MDM2-CDK4

MDM2 inhibits the action of p53 by inhibiting the transfer of p53 from cytoplasm to nucleus, blocking the interaction of p53 with DNA and by ubiquitinisation of p53.: these combined actions inhibit apoptosis. CDK4 inhibits RB1 by causing its phosphorylation: this releases the G1-S checkpoint.

The genes MDM2 and CDK4 are often co-amplified in well differentiated and dedifferentiated liposarcomas but not in benign lipomatous tumours. The amplificons of MDM2 and CDK4 for ring and/or giant chromosomes. Amplification of MDM2 and CDK4 has also been demonstrated in a range of carcinomas, sarcomas and haemopoietic neoplasms.

Immunohistochemical expression, FISH and real-time (quantitative) PCR in lipomatous tumours

Amplification of MDM2 and CDK4 can be equally demonstrated in formalin-fixed and Holland Bouin-fixed tissues2.

FISH and Q-PCR have greater specificities than does IHC for liposarcoma. FISH has the advantage in inflamed lesion, and in lesions with a prominent reactive stromal component, that the tumour cells can be specifically inspected.

		MDM2			CDK4
		FISH	Q-PCR	IHC	FISH	Q-PCR	IHC
Benign lipoma	Conventional lipoma	0/131	0/151, 0/263	1/161	0/131	0/151, 2/263	0/161
	Lipoma with secondary changes	0/71	0/51	2/51	0/71	0/51	0/51
	Intramuscular and deep-seated lipoma	0/81	0/71	0/91	0/81	0/71	0/91
	Spindle cell / pleomorphic lipoma	0/111	0/111, 1/93	0/111	0/111	0/111	0/111
	Angiomyolipoma		0/11, 0/13	0/11	1/11	0/11	0/11
	Fibrolipoma	0/11	0/11	0/11	0/11	0/11	0/11
	Lipoblastoma	0/11	0/11	0/11	0/11	0/11	0/11
	Angiomyofibroblastoma / cellular angiofibroma	0/41	0/41	0/41	0/41	0/41	0/41
	Total	0/451	0/451	3/481	0/451	0/451	0/481
Well differentiated & dedifferentiated liposarcoma	Well differentiated liposarcoma	30/321	24/331, 31/333	26/341	28/321	23/331	28/341
	Dedifferentiated liposarcoma	8/81, 13/134	8/81, 14/153, 13/164	8/81, 39/392, 20/204, 20/205	8/81, 12/124	8/81, 14/164	8/81, 36/392, 17/204, 20/205
	Total	38/401	32/411	73/81	36/401	31/411	72/81
Other liposarcomas	Myxoid liposarcoma			0/92			0/92
Other liposarcomas	Pleomorphic liposarcoma			0/42			0/42
Non-lipomatous sarcomas	Leiomyosarcoma	0/11		0/11, 4/292, 0/355	0/11		1/11, 1/292, 0/355
	Rhabdomyosarcoma	0/11	0/21	2/21	0/21	1/21	2/21
	Alveolar rhabdomyosarcoma			0/52			0/52
	Embryonal rhabdomyosarcoma			4/82			2/82
	Pleomorphic rhabdomyosarcoma			0/12			0/12
	Alveolar soft part sarcoma			0/22			0/22
	Myxofibrosarcoma	1/11		0/11, 9/212	1/11		0/11, 3/212
	Malignant peripheral nerve sheath tumour	0/11	0/11	1/11, 4/62	0/11	0/11	1/11, 0/62
	Clear cell sarcoma of soft tissue			2/52			0/52
	Angiosarcoma			2/82			0/82
	Myxoid chondrosarcoma			0/32			0/32
	DFSP			2/82			0/82
	DSRCT			0/12			0/12
	GIST			0/82			0/82
	MFH			5/322			1/322
	PNET			0/42			0/42
	Synovial sarcoma			2/102			0/102
	Malignant mesenchymoma			0/15			0/15
	Sarcoma NOS	0/141	0/141	7/151	0/141	0/141	6/121
	Total	0/181	0/171	10/201	0/181	1/171	10/171

Diagnostic utility

Diagnosis of Well differentiated and dedifferentiated liposarcoma, and the differentiation of the former from benign adipocytic tumours, cellular angiofibroma, angiomyofibroblastoma, the latter from non-lipomatous sarcomata. In difficutl cases, FISH or Q-PCR is recommended in addition to immunohistochemistry1.

References

1 Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol 2007; 31:1476-89

2 Binh MB, Garau XS, Guillou L, et al. Reproducibility of MDM2 and CDK4 staining in soft tissue tumors. Am J Clin Pathol 2006; 125:693-7

3 Hostein I, Pelmus M, Aurias A, et al. Evaluation of MDM2 and CDK4 amplification by real-time PCR on paraffin wax-embedded material: a potential tool for the diagnosis of atypical lipomatous tumours/well-differentiated liposarcomas. J Pathol 2004; 202:95-102

4 Coindre JM, Hostein I, Maire G, et al. Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile, and MDM2 and CDK4 status favour a single entity. J Pathol 2004; 203:822-30

5 Binh MB, Guillou L, Hostein I, et al. Dedifferentiated liposarcomas with divergent myosarcomatous differentiation developed in the internal trunk: a study of 27 cases and comparison to conventional dedifferentiated liposarcomas and leiomyosarcomas. Am J Surg Pathol 2007; 31:1557-66

This page last revised 15.2.2008.