p63

p63 is a member of the p53 gene family. The gene is located on chromosome 3q27-29. It encodes at least six different transcripts with transactivation (TAp63) or negative effects (DNp63) on the p53 reporter genes, resulting in tumour suppressor and oncogenic effects respectively⁶. The DNp63 isoforms lack the N-terminal transactivation domain and inhibit p53⁸. During embryogenesis, it is essential for the development of several epithelia. Human germline mutations result in limb mammary syndrome (ectrodactily, ectodermal dysplasia and facial clefts) with hypoplasia/aplasia of the breasts. p63(-/-) mice do not develop a prostate³.

It appears to be a sensitive and specific marker of myoepithelial cells. It is superior to SMA and calponin, in that myofibroblastic cells are negative.

Immunohistochemical expression

Immunoreactivity is nuclear.

In normal tissues, expression was restricted to epithelial cells of stratified epithelia, such as skin, esophagus, exocervix, tonsil, and bladder, and to certain subpopulations of basal cells in glandular structures of prostate and breast, as well as in bronchi⁴. In keratinocytes, the expresed isoform is DNp63, which presumably maintains epithelial cell proliferation⁸.

Carcinomas: p63 is expressed predominantly in basal cell and squamous cell carcinomas, as well as transitional cell carcinomas, but not in adenocarcinomas, including those of breast and prostate⁸. Thymomas expressed high levels of p63⁴.

	Squamous cell carcinoma (various sites: lung, head/neck, oesophagus, cervix, anus)	59/735, 25/27 (lung)9
	Urothelial carcinoma	14/205
	Non-squamous carcinomas (various sites)	20/1415, 1/3 (poorly differentiated, lung)9
	Adenocarcinoma	4/29 (lung)9, 1/69 (colon)9, 5/45 (ovary)9
	Malignant mesothelioma	0/145

A subset of non-Hodgkin's lymphoma express p63⁴.

Breast tissue:

• normal breast tissue shows immunoreactivity of basal cells, coexpressing with established markers of myoepithelial cells.

• benign breast lesions show a continuous basal rim of immunoreactivity with negativity of stromal and myofibroblastic cells. Adenomyoepitheliomas show staining of most cells.

• DCIS and LCIS shows a rim of reactive cells

• Most invasive carcinomas are devoid of p63 staining. About 5% of ductal carcinomas show a few positive cells. Adenoid cystic carcinomas show staining of most cells. Carcinomas with squamous metaplasia show positivity of the squamous foci.

	ductal carcinoma in situ	0/19
	invasive ductal carcinoma	6/59 (<25% of cells: 5 cases, >25% of cells: 1 case)9
	invasive lobular carcinoma	0/89

• In cytological preparation, the "naked nuclei" seen in fibroadenomas and benign hyperplastic lesions are positive.

Prostate shows similar staining of glandular basal cells to that seen in the breast.

	p63	34ßE12
benign needle biopsies	108/108 (of 108 cores from 78 cases, 57 showed a similar level of staining with 34ßE12 and p63, 45 showed a greater level of staining with p63 and only 10 showed a greater level of staining with 34ßE12. 10 of 108 cores showed a lack of staining of more than two glands with p63)2	108/108 (25 of 108 cores showed a lack of staining in more than two glands with 34ßE12.)2
benign TURPs	a mean of 95% of basal cells stained: 2 of 12 cases showed a lack of staining in more than 2 benign glands.2	a mean of 75% of basal cells stained: 12 of 12 cases showed a lack of staining in of more than 2 benign glands.2
equivocal lesions, 25 needle biopsies and 2 TURPs	10 cases positive for both; interpreted as benign2
	1 case remained unresolved2
	16 cases negative for both: interpreted as malignant2
unequivocal carcinoma	0/512, 0/699	0/512

Melanoma: 2/24⁹

• Glioblastoma: 1/25⁹

Diagnostic utility

• Identification of basal cells to differentiate benign from malignant prostatic glands. p63 may show a slight superiority to 34ßE12², but a cocktail of 34ßE12 and p63 may be superior to either alone. Nuclear staining for p63 as a basal cell marker may be combined in a section with cytoplasmic staining for AMACR as a neoplasm-associated marker. When using such cocktails, it is important to titrate the dilution of the p63 antibody such that it does not produce any confounding cytoplasmic staining¹⁰.

• Identification of squamous differentiation in poorly differentiatied carcinoma from various sites, particularly when coexpressed with CK5/6⁵. Coexpression of p63 and CK5/6 had a sensitivity of 0.77 and a specificity of 0.96 for squamous cell carcinomas. Increasing the minimal criterion of positive immunostaining for both markers to more than 50% of immunoreactive tumor cells resulted in a specificity of 0.99, although the sensitivity diminished to 0.66⁵. In particular, small cell versus poorly differentiated squamous cell carcinoma of lung.

• Distinction of epithelioid trophoblastic and placental site trophoblastic tumours.

References

¹Barbareschi, M., Pecciarini, L., Cangi, M. G., Macri, E., Rizzo, A., Viale, G., Doglioni, C. p63, a p53 homologue, is a selective nuclear marker of myoepithelial cells of the human breast. Am J Surg Pathol 2001;25:1054-1060.

²Shah, R. B., M. Zhou, et al. (2002). "Comparison of the basal cell-specific markers, 34betaE12 and p63, in the diagnosis of prostate cancer." Am J Surg Pathol 26(9): 1161-8.

³Signoretti, S., D. Waltregny, et al. (2000). "p63 is a prostate basal cell marker and is required for prostate development." Am J Pathol 157(6): 1769-75.

⁴Di Como, C. J., M. J. Urist, et al. (2002). "p63 expression profiles in human normal and tumor tissues." Clin Cancer Res 8(2): 494-501.

⁵Kaufmann, O., E. Fietze, et al. (2001). "Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas." Am J Clin Pathol 116(6): 823-30.

⁶Shih Ie, M. and R. J. Kurman (2004). "p63 expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations." Am J Surg Pathol 28(9): 1177-83.

⁷Koker, M. M. and C. G. Kleer (2004). "p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma." Am J Surg Pathol 28(11): 1506-12.

⁸Ivan D, Hafeez Diwan A,Prieto VG Expression of p63 in primary cutaneous adnexal neoplasms and adenocarcinoma metastatic to the skin. Mod Pathol 2005; 18:137-42

⁹Reis-Filho JS, Simpson PT, Martins A, Preto A, Gartner F,Schmitt FC Distribution of p63, cytokeratins 5/6 and cytokeratin 14 in 51 normal and 400 neoplastic human tissue samples using TARP-4 multi-tumor tissue microarray. Virchows Arch 2003; 443:122-32 This study used tissue microarrays.

¹⁰ Hammed O, Humphrey PA. Immunohistochemistry in the diagnosis of minimal prostate cancer. Current Diagnostic Pathology 2006;12:279-291.

This page last revised 23.9.2006.

©SMUHT/PW Bishop