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

This gene was first identified from parathyroid adenomas and designated PRAD1 (parathyroid adenomatosis)16,17. 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. The gene is overexpressed in mantle cell lymphomas due to a chromosomal rearrangement t(11;14)(q13;q32)20. This translocation can be demonstrated with high sensitivity by FISH14,15.

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

Immunohistochemical expression

Lymphoid cells of normal lymph node, spleen and tonsil are negative for cyclin D111.

• 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 B-cell neoplasms has been reported using a rabbit monoclonal antibody, which has a greater sensitivity than does the mouse monoclonal antibody9:

There was less background staining with the rabbit monoclonal antibody.

• parathyroid adenoma

• normal suprabasal 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 among lymphoma subtypes and overexpression may be associated with a poor outcome8.

References

1 Mishina, 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.

2 SCC 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

3 Chan, 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.

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

5 Yatabe, 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.

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

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

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

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

10 Aguilera NS, Uusafr M, Wenig BM, et al. The blastic variant of mantle cell lymphoma arising in Waldeyer's tonsillar ring. J Laryngol Otol 1998; 112:991-4

11 de Boer CJ, Schuuring E, Dreef E, et al. Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma. Blood 1995; 86:2715-23 FULL TEXT

12 de Leon ED, Alkan S, Huang JC, et al. Usefulness of an immunohistochemical panel in paraffin-embedded tissues for the differentiation of B-cell non-Hodgkin's lymphomas of small lymphocytes. Mod Pathol 1998; 11:1046-51

13 Kuroda H, Komatsu H, Nakamura S, et al. The positive nuclear staining observed with monoclonal antibody against PRAD1/cyclin D1 correlates with mRNA expression in mantle cell lymphoma. Jpn J Cancer Res 1995; 86:890-8

14 Li JY, Gaillard F, Moreau A, et al. Detection of translocation t(11;14)(q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization. Am J Pathol 1999; 154:1449-52 FULL TEXT

15 Monteil M, Callanan M, Dascalescu C, et al. Molecular diagnosis of t(11;14) in mantle cell lymphoma using two-colour interphase fluorescence in situ hybridization. Br J Haematol 1996; 93:656-60

16 Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 1991; 350:512-5

17 Rosenberg CL, Wong E, Petty EM, et al. PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc Natl Acad Sci U S A 1991; 88:9638-42

18 Singh N,Wright DH. The value of immunohistochemistry on paraffin wax embedded tissue sections in the differentiation of small lymphocytic and mantle cell lymphomas. J Clin Pathol 1997; 50:16-21 FULL TEXT

19 Vasef MA, Medeiros LJ, Koo C, et al. Cyclin D1 immunohistochemical staining is useful in distinguishing mantle cell lymphoma from other low-grade B-cell neoplasms in bone marrow. Am J Clin Pathol 1997; 108:302-7

20 Williams ME, Swerdlow SH, Rosenberg CL, et al. Chromosome 11 translocation breakpoints at the PRAD1/cyclin D1 gene locus in centrocytic lymphoma. Leukemia 1993; 7:241-5

21 Yang WI, Zukerberg LR, Motokura T, et al. Cyclin D1 (Bcl-1, PRAD1) protein expression in low-grade B-cell lymphomas and reactive hyperplasia. Am J Pathol 1994; 145:86-96

22 Zukerberg LR, Yang WI, Arnold A, et al. Cyclin D1 expression in non-Hodgkin's lymphomas. Detection by immunohistochemistry. Am J Clin Pathol 1995; 103:756-60

This page last revised 28.10.2006.

©SMUHT/PW Bishop