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Stains

p63

Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 16 April 2012, last major update April 2012
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.

Definition
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● Member of p53 gene family at 3q27-29, but does not appear to be a tumor suppressor gene
● Myoepithelial marker; others are smooth muscle myosin heavy chains, calponin, p75, P-cadherin, basal cytokeratins (CK 5/6), maspin, and CD10 (Arch Pathol Lab Med 2011;135:422)

Pathophysiology
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● Encodes at least 6 different proteins with different biologic functions
● Appears to regulate growth and development of epithelial organs (J Biomed Biotechnol 2011;2011:864904), as germline mutations cause ectrodactyly (missing or irregular fingers or toes), ectodermal dysplasia and facial clefts syndrome, also called limb mammary syndrome (hypoplasia / aplasia of mammary glands and nipple)
● May be molecular switch for initiation of “epithelial stratification program”
● Regulates human keratinocyte proliferation (J Biol Chem 2012;287:5627), olfactory stem cell self-renewal and differentiation (Neuron 2011;72:748)
● Gene and protein expression may not correlate due to presence of isoforms and post-translation modification
● Main isoforms are TAp63 and deltaNp63
● TAp63 ("full length" p63) activates p53 target genes, but deltaNp63 inhibits transcription activation of p53 gene and transactivating isoforms
● TAp63 is highly expressed in most benign tumors; negative / weak in most carcinomas, but deltaNp63 is negative / weak in most benign tumors and highly expressed in adenoid cystic, mucoepidermoid and myoepithelial carcinomas (Hum Pathol 2005;36:821)

Interpretation
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● Typically a nuclear stain
● Cytoplasmic staining of Z-bands of benign and malignant skeletal muscle tumors (Mod Pathol 2011;24:1320)

Uses by pathologists
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● Rule out invasion in breast tumors by determining presence of myoepithelial cells (Am J Surg Pathol 2001;25:1054)
● 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); note that 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)
● 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)
● 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)
● 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)
● Differentiate renal collecting duct carcinoma (p63-/PAX8+) from upper tract urothelial carcinoma (opposite, Am J Surg Pathol 2010;34:965)
● 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)
● 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)

Micro images
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Anus:
   
Normal anal glands (p63+, fig A/B) and anal gland carcinoma (p63-, fig A)

Bladder or other GU:

Normal urothelium and urothelial carcinoma


Invasive urothelial carcinoma - p63 and beta catenin


Invasive urothelial carcinoma - p63 and Uroplakin III

Bone:
   
Giant cell tumor

   
Various - bone tumors

Breast:
   
Normal

       
Left-cylindroma, middle-papilloma, right-tubular adenoma

   
Nipple adenoma - p63 shows intact myoepithelial layer


Papillary lesions

           
Collagenous spherulosis versus adenoid cystic carcinoma

   
DCIS

       
Left-adenoid cystic carcinoma (solid variant), middle-medullary carcinoma, right-myoepithelial carcinoma

   
Left-triple negative breast cancer, right-matrix producing carcinoma

Lung (left to right):
           
Adenomatous hyperplasia, atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and well-differentiated adenocarcinoma

Lymph nodes:

Benign epithelial inclusions - fig 1: CK5/6+; 2: p63+

Lymphoma:
   
Left-anaplastic large cell lymphoma is p63+ (fig D) versus right-Reed-Sternberg cells in Hodgkin lymphoma are p63- (fig B)

Maxilla:
   
Left-nasolabial cyst; right-respiratory epithelial adenomatoid hamartoma (fig 2B, site unspecified)

Nasal septum:
   
Seromucinous hamartoma is p63 negative (no myoepithelial cells) with positive internal control

Pancreas:
   
Lymphoepithelial cyst; adenosquamous carcinoma

Prostate:
   
Biopsies


Nephrogenic adenoma with triple stain mimics adenocarcinoma, with negative staining for p63 and CK903 and positive staining for P504S (red)

   
Pseudohyperplastic adenocarcinoma - triple stain (p63 stains basal cell nuclei brown, CK903 stains basal cell cytoplasm brown, p504S stains adenocarcinoma cytoplasm red)

   
Intraductal carcinoma; normal adenocarcinoma versus urothelial carcinoma

Salivary gland:

Adenoid cystic carcinoma (solid)

Sarcomatoid carcinoma:
   
Various

Skin:
       
Primary and metastatic tumors

   
Left-syringocystadenocarcinoma papilliferum (fig 5); right-sweat gland carcinoma (fig 2B)


Primary adnexal and metastatic carcinomas

Thyroid:

Solid cell nests

Uterus:

Endometriosis

Vulva:

Vulvar intraepithelial neoplasia and vulvar squamous cell carcinoma

Positive staining - normal
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● Breast: myoepithelium (Am J Surg Pathol 2001;25:1054), Toker cells
● Gynecologic tract: basal and parabasal cells of mature cervical, vaginal and vulval squamous epithelium; cervical reserve cells at transformation zone, immature metaplastic and atrophic cervical squamous epithelium (Adv Anat Pathol 20 09;16:316)
● Lung: bronchial reserve cells; metaplastic squamous bronchial epithelium (lower strata)
● Also prostate (basal cells), skin (basal cells), thymus (epithelial cells), urothelium

Positive staining - disease
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● Adenoid cystic carcinoma: but not cases with basaloid growth pattern (Mod Pathol 2005;18:1277)
● Alveolar rhabdomyosarcoma: p63 cytoplasmic staining of Z-bands of skeletal muscle (Mod Pathol 2011;24:1320)
● Bladder: invasive urothelial carcinoma (87%, Am J Surg Pathol 2007;31:673), lymphoepithelioma-like carcinoma (53%, Am J Surg Pathol 2011;35:474)
● Bone: aneurysmal bone cyst (63%), chondroblastoma (83%), giant cell reparative granuloma (100%), giant cell tumor (87%), nonossifying fibroma (17%), osteosarcoma (50%), pigmented villonodular synovitis (25%), tenosynovial giant cell tumor (7%, Arch Pathol Lab Med 2011;135:776)
● Breast: adenoid cystic carcinoma, collagenous spherulosis (Mod Pathol 2006;19:1351), cylindroma, medullary carcinoma, metaplastic carcinoma (Am J Surg Pathol 2008;32:345), myoepithelioma, nipple adenoma, tubular carcinoma; discontinuous staining in LCIS and DCIS (Am J Surg Pathol 2001;25:1054)
● Cervix: epithelioid trophoblastic tumor, lymphoepithelioma-like carcinoma, placental site nodule, spindle cell carcinoma
● Heart: cystic tumor of the atrioventricular node (Am J Clin Pathol 2005;123:369)
● Jaw: nasolabial cyst (Arch Pathol Lab Med 2011;135:1499), sclerosing odontogenic carcinoma (Am J Surg Pathol 2008;32:1613)
● Lymphoma: anaplastic large cell lymphoma (44%) versus 0% for Hodgkin lymphoma (Hum Pathol 2008;39:1505)
● Neuroendocrine carcinoma: variable staining, may be focal / weak (Hum Pathol 2008;39:591)
● Prostate: basal cell hyperplasia (Hum Pathol 2005;36:480), high grade PIN, adenoid basal cell tumor
● Salivary gland: benign or malignant tumors (Hum Pathol 2005;36:821), staining of basal and myoepithelial cells; diffuse staining in oncocytic mucoepidermoid carcinoma (Am J Surg Pathol 2009;33:409)
● Sarcomatoid carcinoma: Mod Pathol 2005;18:1471
● Squamous cell carcinoma and squamous component of adenosquamous carcinoma: Hum Pathol 2001;32:479 - Cervix, Hum Pathol 2002;33:921 - Lung, Am J Clin Pathol 2001;116:823 - poorly differentiated/undifferentiated tumors from various sites
● Thymus: hyperplasia and thymoma (Am J Clin Pathol 2009;131:689), thymic carcinoma (Am J Surg Pathol 2009;33:1113)
● Thyroid gland: CASTLE, Hashimoto's thyroiditis, papillary carcinoma (Hum Pathol 2003;34:764), sclerosing mucoepidermoid carcinoma with eosinophilia, solid cell nests (Mod Pathol 2003;16:43)
● Uterus: endometriosis of peritoneal wall (nuclear staining in glandular component), but rectovaginal/abdominal wall endometriosis is p63- (Arch Pathol Lab Med 2007;131:1099), epithelioid trophoblastic tumor (Arch Pathol Lab Med 2006;130:1875)

Negative staining
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● Anus: anal gland carcinoma (Arch Pathol Lab Med 2007;131:1304), but anal squamous cell carcinoma is usually p63+ (Am J Surg Pathol 2007;31:285)
● Breast: normal epithelium, stromal cells, myofibroblasts; may be reduced or occasionally absent in benign apocrine lesions (Am J Surg Pathol 2011;35:202), benign sclerosing lesions (Am J Surg Pathol 2010;34:896) or microglandular adenosis (Am J Surg Pathol 2009;33:496); invasive ductal adenocarcinoma (usually)
● Cervix: glassy cell carcinoma
● Melanoma: Am J Clin Pathol 2008;130:213
● Mesothelioma
● Prostate: adenocarcinoma, nephrogenic adenoma, partial atrophy (Am J Surg Pathol 2008;32:851)
● Most soft tissue tumors (Am J Clin Pathol 2011;136:762)
● Many glandular tumors are negative/weak

End of Stains > p63

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