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.