BMC Cancer 2006, 6:10 http://www.biomedcentral.com/1471-2407/6/10 Nodal negative OSCCs Cytokeratin 8/18 expression p<0.04 Ck 8/18 negative Ck 8/18 postive 0 20 40 60 80 Overall survival time (month) 100 scFOieoivgllneucrcraaerllccs4iunuloravmteivadalibnoyfdtpehpaeteiKnendatepnlwacniet-hMonneoieCdraylmtoneketegharotaidtvien o8r–a1l8sqeuxapmreosu-s Overall survival of patient with nodal negative oral squamous cell carcinoma in dependence on Cytokeratin 8–18 expres- sion calculated by the Kaplan-Meier method. typically characterized by the expression of Ck 5. Adult healthy non-keratinizing stratified squamous epithelium of the upper aerodigestive tract express Ck 19 in basal lay- ers but normally do not express Ck 8/18 [19]. Typical glandular cytokeratin Ck 8/18 are normally not expressed in SCC's [2,4]. On the other hand, Ck 8 and 18 is expressed in fetal buccal mucosa and tongue epithelium till 27 weeks of gestation [20]. Our study shows in a series of more than 300, uniformly treated, primary SCC's of the oral cavity that the expres- P valuea *0.036 *0.000 0.350 0.931 0.852 0.227 0.470 *0.024 RRb 1.239 1.866 1.167 0.985 0.968 1.163 0.872 1.487 a The partially nonparametric regression model of Cox (1972) was used to evaluate the predictive power of vatious combinations of prognosticators in a multivariate manner. b RR, relative risk c 95% confidence interval 1,0 s e i t lii0,8 b a b o r lp0,6 a v i v r u0,4 s e v i t a lu0,2 m u c 0,0 Prognosticator Tumor size Nodal status CK5/6 CK1 CK10 CK19 CK14 CK8/18 Table 5: Multivariate analysis of the time of survival in relation to the Cytokeratins expression and other prognostic factors sion of glandular cytokeratins such as Ck 8, 18 and 19, pinpoints a significant subgroup of SCC's. These carcino- mas were associated with a poor prognosis, independ- ently of the primary, preoperative lymph node status. It is important to stress that this held also true in multivariate analysis. This might be surprising on a first glance, since recent other clinico-pathological studies in SCC's of the oral cavity, especially with the focus on Ck 19 revealed inhomogeneous results [21-24]. This might on the one hand be due to significantly lower numbers of investi- gated tumour samples, and on the other hand caused by different techniques for the determination for the expres- sion of cytokeratins 8/18 and 19 on the RNA and protein level. However, similar results to our findings have also been reported for skin carcinomas. Nevertheless, recent cell culture and studies with chemical carcinogens strongly support our results and revealed an important role of CK 8/18 in various steps of the pathogenesis and progression of SCC's. A spontaneous induction of Ck's 8 and 18 expression could be shown in SV40T-immortal- ized buccal mucosa cells, in tobacco induced leukoplakias and after introduction of v-H-Ras in epidermal mouse keratinocytes [25]. The transfection of buccal mucosa cells with a vector for Ck 8/18 resulted additionally in a signif- icantly altered cellular morphology and increased cell motility – features associated with or being prerequisites for invasive tumour behaviour [10]. This was in line with previous experiments in melanoma cells [26]. The involvement of Ck 8/18 in SCC progression could further be demonstrated in chemically induced SCC's in the mouse skin. Whereas SCC's in mouse epidermis were Ck 8/18 positive, non-invasive papillomas did not show this feature. However, the underlying disturbed intra- and extra cellular regulation mechanisms have been character- ized not in detail yet. A central role for TGF-alpha via the Epidermal Growth Factor Receptor (EGFR) has been pos- tulated [27,28]. In contrast, the induction of Ck 8/18 expression in a similar experimental setting has also been described for TGF-alpha deficient mice, with putative involvement of H-Ras [29]. In consequence, multiple Confidance intervalc 1.0–1.5 1.4–2.4 0.8–1.6 0.7–1.4 0.7–1.4 0.9–1.5 0.6–1.3 1.1–2.1 Page 6 of 8 (page number not for citation purposes)