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, ectocervix, tonsil, and bladder, and to certain subpopulations of basal cells in glandular structures of prostate and breast, as well as in bronchi4. In the respiratory tract, normal ciliated and goblet cells were p63 negative, but reserve cells were p63 positive12. In keratinocytes, the expressed 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.

The positivity of squamous carcinomas for p63 has been investigated in anal carcinomas:

Thymomas expressed high levels of 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.

• Metaplastic carcinoma of the breast is usually positive for p637.

• 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.

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

• 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 differentiated 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

1 Barbareschi, 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.

2 Shah, 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.

3 Signoretti, 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.

4 Di 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.

5 Kaufmann, 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.

6 Shih 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.

7 Koker, 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.

8 Ivan 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

9 Reis-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.

11 Owens SR,Greenson JK. Immunohistochemical staining for p63 is useful in the diagnosis of anal squamous cell carcinomas. Am J Surg Pathol 2007; 31:285-90

This page last revised 20.2.2007.

©SMUHT/PW Bishop