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TP63

MIM.603273 HGNC:15979

Tuesday 4 November 2008

p63

PO

Definition: p63 is a nuclear protein encoded by a gene on chromosome 3q27-29 with homology to p53 (a tumour suppressor gene). It has been shown to regulate growth and development in epithelium of the skin, cervix, breast and urogenital tract.

TP63 gene encodes a member of the p53 family of transcription factors: p63. Both alternative splicing and the use of alternative promoters results in multiple transcript variants encoding different proteins. Many transcripts encoding different proteins have been reported but the biological validity and the full-length nature of these variants have not been determined.

Specific isotypes are expressed in basal cells of pseudostratified epithelia (prostate, bronchial), reserve cells of simple columnar epithelia (endocervical, pancreatic ductal), myoepithelial cells (breast, salivary glands, cutaneous apocrine/eccrine glands), urothelium and squamous epithelium.

Immunochemistry

- In prostate adenocarcinoma

  • p63 has similar applications to those of high molecular weight cytokeratins in the diagnosis of prostatic adenocarcinoma, but with the advantages that p63: 1) stains a subset of 34βE12 negative basal cells, 2) is less susceptible to the staining variability of 34βE12 (particularly in TURP specimens with cautery artefact), 3) is easier to interpret because of its strong nuclear staining intensity and low background.
  • Interpretative limitations related to presence or absence of basal cells in small numbers of glands for 34βE12 apply to p63, requiring correlation with morphology.
  • Prostatic adenocarcinomas have occasional p63 immunoreactive cells, most representing entrapped benign glands or intraductal spread of carcinoma with residual basal cells.
  • Confirm diagnosis of prostatic adenocarcinoma (p63-, Am J Surg Pathol 2002;26:1161);
  • triple stain with P504S (AMACR) and CK903 (HMWCK) is recommended (Am J Clin Pathol 2007;127:248);
  • partial atrophy may have similar staining as carcinoma (Am J Surg Pathol 2008;32:851);
  • prostate cancer rarely expresses diffuse p63 staining in a nonbasal cell distribution (Am J Surg Pathol 2008;32:461)
  • Differentiate high-grade prostate cancer (p63-) from infiltrating high-grade urothelial cancer (often p63+) as part of panel (Am J Surg Pathol 2007;31:1246)

- Prostatic adenocarcinoma with aberrant diffuse expression of p63 (p63-PCa) is a recently described variant of prostatic adenocarcinoma. (23774168)

  • p63-PCa can show a distinctive morphology consisting of atrophic, poorly formed glands, with multilayered and often spindled nuclei.
  • It is recommended that these tumors not be assigned a Gleason score and their favorable findings at RP be noted.

- In breast cancer

  • Rule out invasion in breast tumors by determining presence of myoepithelial cells (Am J Surg Pathol 2001;25:1054)

- salivary gland tumors

  • Rule out invasion in salivary gland tumors by determining presence of myoepithelial cells

- Determine squamous differentiation (p63+) for H&E or cytology cases as part of panel (Am J Clin Pathol 2011;136:81), but p63 rarely stains adenocarcinoma (Am J Surg Pathol 2011;35:15)

- skin/breast

  • Differentiate cutaneous sweat gland / adnexal carcinoma (p63+) from metastatic breast / adenocarcinoma to skin (p63-) as part of panel (Arch Pathol Lab Med 2011;135:975, Mod Pathol 2010;23:713)

- in olfactory neuroblastoma

  • Differentiate olfactory neuroblastoma (p63-/calretinin+) from other small round blue cell tumors of sinonasal tract (often p63+/calretinin-, Am J Surg Pathol 2011;35:1786)

- in renal tumors

- Merkel cell carcinoma

  • Associated with poorer prognosis for Merkel cell carcinoma (Mod Pathol 2011;24:1451)

- Identifies "false" lymphatic invasion (tumor cells surrounded by D2-40+/p63- ducts), which have good prognosis (Mod Pathol 2011;24:502)

Immunochemistry

- PAX8 (+)/p63 (-) immunostaining pattern in renal collecting duct carcinoma (CDC): a useful immunoprofile in the differential diagnosis of CDC versus urothelial carcinoma of upper urinary tract. (20463571)

Diagnostic pathology

- p63 is a reliable marker in the diagnosis of conventional mucoepidermoid carcinomas.

Germline mutations

Germline mutations in this gene are associated with :
- ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) (MIM.604292)
- split-hand/foot malformation 4 (SHFM4) (MIM.605289)
- ankyloblepharon-ectodermal defects-cleft lip/palate (Hay-Wells syndrome) (MIM.106260)
- ADULT syndrome (acro-dermato-ungual-lacrimal-tooth) (MIM.103285)
- limb-mammary syndrome (MIM.603543)
- Rapp-Hodgkin syndrome (RHS) (MIM.129400)
- orofacial cleft 8 (MIM.129400)

Animal models

- An animal model, p63 -/- mice, has been useful in defining the role this protein plays in the development and maintenance of stratified epithelial tissues.

- p63 -/- mice have several developmental defects which include the lack of limbs and other tissues, such as teeth and mammary glands, which develop as a result of interactions between mesenchyme and epithelium.

References

- Aberrant Expression of p63 in Adenocarcinoma of The Prostate: A Radical Prostatectomy Study. Giannico GA, Ross HM, Lotan T, Epstein JI. Am J Surg Pathol. 2013 Jun 14. PMID: 23774168

- PAX8 (+)/p63 (-) immunostaining pattern in renal collecting duct carcinoma (CDC): a useful immunoprofile in the differential diagnosis of CDC versus urothelial carcinoma of upper urinary tract. Albadine R, Schultz L, Illei P, Ertoy D, Hicks J, Sharma R, Epstein JI, Netto GJ. Am J Surg Pathol. 2010 Jul;34(7):965-9. PMID: 20463571