Colorectal carcinoma (CRC) is associated with significant morbidity and mortality worldwide. Cytokeratins (CKs) are widely expressed in various types of carcinomas, whereas in CRC it is usually CK7 - and CK20 + . A subset of CRCs is CK7 + . This study aims to determine the prevalence of CK7 expression in CRC and its impact on overall survival. We analyzed 300 randomly selected surgically treated CRC cases using paraffin embedded tumor tissue samples and evaluated CK7 and CK20 expression using the tissue microarray method. Tumors with positivity > 10% and > 25% of tumor cells were considered CK7 and CK20 positive, respectively. Expression of both CKs and several clinical-pathological variables (stage, grade, laterality, mismatch-repair/MMR status) were evaluated using patient follow up data (Kaplan-Meier analysis of cancer-specific survival (CSS)). Significant results include shorter CSS (restricted mean 4.98 vs. 7.74 years, P = 0.007) and 5-year survival (29.4% vs. 64.6%, P = 0.0221) in CK7 + tumors compared to CK7 - tumors, respectively; without significant association with grade, stage or right-sided location. These results were significant in a multivariate analysis. CK20 + tumors are more frequently MMR-proficient and left-sided. MMR-deficient tumors are more frequently right-sided and had longer survival. CK7 expression, right-sided location (rmean CSS 6.83 vs. 8.0 years, P = 0.043), MMR-proficiency (rmean CSS 7.41 vs. 9.32 years, P = 0.012), and UICC stages III + IV (rmean CSS 6.03 vs. 8.92 years, P < 0.001) of the tumor correlated with negative prognostic outcomes, whereas the most significant results concern stage and CK7 positivity. The result concerning negative prognostic role of CK7 differs from those obtained by several previous studies focused on this topic.

Department of Anaesthesia and Intensive Care Medicine 3rd Faculty of Medicine Charles University University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine Charles University University Hospital Kralovske Vinohrady Ruská 87 100 00 Praha 10 Prague Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University Thomayer University Hospital Prague Czech Republic

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Siegal R, Miller KD, Jemal A. Cancer statistics, 2012. Can. Cancer J. Clin. 2014;64:9–29. doi: 10.3322/caac.21208. PubMed DOI

Cronin KA, et al. Annual report to the nation on the status of cancer, part I: national cancer statistics. Cancer. 2018;124:2785–2800. doi: 10.1002/cncr.31551. PubMed DOI PMC

Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982;31:11–24. doi: 10.1016/0092-8674(82)90400-7. PubMed DOI

Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod. Pathol. 2000;13:962–972. doi: 10.1038/modpathol.3880175. PubMed DOI

Al-Maghrabi J, Emam E, Gomaa W. Immunohistochemical staining of cytokeratin 20 and cytokeratin 7 in colorectal carcinomas: four different immunostaining profiles. Saudi J. Gastroenterol. 2018;24:129–134. doi: 10.4103/sjg.SJG_465_17. PubMed DOI PMC

Bayrak R, Yenidünya S, Haltas H. Cytokeratin 7 and cytokeratin 20 expression in colorectal adenocarcinomas. Pathol. Res. Pract. 2011;207:156–160. doi: 10.1016/j.prp.2010.12.005. PubMed DOI

Bayrak R, Haltas H, Yenidunya S. The value of CDX2 and cytokeratins 7 and 20 expression in differentiating colorectal adenocarcinomas from extraintestinal gastrointestinal adenocarcinomas: cytokeratin 7-/20+ phenotype is more specific than CDX2 antibody. Diagn. Pathol. 2012;7:9. doi: 10.1186/1746-1596-7-9. PubMed DOI PMC

Gurzu S, Jung I. Aberrant pattern of the cytokeratin 7/cytokeratin 20 immunophenotype in colorectal adenocarcinomas with BRAF mutations. Pathol. Res. Pract. 2012;208:163–166. doi: 10.1016/j.prp.2012.01.003. PubMed DOI

Harbaum L, et al. Keratin 7 expression in colorectal cancer–freak of nature or significant finding? Histopathology. 2011;59:225–234. doi: 10.1111/j.1365-2559.2011.03694.x. PubMed DOI

Hernandez BY, et al. CK20 and CK7 protein expression in colorectal cancer: demonstration of the utility of a population-based tissue microarray. Hum. Pathol. 2005;36:275–281. doi: 10.1016/j.humpath.2005.01.013. PubMed DOI

Kummar S, Fogarasi M, Canova A, Mota A, Ciesielski T. Cytokeratin 7 and 20 staining for the diagnosis of lung and colorectal adenocarcinoma. Br. J. Cancer. 2002;86:1884–1887. doi: 10.1038/sj.bjc.6600326. PubMed DOI PMC

Landau MS, Kuan SF, Chiosea S, Pai RK. BRAF-mutated microsatellite stable colorectal carcinoma: an aggressive adenocarcinoma with reduced CDX2 and increased cytokeratin 7 immunohistochemical expression. Hum. Pathol. 2014;45:1704–1712. doi: 10.1016/j.humpath.2014.04.008. PubMed DOI

Loupakis F, et al. CK7 and consensus molecular subtypes as major prognosticators in V600EBRAF mutated metastatic colorectal cancer. Br. J. Cancer. 2019;121:593–599. doi: 10.1038/s41416-019-0560-0. PubMed DOI PMC

Lugli A, Tzankov A, Zlobec I, Terracciano LM. Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status. Mod. Pathol. 2008;21:1403–1412. doi: 10.1038/modpathol.2008.117. PubMed DOI

McGregor DK, Wu TT, Rashid A, Luthra R, Hamilton SR. Reduced expression of cytokeratin 20 in colorectal carcinomas with high levels of microsatellite instability. Am. J. Surg. Pathol. 2004;28:712–718. doi: 10.1097/01.pas.0000126757.58474.12. PubMed DOI

Park SY, Kim HS, Hong EK, Kim WH. Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary. Hum. Pathol. 2002;33:1078–1085. doi: 10.1053/hupa.2002.129422. PubMed DOI

Saad RS, Silverman JF, Khalifa MA, Rowsell C. CDX2, cytokeratins 7 and 20 immunoreactivity in rectal adenocarcinoma. Appl. Immunohistochem Mol. Morphol. 2009;17:196–201. doi: 10.1097/PAI.0b013e31819268f2. PubMed DOI

Yamagishi H, et al. Aberrant cytokeratin expression as a possible prognostic predictor in poorly differentiated colorectal carcinoma. J. Gastroenterol. Hepatol. 2013;28:1815–1822. doi: 10.1111/jgh.12319. PubMed DOI

Zhang PJ, Shah M, Spiegel GW, Brooks JJ. Cytokeratin 7 immunoreactivity in rectal adenocarcinomas. Appl. Immunohistochem Mol. Morphol. 2003;11:306–310. doi: 10.1097/00129039-200312000-00005. PubMed DOI

Droy-Dupré L, et al. Hierarchical clustering identifies a subgroup of colonic adenocarcinomas expressing crypt-like differentiation markers, associated with MSS status and better prognosis. Virchows Arch. 2015;466:383–391. doi: 10.1007/s00428-015-1724-9. PubMed DOI

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. Can. Cancer J. Clin. 2014;64:9–29. doi: 10.3322/caac.21208. PubMed DOI

Brierley, J. D., Gospodarowicz, M. K., Wittekind, C. TNM Classification of Malignant Tumors, 8th edition. 73–76 (Wiley Blackwell, 2017).

R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/ (2019).

Therneau, T. A Package for Survival Analysis in R. version 3.1–7, https://CRAN.R-project.org/package=survival (2015).

Fei F, et al. CK7 expression associates with the location, differentiation, lymph node metastasis, and the Dukes’ stage of primary colorectal cancers. J. Cancer. 2019;10:2510–2519. doi: 10.7150/jca.29397. PubMed DOI PMC

Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr. Treat Options Oncol. 2015;16:30. doi: 10.1007/s11864-015-0348-2. PubMed DOI PMC

Jourdan F, et al. Tissue microarray technology: validation in colorectal carcinoma and analysis of p53, hMLH1, and hMSH2 immunohistochemical expression. Virchows Arch. 2003;443:115–121. doi: 10.1007/s00428-003-0833-z. PubMed DOI

Lin HT, et al. Epidemiology and survival outcomes of lung cancer: a population-based study. Biomed. Res. Int. 2019;2019:8148156. PubMed PMC

Mäkinen JM, et al. Nonpredominant lepidic pattern correlates with better outcome in invasive lung adenocarcinoma. Lung Cancer. 2015;90:568–574. doi: 10.1016/j.lungcan.2015.10.014. PubMed DOI

Jiang, N., & Xu, X. Exploring the survival prognosis of lung adenocarcinoma based on the cancer genome atlas database using artificial neural network. Medicine (Baltimore). 98, e15642 (2019). PubMed PMC

Warth A, et al. Prognostic impact and clinicopathological correlations of the cribriform pattern in pulmonary adenocarcinoma. J. Thorac. Oncol. 2015;10:638–644. doi: 10.1097/JTO.0000000000000490. PubMed DOI

Hase K, Shatney C, Johnson D, Trollope M, Vierra M. Prognostic value of tumor "budding" in patients with colorectal cancer. Dis. Colon Rectum. 1993;36:627–635. doi: 10.1007/BF02238588. PubMed DOI

Fei F, et al. The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer. J. Exp. Clin. Cancer Res. 2015;34:158. doi: 10.1186/s13046-015-0277-8. PubMed DOI PMC

Lv H, et al. Polyploid giant cancer cells with budding and the expression of cyclin E, S-phase kinase-associated protein 2, stathmin associated with the grading and metastasis in serous ovarian tumor. BMC Cancer. 2014;14:576. doi: 10.1186/1471-2407-14-576. PubMed DOI PMC

Kirchner T, et al. Metaplasia, intraepithelial neoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis. Virchows Arch. 2001;439:512–522. doi: 10.1007/s004280100477. PubMed DOI

Ormsby AH, et al. Cytokeratin immunoreactivity patterns in the diagnosis of short-segment Barrett’s esophagus. Gastroenterology. 2000;119:683–690. doi: 10.1053/gast.2000.16482. PubMed DOI

Lechene de la Porte P, et al. Involvement of tubular complexes in pancreatic regeneration after acute necrohemorrhagic pancreatitis. Pancreas6, 298–306 (1991). PubMed

Blaheta RA, et al Dedifferentiation of human hepatocytes by extracellular matrix proteins in vitro: quantitative and qualitative investigation of cytokeratin 7, 8, 18, 19 and vimentin filaments. J. Hepatol.28, 677–690 (1998). PubMed

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