Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Negative staining | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Terlević R, Vranić S. Cytokeratin 5/6 and CK5. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsck5and6.html. Accessed February 8th, 2023.
Definition / general
- Basic (type II) cytokeratins of molecular weight 58 kDa (CK5) and 56 kDa (CK6) (Cell 1982;31:11)
- Common antibodies are directed against both cytokeratin 5 and 6
- Major partner of CK5 is CK14, while CK6 pairs with CK16/17 (Exp Cell Res 2007;313:2244, Eur J Cell Biol 2004;83:735)
- CK5 also detected by antibodies against high molecular weight cytokeratins (such as 34βE12, also known as K903) and pan-CK markers (such as CK AE1/AE3)
Essential features
- Stains basal cells of prostate and basal / myoepithelial cells of breast and is used to rule out invasion
- Useful for detecting benign breast proliferations (mosaic-like pattern) versus ductal carcinoma in situ (DCIS) (negative or rarely diffusely positive) (Pathology 2009;41:68)
- Together with p63, used to detect squamous cell origin in poorly differentiated carcinomas (Am J Clin Pathol 2001;116:823)
Terminology
- K5, K6, keratin 5, keratin 6, basal cytokeratins, intermediate molecular weight cytokeratins
Pathophysiology
- Cytoskeletal constituents of the intermediate filament family of proteins, which provide the cell with a structural framework stretching from around the nucleus to desmosomes and hemidesmosomes (Science 1998;279:514)
- CK5 and its partner CK14 constitute up to 25% of total cell protein in basal cells of epidermis (Science 1998;279:514); expression in skin correlates with mitotic activity (J Biol Chem 1995;270:21362, Development 1994;120:2369)
- CK6 expressed in wound healing and hyperproliferative cancer cells (J Biol Chem 1995;270:21362)
- CK5/6 expression may be useful in subclassifying epidermolysis bullosa cases (Appl Immunohistochem Mol Morphol 2018;26:586)
- CK5 is a marker of breast luminal progenitor and stem cells (Breast Cancer Res Treat 2011;128:45)
- CK5 positive cells may represent a chemoresistant population in breast and ovarian cancer (Breast Cancer Res Treat 2011;128:45, Int J Gynecol Cancer 2015;25:1565)
Clinical features
- CK5 and CK14 mutations may cause epidermolysis bullosa simplex (Hum Mutat 2006;27:719) and Dowling-Degos disease (Am J Hum Genet 2006;78:510)
- Important in tooth enamel formation (J Biol Chem 2003;278:20293)
- CK6 mutations involved in pachyonychia congenita (Nat Genet 1995;10:363)
Interpretation
- CK5 and CK5/6: diffuse cytoplasmic staining with perinuclear enhancement
Uses by pathologists
- Identify breast basal / myoepithelial cells and prostate basal cells
- Distinguish breast usual ductal hyperplasia (UDH) and papillary lesions (mosaic-like pattern) from DCIS (usually negative, rarely diffusely positive) (Pathology 2009;41:68)
- Distinguish epithelioid mesothelioma (CK5/6+ in 83%) from lung adenocarcinoma (CK5/6- in 85%) (Histopathology 2006;48:223), including in pleural effusions (CK5/6+ in 90% mesothelioma, 0% adenocarcinoma) (Diagn Cytopathol 2006;34:801)
- Distinguish cutaneous spindle squamous cell carcinoma (CK5/6+ in 100%) from superficial epithelioid sarcoma (rare focal positivity) (J Cutan Pathol 2003;30:114)
- Together with p63+, identify squamous origin in poorly differentiated metastatic carcinomas (e.g., cervical) (Am J Clin Pathol 2001;116:823)
- CK5 preferred to K903 in antibody cocktails to rule out prostate carcinoma (Diagn Pathol 2012;7:81)
- As part of panel to discriminate between undifferentiated sinonasal carcinoma (CK5/6-) and other poorly differentiated head and neck tumors (poorly differentiated squamous cell carcinoma, olfactory neuroblastoma and nasopharyngeal carcinoma) (Ann Diagn Pathol 2014;18:261)
- CK5 used as part of panel to distinguish cutaneous metastasis of breast cancer from sweat gland carcinoma (Arch Pathol Lab Med 2011;135:975)
Prognostic factors
- CK5/6+ / p63+ breast intraductal papillomas show less risk of subsequent invasive carcinoma (Pathol Int 2015;65:81)
- Diffuse positivity in DCIS defines basal-like subtype with poorer prognosis (Hum Pathol 2007;38:197)
- CK5/6 positivity helps define a basal-like subtype of triple negative breast carcinoma (TNBC) with poorer prognosis (Clin Cancer Res 2006;12:1533); associated with premenopausal African American women (JAMA 2006;295:2492), BRCA1 mutations (Mod Pathol 2005;18:1321, J Natl Cancer Inst 2003;95:1482) and higher propensity for brain metastases (Am J Surg Pathol 2006;30:1097)
- CK5+ together with CD44+ defines invasive and noninvasive basal-like urothelial carcinoma subtype associated with more aggressive behavior (Pathol Res Pract 2015;211:610, Appl Immunohistochem Mol Morphol 2016;24:575)
Microscopic (histologic) images
Contributed by Jijgee Munkhdelger, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D. and Semir Vranić, M.D., Ph.D.
Contributed by Leica Microsystems, Biosystems Division
Positive staining - normal
- CK5 is the major keratin of basal and suprabasal cells in the epidermis (Exp Cell Res 2007;313:2244)
- Also expressed in basal cells of respiratory epithelium, male genital tract (efferent ducts, epididymis, deferent duct and seminal vesicle), breast basal / myoepithelial cells, mesothelium, prostate basal cells (J Pathol 2001;195:563), cornea, endocervical squamous metaplasia (Ann N Y Acad Sci 1985;455:282), spermatogenic cells (Mol Reprod Dev 2002;61:1), basal cells of urinary tract transitional epithelium (J Histochem Cytochem 1985;33:415, Mol Cell Proteomics 2002;1:269)
- CK5 stains thyroid solid cell nests (Endocr Pathol 2016;27:83)
- CK5 and CK6 both expressed in palmar and plantar epidermis; basal cells of eccrine and apocrine glands; hair follicle; myoepithelial cells of salivary gland acini; basal cells of excretory ducts; mucosal stratified epithelia of the oral cavity, esophagus, female genital tract and glans penis; thymus epithelial cells (J Biol Chem 1995;270:21362, Ann N Y Acad Sci 1985;455:282)
Positive staining - disease
- Tumors derived from stratified epithelia (skin and mucosa) are positive (Mod Pathol 2002;15:6)
- Some adenocarcinomas may show focal staining (pancreas, breast, lung, uterine endometrioid, cholangiocarcinoma and hepatocellular carcinoma, lung) (Mod Pathol 2002;15:6)
- Poorly differentiated squamous cell carcinoma identified by both CK5/6+ and p63+ with 77% sensitivity and 96% specificity (Am J Clin Pathol 2001;116:823)
- Urothelial carcinoma (63%) (Mod Pathol 2002;15:6)
- Breast usual ductal hyperplasia and papillary lesions (mosaic-like pattern) (Pathology 2009;41:68)
- Basal-like breast DCIS (Hum Pathol 2007;38:197)
- In breast and salivary gland, adenoid cystic carcinoma CK5/6 stains cells lining true lumina (Virchows Arch 2016;469:213, Int J Clin Exp Pathol 2011;4:336)
- High grade serous ovarian carcinoma (focal or diffuse pattern in 69%) (Hum Pathol 2017;67:30)
- Epithelioid mesothelioma (CK5/6+ in 83%) (Histopathology 2006;48:223)
- Stains both glandular and myoepithelial components of salivary gland tumors (Mod Pathol 2002;15:6, Arch Pathol Lab Med 2015;139:55)
- Thymoma (100%) (Mod Pathol 2002;15:6)
- Nasopharyngeal carcinoma (90%) and poorly differentiated squamous cell carcinoma of the nasal tract (100%) (Ann Diagn Pathol 2014;18:261)
- Cutaneous adnexal neoplasms (97%) (Am J Dermatopathol 2004;26:447)
Negative staining
- Adenocarcinoma (colon, stomach), renal cell carcinoma, germ cell tumors, thyroid carcinomas, neuroendocrine carcinoma (lung, skin and gastrointestinal), epithelioid sarcoma, synovial sarcoma (Mod Pathol 2002;15:6)
- Benign epithelial breast lesions other than UDH and papillary lesions: apocrine metaplasia and columnar cell change (Am J Surg Pathol 2005;29:734)
- Sinonasal undifferentiated carcinoma (Ann Diagn Pathol 2014;18:261)
- Well differentiated neuroendocrine tumors of skin (100%) (J Cutan Pathol 2017;44:557)
Board review style question #1
- Which of the following immunohistochemical stains is specific for basal cells of stratified epithelia?
- CKAE1/AE3
- CD5
- CK5/6
- CK7
- K903
Board review style answer #1
Board review style question #2
- Which of the following differential diagnoses cannot be solved with a basal cell stain (such as CK5/6)?
- Breast usual ductal hyperplasia versus ductal carcinoma in situ
- Cribriform high grade prostatic intraepithelial neoplasia versus prostatic adenocarcinoma Gleason pattern 4
- Metastatic undifferentiated squamous cell carcinoma versus epithelioid sarcoma
- In situ high grade urothelial carcinoma versus T2 high grade urothelial carcinoma
- Basal-like triple negative breast carcinoma versus breast ductal carcinoma, NOS
Board review style answer #2
D. In situ high grade urothelial carcinoma versus T2 high grade urothelial carcinoma
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Reference: Cytokeratin 5/6 and CK5
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Reference: Cytokeratin 5/6 and CK5