistopathology 1999;34:497-501.

11 Kume, T., Oshima, K., Shinohara, T., Takeo, H., Yamashita, Y., Shirakusa, T., Kikuchi, M. Low rate of apoptosis and overexpression of bcl-2 in Epstein-Barr virus- associated gastric carcinoma Histopathology 1999;34:502-509.

12 Leal, C., Henrique, R., Monteiro, P., Lopes, C., Bento, M. J., De Sousa, C. P., Lopes, P., Olson, S., Silva, M. D., Page, D. L. Apocrine ductal carcinoma in situ of the breast: histologic classification and expression of biologic markers. Human Pathol 2001;32:487-493.

13 Han, H., Landreneau, R. J., Santucci, T. S., Tung, M. Y., Macherey, R. S., Shackney, S. E., Sturgis, C. D., Raab., S. S., Silverman, J. F. Prognostic value of immunohistochemical expressions of p53, HER-2/neu, and bcl-2 in stage I non-small-cell lung cancer. Human Pathol 2002;3:105-110.

14 Cameron RI, Maxwell R, Jenkins D, McCluggage WG. Immunohistochemical staining with MIB1, bcl-2 and p16 assists in the distinction of cervical glandular neoplasia from benign mimics. Pathological Society, July 2002, abstract no 67.

15 Cooper K, Hafajee Z. bcl-2 immunohistochemistry distinguishes follicular lymphoma from follicular hyperplasia in formalin-fixed tissue with microwave antigen retrieval. J Cellular Pathol 1996;1:52-56.

16 Meda, B. A., M. Frost, et al. (2003). "BCL-2 is consistently expressed in hyperplastic marginal zones of the spleen, abdominal lymph nodes, and ileal lymphoid tissue." Am J Surg Pathol 27(7): 888-94.

17 Tsujimoto Y,Croce CM Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci U S A 1986; 83:5214-8

18 Cleary ML, Smith SD,Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 1986; 47:19-28

19 Pezzella F, Tse AG, Cordell JL, et al. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol 1990; 137:225-32

 

©SMUHT/PW Bishop