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. 2021 Feb 15;27(1):16.
doi: 10.1186/s10020-021-00274-7.

Diagnostic and prognostic impact of cytokeratin 18 expression in human tumors: a tissue microarray study on 11,952 tumors

Anne Menz  1 , Timo Weitbrecht  1 , Natalia Gorbokon  1 , Franziska Büscheck  1 , Andreas M Luebke  1 , Martina Kluth  1 , Claudia Hube-Magg  1 , Andrea Hinsch  1 , Doris Höflmayer  1 , Sören Weidemann  1 , Christoph Fraune  1 , Katharina Möller  1 , Christian Bernreuther  1 , Patrick Lebok  1 , Till Clauditz  1 , Guido Sauter  1 , Ria Uhlig  1 , Waldemar Wilczak  1 , Stefan Steurer  1 , Sarah Minner  1 , Eike Burandt  1 , Rainer Krech  2 , David Dum  1 , Till Krech  1   2 , Andreas Marx  1   3 , Ronald Simon  4
Affiliations

Diagnostic and prognostic impact of cytokeratin 18 expression in human tumors: a tissue microarray study on 11,952 tumors

Anne Menz et al. Mol Med. .

Abstract

Background: Cytokeratin 18 (CK18) is an intermediate filament protein of the cytokeratin acidic type I group and is primarily expressed in single-layered or "simple" epithelial tissues and carcinomas of different origin.

Methods: To systematically determine CK18 expression in normal and cancerous tissues, 11,952 tumor samples from 115 different tumor types and subtypes (including carcinomas, mesenchymal and biphasic tumors) as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format.

Results: CK18 was expressed in normal epithelial cells of most organs but absent in normal squamous epithelium. At least an occasional weak CK18 positivity was seen in 90 of 115 (78.3%) tumor types. Wide-spread CK18 positivity was seen in 37 (31.9%) of tumor entities, including adenocarcinomas of the lung, prostate, colon and pancreas as well as ovarian cancer. Tumor categories with variable CK18 immunostaining included cancer types arising from CK18 positive precursor cells but show CK18 downregulation in a fraction of cases, tumor types arising from CK18 negative precursor cells occasionally exhibiting CK18 neo-expression, tumors derived from normal tissues with variable CK18 expression, and tumors with a mixed differentiation. CK18 downregulation was for example seen in renal cell cancers and breast cancers, whereas CK18 neo-expression was found in squamous cell carcinomas of various origins. Down-regulation of CK18 in invasive breast carcinomas of no special type and clear cell renal cell carcinomas (ccRCC) was related to adverse tumor features in both tumors (p ≤ 0.0001) and poor patient prognosis in ccRCC (p = 0.0088). Up-regulation of CK18 in squamous cell carcinomas was linked to high grade and lymph node metastasis (p < 0.05). In summary, CK18 is consistently expressed in various epithelial cancers, especially adenocarcinomas.

Conclusions: Down-regulation or loss of CK18 expression in cancers arising from CK18 positive tissues as well as CK18 neo-expression in cancers originating from CK18 negative tissues is linked to cancer progression and may reflect tumor dedifferentiation.

Keywords: Cytokeratin 18 (CK18); Immunohistochemistry; Tissue microarray.

PubMed Disclaimer

Conflict of interest statement

The Institute of Pathology of the UKE receives royalties on the sale of CK18 clone MSVA-118 from MS Validated Antibodies GmbH (owned by a family member of GS).

Figures

Fig. 1
Fig. 1
Cytokeratin 18 (CK18) expression in normal tissues. The images show strong CK18 staining in epithelial cells from rectum (a) and pancreas (b), a zonal staining variability in the liver (c), strongly positive umbrella cells and a gradually decreasing staining intensity from superficial to basal urothelial cells in the bladder (d), strong positivity in acinus cells but absent staining in basal cells of the breast epithelium (e) and a complete lack of staining in squamous epithelium of the oral mucosa (f)
Fig. 2
Fig. 2
Cytokeratin 18 (CK18) expression in tumors. The images show diffuse strong CK18 staining in a colorectal carcinoma (a), an invasive breast carcinoma of no special type (b), a clear cell carcinoma of the kidney (c), and a squamous cell carcinoma of the cervix uteri (d). CK18 immunostaining is focal in a squamous cell carcinoma of the larynx (e) and absent in another renal cell  clear cell carcinoma (f)
Fig. 3
Fig. 3
Ranking order of Cytokeratin 18 (CK18) immunostaining in cancers. Both the frequency of positive cases (blue dots) and the frequency of strongly positive cases (orange dots) are shown. The conspicuously low rate of strongly positive Whartin tumors is due to the fact, that only basal cells react with CK18 resulting in a low overall percentage of positive cells. 25 additional tumor entities without any CK18 positive cases are not shown due to space restrictions
Fig. 4
Fig. 4
Cytokeratin 18 (CK18) immunostaining and patient prognosis. All bladder cancer patients had at least pT2 cancers and were treated by cystectomy
Fig. 5
Fig. 5
Graphical comparison of Cytokeratin 18 (CK18)  data from this study (x) in comparison with the previous literature. Orange dots are used for studies involving ≤ 20 cases, green dots are used for studies > 20 cases, blue dots are from Chu and Weiss 2002 (Review) (Chu and Weiss 2002). All studies are quoted in the list of references
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