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

Cosima Völkel,Noémi De Wispelaere,Katharina Möller,Sören Weidemann,Frank Jacobsen,Martina Kluth,Andreas Marx ,Natalia Gorbokon,Ronald Simon,Stefan Steurer,Andreas M Luebke,Rainer Krech ,Christian Bernreuther,Eike Burandt,David Dum,Waldemar Wilczak,Claudia Hube‐Magg ,Till Krech,Ria Uhlig,Christoph Fraune,Sarah Minner,Maximilian Lennartz,Till S Clauditz,Guido Sauter,Patrick Lebok,Anne Menz

doi:10.1007/s00428-021-03204-4

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.

Highlights

Cytokeratins 5 and 6 are basic type II cytokeratins which are not functionally related [1]
A total of 12,525 (78.5%) of 15,966 tumor samples were interpretable for Cytokeratin 5 (CK5) and 12,898 (80.8%) of 15,966 tumor samples were interpretable for cytokeratin 6 (CK6) in this tissue microarray (TMA) analysis
The data collected in this study suggest a superior diagnostic utility of monospecific CK5 or CK6 antibodies for immunohistochemical analysis as compared to bispecific CK5/6 antibodies

Summary

Introduction

Cytokeratins 5 and 6 are basic type II cytokeratins which are not functionally related [1]. CK5/6 immunostaining has been proposed to have prognostic utility in triplenegative breast cancer [7,8,9], urothelial carcinoma [10,11,12], and other tumors [13,14,15]. CK5 positivity has been described in 13.6 to 91% of bladder carcinomas [11, 16], 2.5 to 100% of breast carcinomas [17, 18], 59.5 to 100% of head and neck carcinoma [14, 19], 0 to 100% of lung carcinomas [20,21,22,23,24,25] and 74.8 to 93.8% of mesothelioma carcinomas [26,27,28]. Even less is known about CK6 positivity alone, which has been reported to occur in 18% of endometrial stromal sarcomas [29], 28% of gastric cancers [30], 38% of basal cell carcinomas of the skin [31], and 100% of squamous cell cancers of the head and neck [32, 33]

Methods

Results

Conclusion