Cytokeratin 5/6 and CK5

Stains & molecular markers
Cytokeratin 5/6 and CK5

Authors: Robert Terlević, M.D., Semir Vranić, M.D., Ph.D.

Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 3 June 2019

Minor changes: 17 September 2020

Copyright: 2019-2020, PathologyOutlines.com, Inc.

PubMed Search: CK5/6 [title]

Page views in 2019: 14,470

Page views in 2020 to date: 20,695

Table of Contents

Cite this page: Terlević R, Vranić S. Cytokeratin 5/6 and CK5. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsck5and6.html. Accessed September 20th, 2020.

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.

Breast tubular adenoma immunoprofile

Intraductal papilloma with DCIS immunoprofile

Intraductal papilloma with DCIS, CK5/6

Basal-like triple negative breast cancer

Apocrine metaplasia of the breast

Metastatic squamous cell carcinoma of the cervix

Apocrine carcinoma of the breast

Contributed by Leica Microsystems, Biosystems Division

Mesothelioma CK5
(XM26) with intense
cytoplasmic and
membranous staining

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

CKAE1/AE3
CD5
CK5/6
CK7
K903

Board review answer #1

C. CK5/6

Reference: Cytokeratin 5/6 and CK5

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Board review style question #2

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 answer #2

D. In situ high grade urothelial carcinoma versus T2 high grade urothelial carcinoma

Reference: Cytokeratin 5/6 and CK5

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