What is CK5/6 (cytokeratin 5/6) in the context of breast cancer?

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What is CK5/6 (Cytokeratin 5/6)?

CK5/6 is an immunohistochemical marker that identifies basal/myoepithelial cells and is used primarily to distinguish squamous cell carcinomas, urothelial carcinomas, and mesotheliomas from adenocarcinomas, and in breast cancer, it identifies the aggressive "basal-like" subtype associated with poor prognosis. 1

Primary Diagnostic Applications

Distinguishing Squamous Cell Carcinoma from Adenocarcinoma

  • CK5/6 shows 84% positivity in poorly differentiated squamous cell carcinomas (SCC), while only 21% of non-SCCs express this marker, making it highly useful for identifying squamous differentiation in metastatic disease of unknown primary. 1

  • In lung cancer diagnosis, squamous cell carcinomas are typically CK5/6-positive, p63-positive, and TTF-1-negative, whereas adenocarcinomas are usually TTF-1-positive and CK5/6-negative. 1

  • A panel combining CK5/6 with p63 and TTF-1 is sufficient to distinguish adenocarcinomas from squamous cell carcinomas in small biopsy specimens. 1

Mesothelioma Diagnosis

  • CK5/6 is one of the four essential markers used to distinguish mesothelioma from adenocarcinoma, along with calretinin, CEA, and MOC-31. 1

  • In the standard diagnostic panel, mesothelioma shows positivity for CK5/6 and calretinin (or WT-1), while being negative for CEA and MOC-31, whereas adenocarcinomas show the opposite pattern. 1

  • All mesotheliomas express CK5/6, making it a highly sensitive marker for this diagnosis. 1

Urothelial Carcinoma Identification

  • Approximately 35% of urothelial carcinomas express CK5/6, which helps distinguish them from other carcinoma types. 1

  • Urothelial carcinomas typically show a CK5/6-positive, uroplakin-positive, p63-positive, and thrombomodulin-positive pattern. 1

Breast Cancer Applications

Basal-Like Breast Cancer Identification

  • In breast cancer, CK5/6 identifies the "basal-like" molecular subtype, which is associated with triple-negative phenotype, higher histological grade, and poor prognosis. 2, 3

  • CK5/6 expression in breast carcinoma shows significant inverse relationship with estrogen receptor, progesterone receptor, and HER2 expression, and is directly associated with triple-negative phenotype. 2

  • CK5/6 positivity occurs in approximately 22-50% of invasive ductal carcinomas, with expression limited to high-grade tumors. 2, 4

Prognostic Implications in Breast Cancer

  • CK5/6 expression is an independent predictor of recurrence (HR = 2.99) and death (HR = 3.74) in triple-negative breast cancer patients. 3

  • The marker correlates with increased number of metastatic lymph nodes and represents a poor prognostic group requiring closer surveillance. 3

Important Caveat in Breast Pathology

  • Invasive lobular carcinomas (ILC) do not express CK5/6, with 0% positivity in all subtypes including classic, tubular-lobular, and pleomorphic variants. 5

  • This complete absence of CK5/6 in ILC helps distinguish lobular from ductal carcinomas and indicates that ILC rarely demonstrates a basal phenotype. 5

Technical Considerations

Antibody Selection

  • The CK5 antibody (clone XM26) alone is more sensitive than CK5/6 (clone D5/16B4) for identifying basal-like breast carcinomas, with 97% sensitivity versus 59% for CK5/6. 6

  • When CK5 is positive, it shows significantly higher percentage and intensity of staining compared to CK5/6 (P = 0.0001). 6

Interpretation in Benign vs Malignant Breast Lesions

  • All benign breast lesions show positive CK5/6 immunoreaction in myoepithelial cells (staining index 6-9), which helps distinguish them from malignant lesions. 4

  • In malignant breast lesions, CK5/6 staining is only cytoplasmic and significantly less intense than in benign lesions, appearing only in grade III invasive ductal carcinomas (staining index 2-6). 4

  • Ductal carcinoma in situ (DCIS) shows no CK5/6 immunoreaction, which can help distinguish it from benign proliferative lesions. 4

Clinical Utility in Cancer of Unknown Primary

  • CK5/6 should be used as part of a targeted immunohistochemical panel rather than extensive marker studies, as recommended for occult primary workup. 1

  • The marker is particularly valuable when combined with CK7/CK20 patterns to narrow differential diagnosis in metastatic carcinomas. 1

  • In brain metastases from unknown primary, CK5/6 positivity in urothelial/transitional cell carcinoma is accompanied by Uroplakin-II, p40, p63, and GATA-3 positivity. 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

4
Research

Cytokeratin 5/6 expression in benign and malignant breast lesions.

Indian journal of pathology & microbiology, 2010

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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