bcl-6

The bcl-6 gene is located at 3q27⁵. Bcl-6 is a 79-kDa POZ/zinc finger transcriptional repressor³. It plays a role in the activation and proliferation of B cells within the germinal centre⁴. It is therefore a marker for germinal centre cells and their derivative lymphomas, particularly if there is no gene rearrangement to account for the activation¹. BCL-6 represses many lymphocyte activation genes, including blimp-1. Since blimp-1 plays a role in plasma cell differentiation, bcl-6 may play a role in malignant transformation by the inhibition of differentiation⁷. Over-expression of bcl-6 results in delayed progression through the S phase of the cell cycle or apoptosis. Bcl-6 activation occurs by translocations involving immunoglobulin light or heavy chain genes, which occurs in one third of diffuse large B cell lymphoma, or by mutation in the 5 non-coding region.

Immunoreactivity is nuclear.

Immunohistochemical expression

normal follicle centre cells

• follicles and interfollicular areas of follicular lymphomas

• mediastinal large B-cell lymphoma¹

  20%-40% diffuse large B cell lymphomas: it is unclear how over-expression of bcl-6 leads to transformation⁴.

• acquisition of bcl-6 positivity may be associated with transformation of splenic marginal zone lymphoma to large B-cell lymphoma

• rarely in other B cell lymphomas; aberrant expression may occur in mantle cell lymphoma⁵.

• approximately 45% of CD30+ anaplastic large cell lymphomas

• only rarely in other T-cell lymphomas

• L&H cells of nodular lymphocyte predominance Hodgkin's disease².

		bcl-6	CD10
	Follicular hyperplasia	19/19 (reactivity both in the centres of secondary follicles and also in isolated cells in the mantle and large cells of the interfollicular zones9. In two cases of progressive transformation of germinal centres, this was highlighted by both bcl-6 and CD10)6	19/19 (reactivity strictly limited to the centres of secondary follicles of both nodal and extra-nodal lymphoid tissue)6
	Nodal follicular lymphoma	28/28 (in all positive cases follicular cells stained. There was also interfollicular staining, with the exception of two cases where staining was restricted to follicle centre cells. The three cases negative for CD10 were positive for bcl-6)6	36/39 (in all positive cases, both the follicle centre cells stained. 34 of these 36 cases also showed interfollicular staining)6
	Splenic follicular lymphoma	6/7 (the cases positive for bcl-6 included four CD10-negative cases. One cases was negative for both bcl-6 and CD10. Seven cases showed positive cells within the red pulp.)6	4/11 (the positive cases showed staining both of follicles and of small lymphocytes within the red pulp.)6
	MALT lymphoma	0/17 (reactive follicles were positive. Cases with follicular colonization showed bcl-6 negative cells within the germinal centres)6	0/24 (reactive follicles were positive. Cases with follicular colonization showed CD10 negative cells within the germinal centres)6
	Mantle cell lymphoma	0/18 (reactive follicles were positive.)6	0/19 (reactive follicles were positive.)6
	Splenic marginal zone lymphoma	0/10 (reactive follicles were positive.)6	0/13 (reactive follicles were positive.)6
	Diffuse large B cell lymphoma	39/476	21/546
		10 cases had evidence of previous follicular lymphoma: all but one were positive for both bcl-6 and CD106. Of 44 DLBCL, NOS6:   CD10+ CD10- bcl-6+ 11 1 bcl-6- 21 11
	Burkitt lymphoma	17/176	20/206
	CD30+ ALCL	12/27 (using frozen sections, 8/19 T-cell and 4/8 null cell)9
	peripheral T-cell lymphoma	0/24 (using frozen sections, 1 T-CLL, 7 mycosis fungoides, 11 peripheral T-cell lymphoma NOS, 4 AILD-like, 1 angiocentric)9
	T-lymphoblastic leukaemia	0/8 (using frozen sections)9
	NLPHD	11/13 (positivity in both L&H cells and smaller cells.)6	0/166
	Classical HD	4/8 (positivity in a small number of RS cells.)6	0/136

Diagnostic utility

As a marker for follicle centre B-cells, along with CD10. Follicular lymphomas are positive for both bcl-6 and CD10, while other low grade lymphomas which may have a follicular growth pattern, particularly mantle cell lymphoma and marginal zone lymphoma (in which follicles may be colonised), are negative.

References

¹ de Leval, L., Ferry, J. A., Falini, B., Shipp, M., Harris, N. L. Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells? Am J Surg Path 2001;25:1277-1282.

² Falini. Blood 1996;87:465-471.

³ Petitjean, B., Jardin, F., Joly, B., Martin-Garcia, N., Tilly, H., Picquenot, J.M., Briere, J., Danel, C., Mehaut, S., Abd-Al-Samad, I., Copie-Bergman, C., Delfau-Larue, M.H. and Gaulard, P. Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype. Am J Surg Pathol 2002;26:724-32.

⁴ Leoncini, L., Lazzi, S., Bellan, C. and Tosi, P. Cell kinetics and cell cycle regulation in lymphomas. J Clin Pathol 2002;55:648-55.

⁵ Camacho, F. I., J. F. Garcia, et al. (2004). "Aberrant Bcl6 protein expression in mantle cell lymphoma." Am J Surg Pathol 28(8): 1051-6.

⁶ Dogan A, Bagdi E, Munson P, et al. CD10 and BCL-6 expression in paraffin sections of normal lymphoid tissue and B-cell lymphomas. Am J Surg Pathol 2000; 24:846-52

⁷ Shaffer AL, Yu X, He Y, et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 2000; 13:199-212

⁸ Kraus MD,Haley J. Lymphocyte predominance Hodgkin's disease: the use of bcl-6 and CD57 in diagnosis and differential diagnosis. Am J Surg Pathol 2000; 24:1068-78

⁹ Carbone A, Gloghini A, Gaidano G, et al. BCL-6 protein expression in human peripheral T-cell neoplasms is restricted to CD30+ anaplastic large-cell lymphomas. Blood 1997; 90:2445-50 FULL TEXT

This page last revised 13.7.2005.

©SMUHT/PW Bishop