p16 in mesothelioma and reactive mesothelium
Many mesotheliomas show deletion of the
P16/CDKN2A gene. Deletion of 9p21 and p16 are associated with inferior
survival3,4,5. In
situ hybridisation (ISH) to demonstrate p16 deletions has been proposed
as useful in differentiating between malignant mesothelioma and reactive
mesothelial proliferations. Demonstration of gene deletion is thought
to be more sensitive and specific than is the loss of protein expression
as assessed by immunohistochemistry.
Immunohistochemical expression
| |
|
In situ hybridisation |
Immunohistochemistry |
|
| Homozygous deletion |
Hemizygous deletion |
Amplification |
Normal |
loss of p16 expression |
Benign
mesothelial proliferations |
0/70(loss
of p16 gene signal in at least 20% of nuclei that showed at least
one CEP 9 signal)6, 0/12(4
adenomatoid tumours, in uterus, 3 benign multicystic mesotheliomas
of peritoneum, 5 mesothelial hyperplasias. loss of both
p16 gene signals in at least 20% of nuclei that showed at least
one CEP 9 signal) 8,
0/18(cytological
preparations from effusions. At least 12 nuclei totally
lacking p16 signal) 10,
0/40(loss
of both p16 gene signals in at least 20% of nuclei that showed
at least one CEP 9 signal) 11
|
|
|
11/111, 15/15(cytological preparations
from effusions)10 |
6/4011 |
Pleural
|
Malignant mesothelioma |
Epithelioid |
19/42(>10%
of cells show loss of both p16/CDKN2a signals with at least one
chromosome 9 centromeric signal) 1,
11/16(
at least 15 nuclei lacking both signals for p16 and containing
at least one signal for chromosome 9 centromere)7,
24/28(loss of both p16 gene signals in at least
20% of nuclei that showed at least one CEP 9 signal) 8, 49/71(loss of both p16 gene
signals in at least 20% of nuclei that showed at least one CEP
9 signal) 12
|
5/42(>44%
of cells show one p16/CDKN2a signal and one chromosome 9 centromeric
signal or >15% of
cells show one16/CDKN2a signal and two chromosome 9 centromeric
signals)
1 |
2/42(>=10%
of cells show p16/CDKN2a chromosome 9 centromeric signal ratio
>= 2)
1 |
16/421 |
12/167, 23/28(using
clone 6H12)8,
19/28(using
clone G175)8
|
|
Sarcomatoid |
5/5(
at least 15 nuclei lacking both signals for p16 and containing
at least one signal for chromosome 9 centromere) 7, 2/3(loss
of both p16 gene signals in at least 20% of nuclei that showed
at least one CEP 9 signal) 8,
5/5(loss of both p16 gene
signals in at least 20% of nuclei that showed at least one CEP
9 signal) 12
|
|
|
1/11 |
5/57, 3/3(using
clone 6H12)8,
3/3(using
clone G175)8
|
|
Desmoplastic |
2/2(loss
of both p16 gene signals in at least 20% of nuclei that showed
at least one CEP 9 signal) 8
|
|
|
|
2/2(using
clone 6H12)8,
2/2(using
clone G175)8
|
|
Biphasic |
4/11(>10%
of cells show loss of both p16/CDKN2a signals with at least one
chromosome 9 centromeric signal) 1,
4/8(
at least 15 nuclei lacking both signals for p16 and containing
at least one signal for chromosome 9 centromere)7,
6/7(loss of both p16 gene signals in at least
20% of nuclei that showed at least one CEP 9 signal) 8, 16/19(loss
of both p16 gene signals in at least 20% of nuclei that showed
at least one CEP 9 signal) 12
|
5/11(>44%
of cells show one p16/CDKN2a signal and one chromosome 9 centromeric
signal or >15% of
cells show one16/CDKN2a signal and two chromosome 9 centromeric
signals)
1 |
|
2/111 |
6/87, 7/7(using
clone 6H12)8,
5/7(using
clone G175)8
|
|
Lymphohistiocytoid |
1/1(
at least 15 nuclei lacking both signals for p16 and containing
at least one signal for chromosome 9 centromere)7
|
|
|
|
1/17 |
|
Unspecified |
21/35(loss
of both p16 gene signals in at least 20% of nuclei) 3, 19/27(loss
of p16 gene signal in at least 20% of nuclei that showed at least
one CEP 9 signal)6,
12/25(cytological
preparations from effusions. At least 12 nuclei totally
lacking p16 signal) 10,
35/52(loss
of both p16 gene signals in at least 20% of nuclei that showed
at least one CEP 9 signal) 11
|
|
|
|
20/35(p16
expression by IHC was lost in 4 of the 14 cases without a homozygous
deletion and in 16 of the 21 cases with a homozygous deletion)3, 20/5211
|
| Peritoneum |
Malignant mesothelioma |
Epithelioid |
8/25(deletions
were present in 83.5% to 100% of cells analysed)2
|
|
|
|
13/25(All 8 cases with homozygous deletion showed
loss of p16 by IHC)2
|
| Sarcomatoid |
1/12 |
|
|
|
1/12 |
| Unspecified |
21/41(loss
of p16 gene signal in at least 20% of nuclei that showed at least
one CEP 9 signal)6,
5/20(loss
of both p16 gene signals in at least 20% of nuclei that showed
at least one CEP 9 signal) 11
|
|
|
|
14/2011 |
| |
|
|
|
|
|
|
|
| Malignant tumour metastatic to pleura |
3/29(cytological
preparations from effusions)10 |
|
|
|
|
| |
|
|
|
|
|
|
|
Diagnostic utility
References
1 Chung CT, Santos Gda C, Hwang DM, Ludkovski O, Pintilie
M, Squire JA, et al. FISH assay development for the detection of p16/CDKN2A
deletion in malignant pleural mesothelioma. J Clin Pathol. 2010 Jul;63(7):630-4.
2 Krasinskas
AM, Bartlett DL, Cieply K, Dacic S. CDKN2A and MTAP deletions in peritoneal
mesotheliomas are correlated with loss of p16 protein expression and poor
survival. Mod Pathol. 2010 Apr;23(4):531-8.
3 Dacic
S, Kothmaier H, Land S, Shuai Y, Halbwedl I, Morbini P, et al. Prognostic
significance of p16/cdkn2a loss in pleural malignant mesotheliomas. Virchows
Arch. 2008 Dec;453(6):627-35.
4 Lopez-Rios
F, Chuai S, Flores R, Shimizu S, Ohno T, Wakahara K, et al. Global gene
expression profiling of pleural mesotheliomas: overexpression of aurora
kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation
of microarray-based prognostic prediction. Cancer Res. 2006 Mar 15;66(6):2970-9.
FULL TEXT
5 Ladanyi M Implications
of p16/CDKN2A deletion in pleural mesotheliomas Lung Cancer. 2005 Jul;49
Suppl 1:S95-8
6 Monaco
SE, Shuai Y, Bansal M, Krasinskas AM, Dacic S. The diagnostic utility
of p16 FISH and GLUT-1 immunohistochemical analysis in mesothelial proliferations.
Am J Clin Pathol. 2011 Apr;135(4):619-27.
7 Kobayashi
N, Toyooka S, Yanai H, Soh J, Fujimoto N, Yamamoto H, et al. Frequent
p16 inactivation by homozygous deletion or methylation is associated with
a poor prognosis in Japanese patients with pleural mesothelioma. Lung
Cancer. 2008 Oct;62(1):120-5.
8 Takeda M, Kasai
T, Enomoto Y, Takano M, Morita K, Kadota E, Nonomura A. 9p21 deletion
in the diagnosis of malignant mesothelioma, using fluorescence in situ
hybridisation analysis. Pathol Int. 2010 May;60(5):395-9.
9 Savic
S, Franco N, Grilli B, Barascud Ade V, Herzog M, Bode B, et al. Fluorescence
in situ hybridization in the definitive diagnosis of malignant mesothelioma
in effusion cytology. Chest. 2010 Jul;138(1):137-44.
10 Flores-Staino
C, Darai-Ramqvist E, Dobra K, Hjerpe A. Adaptation of a commercial fluorescent
in situ hybridization test to the diagnosis of malignant cells in effusions.
Lung Cancer. 2010 Apr;68(1):39-43.
11 Chiosea
S, Krasinskas A, Cagle PT, Mitchell KA, Zander DS, Dacic S. Diagnostic
importance of 9p21 homozygous deletion in malignant mesotheliomas. Mod
Pathol. 2008 Jun;21(6):742-7.
12 Illei
PB, Rusch VW, Zakowski MF, Ladanyi M. Homozygous deletion of CDKN2A and
codeletion of the methylthioadenosine phosphorylase gene in the majority
of pleural mesotheliomas. Clin Cancer Res. 2003 Jun;9(6):2108-13.
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revised 3.6.2011.
©SMUHT/PW
Bishop