p57KIP2
p57KIP2 is a cyclin-dependent kinase inhibitor7, cell cycle inhibitor and tumour suppressor gene, located at 11p15.52. The Beckwith-Wiedemann syndrome is characterised by fetal overgrowth and predisposition to tumours: it is associated with loss or point mutation of p57KIP2. Mice deficient in p57KIP2 show placentomegaly with trophoblastic hyperplasia1. p57KIP2 shows strong paternal , resulting in expression predominantly from the maternal allele.
Commercial antibodies are available which work on formalin-fixed, paraffin-embedded tissues. Staining is nuclear.
Immunohistochemical expression
The general role of p57KIP2 in malignancy is poorly understood:
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In hepatocellular and bladder carcinomas, expression is downregulated7.
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In follicular adenoma and minimally invasive follicular thyroid carcinoma, it is upregulated, but there is downregulation in widely invasive follicular carcinoma7..
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It shows increased expression in pancreatic carcinoma, by comparison with normal ductal epithelium, but reduced expression in stage IV disease, lymphatic invasion, capsular invasion or lymph node metastasis.
In trophoblast and its tumours:
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Gestational endometrium: decidual cells are positive but secretory glands are negative1,3,6. Most other adult tissues are negative3.
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Normal placenta: immunoreactivity is seen in at least 30% of nuclei of cytotrophoblast, villous mesenchyme, and intervillous trophoblast islands. Syncytiotrophoblast is negative1.
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Complete hydatidiform moles are formed exclusively from paternal DNA. As expected, they therefore do not express p57KIP2. By contrast, partial moles are triploid, consisting of one maternal and two paternal haploid genomes and the pattern of p57KIP2 is normal. The results below are for cytotrophoblast and villous mesenchyme. The reactivity of extravillous trophoblast has been variably reported as negative3 or positive1,6. Syncytiotrophoblast is negative in all situations.
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Normal placenta
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positive3
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Voluntary artificial abortions
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10/10(>50% of cells in 3 cases, 10-50% of cells in 4 cases, 1-10% of cells in 3 cases)4
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spontaneous abortion
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12/123
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Hydropic spontaneous abortion
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51/51(These cases were chosen as showing hydropic change. Strong positivity was seen in cytotrophoblast and villous mesenchyme.)1,
16/20(>50% of cells in 5 cases, 10-50% of cells in 8 cases, 1-10% of cells in 3 cases)4, 2/26
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Partial hydatidiform mole
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39/39(16 of 39 were investigated and confirmed triploid. 23 had not been evaluated. strong positivity was seen in cytotrophoblast and villous mesenchyme, irrespective of whether the villi were sclerotic or oedematous.)1,
16/16(By flow cytometry, 12 cases were triploid, 4 diploid. By image cytometry, 13 were triploid and 3 diploid, requiring reclassification as non-molar gestations.)2, 19/193,
19/20(>50% of cells in 2 cases, 10-50% of cells in 17 cases)4,
2/2(diagnostically difficult cases, triploid by flow cytometry)5, 7/76
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Complete hydatidiform mole
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1/59(These included 2 invasive moles and 10 recurrences of moles. 24 of 59 were investigated by flow cytometry or cytogenetics and confirmed diploid or tetraploid. 35 had not been evaluated. Both cytotrophoblast and villous mesenchyme were negative, although in some cases occasional villi showed positivity of a few cells. The results were independent of the gestational age and of the degree of trophoblastic hyperplasia. [The one positive case was investigated and found to be diploid, lacking a Y chromosome: it was androgenic and dispermic on analysis of microsatellite markers: however, it was triploid for one marker on chromosome 11, suggesting retention of a portion of the maternal chromosome 11 in this case.] Note that intervillous trophoblast was consistently POSITIVE)1,
2/22(20 cases showed no staining of either cytotrophoblast or syncytiotrophoblast. One case showed a population of villi with immunoreactive cytotrophoblast and possibly represented a twin complete mole and hydropic miscarriage. A second showed focal staining of a few cytotrophoblast nuclei. All 22 cases were diploid by flow cytometry. By image cytometry, 21 cases were diploid, one triploid and p57 positive, requiring reclassification as a partial mole.)2, 0/203,
7/44(the seven positive cases showed expression in 1-10% of cells.)4,
4/4(diagnostically difficult cases, diploid by flow cytometry. Two cases were twin gestations with admixed immunoreactive normal and negative complete molar villi. )5,
1/52(includes one invasive mole, which was negative)6,
0/6(including two invasive moles, )7
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Gestational choriocarcinoma
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0/33
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choriocarcinoma post-complete hydatidiform mole
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5/117
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choriocarcinoma post-non-molar pregnancy
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10/127
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placental site trophoblastic tumour post-complete hydatidiform mole
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2/37
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placental site trophoblastic tumour post-non-molar pregnancy
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12/147
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The mechanism by which immunoreactivity is restored on transformation in gestational trophoblastic tumours (choriocarcinomas and placental site trophoblastic tumours) arising from complete hydatidiform mole is not know7.
Diagnostic utility
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Identification of complete hydatidiform mole. The histological differentiation of complete mole, partial mole and hydropic spontaneous abortion is problematic. Most complete hydatidiform moles are diploid, whereas most partial moles are triploid. Ploidy studies will identify partial moles, but will not differentiate complete moles from non-molar gestations. Complete moles carry a high risk of persistent disease and choriocarcinoma, while partial moles have a very low risk. Other markers which may be useful in a panel for differentiating the various forms of gestational trophoblastic disease are hCG, placental alkaline phosphatase and hPL.
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p57KIP2 does not significantly assist in differentiating gestational trophoblastic tumours (choriocarcinomas and placental site trophoblastic tumours) arising secondary to complete hydatidiform moles from those arising from a non-molar pregnancy7..
References
1Castrillon, D. H., D. Sun, et al. (2001). "Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2." Am J Surg Pathol 25(10): 1225-30.
2Crisp, H., J. L. Burton, et al. (2003). "Refining the diagnosis of hydatidiform mole: image ploidy analysis and p57KIP2 immunohistochemistry." Histopathology 43(4): 363-73.
3Chilosi, M., E. Piazzola, et al. (1998). "Differential expression of p57kip2, a maternally imprinted cdk inhibitor, in normal human placenta and gestational trophoblastic disease." Lab Invest 78(3): 269-76.
4Fukunaga, M. (2002). "Immunohistochemical characterization of p57(KIP2) expression in early hydatidiform moles." Hum Pathol 33(12): 1188-92.
5Genest, D. R., D. M. Dorfman, et al. (2002). "Ploidy and imprinting in hydatidiform moles. Complementary use of flow cytometry and immunohistochemistry of the imprinted gene product p57KIP2 to assist molar classification." J Reprod Med 47(5): 342-6.
6Jun, S. Y., J. Y. Ro, et al. (2003). "p57kip2 is useful in the classification and differential diagnosis of complete and partial hydatidiform moles." Histopathology 43(1): 17-25.
7Sebire, N. J., H. C. Rees, et al. (2004). "p57 immunohistochemical staining of gestational trophoblastic tumours does not identify the type of the causative pregnancy." Histopathology 45(2): 135-141.
This page last revised 30.8.2004.
©SMUHT/PW Bishop