Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications

Our plain-English summary of Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications, by C. Völkel, N. De Wispelaere, S. Weidemann, et al (Virchows Archiv, 2022).

The study

• Authors: C. Völkel, N. De Wispelaere, S. Weidemann, N. Gorbokon, M. Lennartz, A.M. Luebke, C. Hube-Magg, M. Kluth, C. Fraune, K. Möller, C. Bernreuther, P. Lebok, T.S. Clauditz, F. Jacobsen, G. Sauter, R. Uhlig, W. Wilczak, S. Steurer, S. Minner, R.H. Krech, D. Dum, T. Krech, A.H. Marx, R. Simon, E. Burandt, A. Menz
• Journal: Virchows Archiv
• Published: 2022;480(2):433-447
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cytokeratins (CKs) 5 and 6 are functionally unrelated but often analyzed together using bispecific antibodies in diagnostic immunohistochemistry. To better understand the diagnostic utility of CK5 or CK6 alone, tissue microarrays with > 15,000 samples from 120 different tumor types as well as 608 samples of 76 different normal tissues were analyzed by immunohistochemistry. In normal tissues, both CKs occurred in the squamous epithelium; CK5 dominated in basal and CK6 in suprabasal layers. CK5 (not CK6) stained basal cells in various other organs. Within tumors, both CK5 and CK6 were seen in > 95% of squamous cell carcinomas, but other tumor entities showed different results: CK5 predominated in urothelial carcinoma and mesothelioma, but CK6 in adenocarcinomas. Joint analysis of both CK5 and CK6 obscured the discrimination of epithelioid mesothelioma (100% positive for CK5 alone and for CK5/6) from adenocarcinoma of the lung (12.8% positive for CK5 alone; 23.7% positive for CK5/6). CK5 and CK6 expressions were both linked to high grade, estrogen receptor, and progesterone receptor negativity in breast cancer (p < 0.0001 each), grade/stage progression in urothelial cancer (p < 0.0001), and RAS mutations in colorectal cancer (p < 0.01). Useful diagnostic properties which are commonly attributed to CK5/6 antibodies such as basal cell staining in the prostate, distinction of adenocarcinoma of the lung from squamous cell carcinoma and epithelioid mesothelioma, and identification of basal-type features in urothelial cancer are solely driven by CK5. At least for the purpose of distinguishing thoracic tumors, monospecific CK5 antibodies may be better suited than bispecific CK5/6 antibodies.

© 2021. The Author(s).

In plain English

This laboratory pathology study did not examine asbestos exposure. It looked at how two proteins, cytokeratin 5 (CK5) and cytokeratin 6 (CK6), appear when tissue is stained, because many diagnostic tests use one antibody that detects both together (called CK5/6). The authors stained tissue arrays from pathology archives in Hamburg, Osnabrueck and Fuerth, Germany. The arrays held 15,966 tumors of 120 types and 608 normal tissue samples. Of these tumors, 12,525 could be read for CK5 and 12,898 for CK6. In normal squamous epithelium, CK6 was strongest in the upper layers, and basal cells were negative or only weakly stained. Both proteins appeared in more than 95% of squamous cell carcinomas. CK5 predominated in mesothelioma, while CK6 predominated in various adenocarcinomas. Epithelioid mesotheliomas were 100% positive whether CK5 alone or CK5 and CK6 together were used. Lung adenocarcinomas, however, rose from 12.8% positive with CK5 alone to 23.7% with either protein, which made the tumors harder to tell apart. The authors concluded that, at least for chest tumors, antibodies detecting CK5 alone may be better suited than combined CK5/6 antibodies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory immunohistochemistry study of archived tissue samples arranged in tissue microarrays
• Who was studied: 15,966 primary tumors from 120 tumor types and subtypes, plus 608 normal tissue samples (8 donors for each of 76 normal tissue types), from pathology archives in Hamburg, Osnabrueck and Fuerth, Germany; collection dates not stated
• Exposure: No asbestos or other environmental or occupational exposure was studied; the study measured staining of tissue for the proteins CK5 and CK6 using separate antibodies
• Main results:
  • Of 15,966 tumor samples, 12,525 (78.5%) were interpretable for CK5 and 12,898 (80.8%) for CK6
  • In normal squamous epithelium, CK6 staining was most intense in the upper (suprabasal) layers, while basal cells were negative or weakly stained; CK5 stained mainly basal cells
  • Both CK5 and CK6 stained more than 95% of squamous cell carcinomas from various sites
  • CK5 was the predominant stain in mesothelioma, basal cell carcinoma of the skin, urothelial carcinoma, thymoma and salivary gland tumors; CK6 predominated in various adenocarcinomas
  • In chest tumors, lung adenocarcinomas were 12.8% positive with CK5 alone and 23.7% positive for CK5 and/or CK6; squamous cell carcinomas and epithelioid mesotheliomas were 100% positive either way
  • Table 1 lists 39 epithelioid mesotheliomas on the arrays, of which 17 were analyzable for both CK5 and CK6
  • Both CK5 and CK6 were statistically linked to high grade, estrogen and progesterone receptor negativity and triple negativity in breast cancer (p < 0.0001 each), grade/stage progression in urothelial cancer (p < 0.0001), and RAS mutations in colorectal cancer (p < 0.01)
  • CK5 was also associated with lymph node metastasis in urothelial cancer (p = 0.0007)
  • CK5 and CK6 status was not related to overall survival in breast cancer patients
• The authors' conclusion: The authors concluded that, especially for chest (thoracic) tumors, analyzing CK5 alone appears advantageous, and that monospecific CK5 antibodies may be better suited than bispecific CK5/6 antibodies in diagnostic immunohistochemistry

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunohistochemistry, Epithelium, Squamous Cell Carcinoma, Carcinoma, Mesothelioma, Adenocarcinoma, Epithelioid, Colorectal Cancer.

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