Renal cell carcinoma (RCC) represents a rather rare cancer with about 71,000 newly diagnosed cases per year in Europe. Approximately 31,000 of these patients die because of RCC 1 . The RCCs are devided in different histological subtypes, of which the group of papillary RCC compromise less than 10% of all RCC 2 . Based on histological criterias type I and type II papillary RCCs can be distinguished: Type I papillary RCCs show papillae covered by a single layer of cuboidal cells with a small cytoplasmic rim; furthermore, type I tumors are often infiltrated by numerous foamy macrophages. Type II tumors also form papillae covered by a monolayer of tumor cells; in contrast to type I papillary RCC these tumor cells display higher nuclear polymorphism with pseudostratification and abundant mostly eosinophilic cytoplasm; foamy macrophages, however, are rarely seen in type II papillary RCCs 3 . As typical chromosomal changes the loss of Y chromosome or significantly higher numbers of gains of 7p, 17p, and 17q were demonstrated in papillary RCCs 4 5 . Klatte et al. 6 could show a loss of 1p, loss of 3p, and a gain of 5q exclusively in type II papillary RCC by cytogenetic analyses. The subdivision of papillary RCC into two subtypes is important, because type II papillary RCC shows a shorter survival rate because of its higher grade of malignancy and progressed stage at the time of diagnosis 7 8 9 .

Cadherins are transmembrane glycoproteins and play a role in Ca²⁺-dependent cell-cell contacts especially in adherent junctions and in the development of different organs 10 11 . They are also involved in genesis of tumors and act as metastasis suppressing proteins 12 . A decreased cadherin expression is normally found in cancers and is associated with increased metastatic potential. This could be shown in breast cancer for the extensively studied E-cadherin 13 . Current investigations showed a worse prognosis for tumors with a non tissue specific cadherin expression 14 . In the present study the expression of N-, E-, P-, and KSP-cadherin in both subtypes of papillary RCC were examined in order to find diagnostically relevant differences.

Immunohistochemical examinations revealed a membranous positivity for N-cadherin in all papillary RCC type II (IRS 6.28 ± 1.57), whereas type I did not show any membranous positivity for N-cadherin (IRS 0). In contrast to the membranous N-cadherin expression the cytoplasmic expression of N-cadherin showed a higher score in papillary RCC type I (IRS 5.68 ± 1.76) than in type II (IRS 2.5 ± 2.0); cytoplasmic N-cadherin was particularly detectable in the apical and basolateral parts of the tumorcells. The comparison between both subtypes of papillary RCC for cytoplasmic N-cadherin showed a significant difference (P < 0.0032) (Figure 1A-D and Figure 2).

The E-cadherin staining showed in the majority of papillary RCC type II a weak membranous (IRS 1.83 ± 2.72) as well as cytoplasmic expression (IRS 1.89 ± 2.49). In papillary RCC type I a decreased expression of membranous (IRS 1.28 ± 1.95) and an approximately similar cytoplasmic E-cadherin (IRS 1.81 ± 1.94) could be determined. A statistical comparison showed no significant difference for membranous as well as cytoplasmic E-cadherin expression in both subtypes of papillary RCC (p = n. s.) (Figure 3A, D and Figure 2).

A weak membranous expression of P-cadherin could be demonstrated for type I (IRS 0.54 ± 1.79) and type II (IRS 0.83 ± 1.38) papillary RCC without significant differences (p = n .s.). The investigation of cytoplasmic P-cadherin demonstrated an almost equal expression in type II and type I papillary RCC (IRS 2.27 ± 2.86 vs. 2.22 ± 1.97) (Figure 3B, E and Figure 2).

A membranous KSP-cadherin expression could only be demonstrated in some cases of papillary RCC type II (IRS 0.83 ± 1.65) and papillary RCC type I (IRS 0.73 ± 1.61). Cytoplasmic KSP-cadherin was only weakly expressed in papillary RCC type II (IRS 2.17 ± 2.71) as well as type I (IRS 2.36 ± 2.44). The statistical analysis showed no significant differences for membranous and cytoplasmic KSP-cadherin expression in both subtypes of papillary RCC (p = n. s.) (Figure 3C, F and Figure 2).

A correlation of cadherin expression with tumor grade or tumor stage could not be observed.

Normal kidney tissue showed an irregular weak to intermediate cytoplasmic expression of the investigated cadherins in proximal and distal tubular. A membranous expression of cadherins could not be observed at all.

Papillary RCC represents a subtype of RCC with a typical morphology and typical characteristic genetic aberrations 3 6 . Several investigations could define a prognostic relevant subdivision into type I and type II papillary RCC 7 8 9 . This subdivision can so far only be done by morphological criteria 16 17 . Several immunohistochemical markers were applied to find any useful differentiation criteria between the two subtypes. Cytokeratin-7 could be etablished as a helpful marker, because it is detectable in more than 80% of type I tumors, whereas type II papillary RCC in only 20% express cytokeratin-7 3 18 . Perret et al. could demonstrate a significant higher MUC-1 expression in type I papillary RCC 19 . Zhou et al. 20 described that E-cadherin could help to distinguish between type I and type II of papillary RCC. Other typical antigens for renal neoplasm such as CD10 were also investigated but did not show any significant differences 21 22 . N-cadherin, primarily described as A-CAM, was shown to be expressed by normal renal epithelium 23 24 . Furthermore Markovic-Lipovski et al. could show an expression of N-cadherin in different types of RCC, but they did not analyse papillary RCC 25 .

We investigated the expression of four different cadherins in type I and type II papillary RCC. It could be demonstrated that all investigated papillary RCC type II showed a membranous expression of N-cadherin, whereas type I did not show any membranous N-cadherin. In contrast, type I papillary RCC showed a significant higher cytoplasmic expression for N-cadherin compared to type II. Cadherins are transmembrane glycoproteins, which act as cell-cell contacts and in signal transduction. Only if the cadherins are localized in the membrane, these functions can be executed 26 . Therefore the observed cytoplasmic cadherin expression must be accompanied by a loss function. N-cadherin is normally expressed in neuronal tissue and plays a key role in organ development 27 . An non tissue specific expression of N-cadherin as found for papillary RCC type II could be shown to induce cell migration, metastases, and invasion especially in breast cancer 14 . This process is also known as epithelial-mesenchymal transition (EMT) and it plays a crucial role in embryonic development 28 . In tumors this transition promotes the mobility and invasive capacity of tumor cells and it is associated with a progression of tumor disease 29 30 . In addition EMT is connected with cancer stem cell-like features, which include the development of resistances to chemotherapy 31 32 .

These observations are well in line with the worse behaviour of papillary RCC type II in comparison to type I as previously described 7 8 9 . For different other tumors it could also be shown that not only the non tissue specific expression of N-cadherin but also the switch from different cadherins to N-cadherin is associated with a worse prognosis 33 34 . In addition the activation of the PI-3 kinase / Akt Pathway induced by N-cadherin could be demonstrated as a survival mechanism for lung cancer 35 .

Our data show a higher expression of E-cadherin in papillary RCC type II. It is widely accepted that an increased expression of E-cadherin in cancer is associated with a better outcome and a decrease occurrence of metastases 13 ; in ovarian carcinoma lower E-cadherin seems to influence the transition from normal ovarian surface epithelium to ovarian cancer 36 . The investigation of KSP-cadherin showed only a weak membranous and cytoplasmic expression in both subtypes of papillary RCC. These findings for KSP-cadherin correlate with those of other working groups 37 . P-cadherin expression which plays an important role in ovarian cancer also in case of cadherin switch 38 did not show a prominent expression in papillary RCC.

In conclusion, N–cadherin could be established as the first immunohistological marker for a clear cut differentiation between papillary RCC subtype I and II. Furthermore, the data implicate that cadherins especially N-cadherin and the involved pathway via p120 catenin, which is used by most cadherins, could play a pivotal role for the therapy of RCC as already shown for other neoplasias 39 40 41 .

The authors declare that they have no competing interests.

CLB constructed the manuscript and carried out pathological examination. BH participated in pathological investigations. AS was responsible for the clinical data. HJR and FB were responsible for critical revision of the manuscript and have been involved in drafting it. All authors read and approved the final manuscript.