Cyclin D1 (PRAD-1, bcl-1, CCND1)

This gene was first identified from parathyroid adenomas and designated PRAD1 (parathyroid adenomatosis). Cyclin D1 and cyclin D3 have similar roles in the regulation of the G₁ check-point of the cell cycle², acting via phosphorylation of the retinoblastoma gene product⁶ . The gene locus is on 11q⁶.

Specific staining is nuclear. The antibodies against cyclin D1 have fastidious requirements³. A newly available monclonal rabbit antibody is reported to to give consistent immunoreactivity, compared with the previously avalable mouse monoclonal antibody⁹.

Immunohistochemical expression

• mantle cell lymphoma: the few mantle cell lymphomas which are negative by immunohistochemistry for cyclin D1 may be shown by cytogenetics or FISH to have the t(11q13;14q32) translocation, juxtaposing the cyclin D1 gene to the immunoglobulin heavy chain on chromosome 14.

• 25% of myelomas over-express cyclin D1 and show a t(11;14) translocation, but with a different breakpoint in the immunoglobulin heavy chain, or show gene amplification.

• not over-expressed by normal B lymphocytes and other B cell lymphomas, with rare exceptions (<2%)³ of positivity in:

  • B-cell chronic lymphocytic leukaemia: proliferation centres and prolymphocytes are present. Immunophenotype CD5+/CD20+/CD23+. Needs to be distinguished from leukaemic mantel cell lymphoma, which has a very poor prognosis.

  • hairy cell leukaemia: the mechanism of increased expression is not well understood, since there is no cytogenetic abnormality of the 11q13 region.

  • lymphoplasmacytic lymphoma

  • about 15% of splenic marginal zone lymphomas (including cases with villous lymphocytes) and some cases of prolymphocytic leukaemia show t(11;14), but without cyclin D1 overexpression. It is arguable that these cases of prolymphocytic leukaemia are in fact mantle cell lymphoma with prolymphocytic differentiation.

  • rarely in Hodgkin's disease⁵.

  • rarely in anaplastic large cell lymphoma⁵.

Staining in a number of these B-cell neoplasms has been reported using a rabbit monoclonal antibody⁹:

			staining score
			0	1-4	6-8	9-12
	mantle cell lymphoma (including two CD5- cases)	mouse MAb	1/25	15/25	7/25	2/25
		rabbit MAb	0/30	8/30	9/30	13/30
	Myeloma	rabbit MAb	9/12	1/12	1/12	1/12
	Hairy cell leukaemia	rabbit MAb	3/5	2/5	0/5	0/5
	CLL/SLL	rabbit MAb	13/15	1/15 (also posiitve using mouse monoclonal antibody, but less strongly so.)	0/15	1/15 (also posiitve using mouse monoclonal antibody, but less strongly so.)
	DLBCL	rabbit MAb	25/25
	Follicular lymphoma	rabbit MAb	10/10
	Extranodal MALT lymphoma	rabbit MAb	14/14
	Nodal marginal zone lymphoma	rabbit MAb	1/1
	Lymphoplasmacytic lymphoma	rabbit MAb	1/1
	Lymphoblastic lymphoma	rabbit MAb	2/2
	Extranodal NK/T-cell lymphoma	rabbit MAb	13/13
	Peripheral T-cell lymphoma NOS	rabbit MAb	6/6
	Anaplastic large cell lymphoma	rabbit MAb	1/1
	Angioimmunoblastic T-cell lymphoma	rabbit MAb	1/1
	PTLD	rabbit MAb	1/1
	Hodgkin lymphoma	rabbit MAb	4/4
	Reactive lymphoid hyperplasia	rabbit MAb	9/9
	staining score = score for percentage positive cells (<25% = 1, 26-50% = 2, 51-75% = 3, >75% = 4) x intensity score (negative = 0, weak = 1, moderate = 2, strong = 3)

There was less background staining with the rabbit monoclonal antibody.

• parathyroid adenoma

• normal supraqbasal squamous epithelial cells, histiocytes and endothelial cells⁹

• carcinoma:

  • breast: expression is high in grade I tumours and reduced in grade III tumours, elevated cyclin D1 correlating positively with oestrogen receptor positivity².

  • supradiaphragmatic squamous cell carcinoma

  • lung;

    • non small cell carcinoma; 12% (13/111) cases stained¹

    • bronchioloalveolar carcinoma; 6/19 cases stained⁴

  • stomach: expression is increased in adenomas, dysplasia and carcinomas. Expression >5% is associated with poor differentiation and signet ring cell phenotype⁶.

  • ovary

  • transitional cell carcinoma

Diagnostic utility

• differentiation of mantle cell lymphoma from other B-cell lymphomas

Cyclin D3

There is recent evidence that cyclin D3 may be expressed differentially amoung lymphoma subtypes and overexpression may be associated with a poor outcome⁸.

References

¹Mishina, T. Dosaka-Akita, H. Kinoshita, I. Cyclin D1 expression in non-small-cell lung cancers: its association with altered p53 expression, cell proliferation and clinical outcome. Br J Cancer 1999;80:1289-95.

²SCC Wong et al. Differential expression of p16/p21/p27 and cyclin D1/D3, and their relationship to cell proliferation, apoptosis and tumour progression invasive ductal carcinoma of the breast. J Pathol 2001;194:35-42

³Chan, J. K., Miller, K. D., Munson, P., Isaacson, P. G. Immunostaining for cyclin D1 and the diagnosis of mantle cell lymphoma: is there a reliable method? Histopathology 1999;34:266-268.

⁴McDonald, J. W., Pilgram, T. K. Nuclear expression of p53, p21 and cyclin D1 is increased in bronchioloalveolar carcinoma Histopathology 1999;34:439-446.

⁵Yatabe, Y., Suzuki, R., Matsuno, Y. et al. Morphological spectrum of cyclin D1-positive mantle cell lymphoma: study of 168 cases. Pathol Int 2001;51:747-61.

⁶Walton S-J, Freakins RM. Expression of retinoblastoma, p16 and cyclin D1 genes in gastric adenocarcinomas and precarcinomatous lesions. Pathological Society July 2002, abstract 131.

⁷Matutes E. New additions to antibody panels in the characterisation of chronic lymphoproliferative disorders. J Clin Pathol 2002;55:180-183.

⁸Leoncini, L., Lazzi, S., Bellan, C. and Tosi, P. Cell kinetics and cell cycle regulation in lymphomas. J Clin Pathol 2002;55:648-55.

⁹Cheuk, W., K. O. Wong, et al. (2004). "Consistent immunostaining for cyclin D1 can be achieved on a routine basis using a newly available rabbit monoclonal antibody." Am J Surg Pathol 28(6): 801-7.

Christie tumour pathology, 7.6.2002.

©SMUHT/PW Bishop