Transrectal core biopsy, the main diagnostic tool for PC, has certain limitations due to small specimen size and frequent mechanical distortion of tissue. Further-more histological similarities between adenocarcinoma and benign glandular components may sometimes be quite challenging even for experienced uropathologists. For these reasons IHC markers have great value in the diagnosis of PC. AMACR is a widely used IHC marker which is known to be positive in PC. On the other hand, while sensitivity of AMACR was reported at a range of 62-100%, AMACR is also known to be expressed by some other entities (eg. AG, AH). Furt-hermore the knowledge of AMACR negative adeno-carcinomas including some rare types makes its interpretation further complicated
18-22.
In this study we aimed to investigate Claudin-3 expressions in prostate tissue and evaluate its utility as a diagnostic marker for PC. For this purpose we compared Claudin-3 expressions with those of AMACR in each group (PC, HGPIN and BG). In our study the sensitivity of AMACR for PC was calculated as 77.4% with 94.8% positive predictive value (ppv) and 82.85 negative predictive value (npv). This rate was within the range indicated by other studies. The statistical analysis demonstrated a significant difference between PC and BG in terms of AMACR positivities. The difference in AMACR profiles of HGST and LGST was not statistically analysed. For BG and HGPIN on the other hand, positivity rates were 7% and 40% respectively and for HGPIN this rate was slightly lower than the previous reports 16-19. One case of foamy gland carcinoma -a rare subtype of PC- in our study did not stain with AMACR and this finding was also consistent with the previous data.
Molecular studies demonstrated an elevation in Claudin-3 genes in PC 8. Correspondingly, immuno-histochemical studies were also demonstrated an overexpression of Claudin-3 in PC. Bartholow et al. 14 reported Claudin-3 overexpression both in primary and metastatic PC. Vare et al. 16 studied 5 members of Claudin family 1-5 in PC and reported strong overexpression with Claudin-3 in 97% of cases. Furthermore although they found an association between high Gleason score and low Claudin expression (combined expressions of 1, 2, 3, 4, 5), no statistical difference was obtained between the Claudin-3 expressions of high and low Gleason score tumors. In our study the sensitivity of Claudin-3 for PC was 94.1% (ppv: 89.4, npv:74.4). In terms of staining intenstity, 58.8% of positively stained PC had score 2. The difference among Gleason groups was not statistically analysed because of the small size of HGST group. On the other hand Claudin-3 positivity among BG was 14.4% and statistical analysis showed a significant difference between Claudin-3 expressions of PC and BG in terms of both frequency and intensity. None of BG showed moderate to strong positivity. Considering the expressions in HGPIN, the positivity rate was 87.9% and compairing with BG, this was also significantly higher. In the study of Bart-holow et al. 14 PIN (not specified as HGPIN or LGPIN) has also been shown to have higher Claudin-3 expressions with respect to BG.
Claudin-3 versus AMACR. 94.1% of PC showed positivity with Claudin-3 whereas this value was 77.4% for AMACR. Using multiple logistic regression analysis, Claudin-3 appeared as a more reliable marker than AMACR in differentiating PC from BG (p <0.001). This analysis demonstrated a 38.724 times increase in probability of malignancy in case of Claudin-3 positivity. On the other hand, this probability was calculated as 9.006 times in AMACR. Further-more considering the expressions of both antibody in HGPIN, the positivity rate with Claudin-3 was higher than AMACR. Likewise, altough statistical comparison of AMACR expressions in BG and HGPIN did not result in a meaningful difference, Claudin-3 positivity in HGPIN were found to be significantly higher than BG. The positivity of Claudin-3 positivity in a case of foamy gland carcinoma was another notable point in our study since this subtype is known to be AMACR negative.
In summary, although the exact roles of Claudin family proteins in carcinogenesis are still being un-covered, it is clear that they represent promising targets for diagnosis and therapy of cancer. In prostate cancer, overexpression of Claudins, particularly Clau-din-3, was previously reported. But to the best of our knowledge, as being a comperative immunohistochemical study with AMACR, this is the first report revealing the utility of Claudin-3 as an immunohistoc-hemical marker in biopsy diagnosis of prostatic adeno-carcinoma. According to our results, Claudin-3 appeared as a more reliable marker than AMACR in differentiating malignant glands from benign ones. We think that our findings strongly suggest the use of Claudin-3 in needle biopsies of prostate, at least as an alternative for AMACR. Considering the pure cytoplasmic positivity in benign prostate tissue in our study, a strict search for membrane bound staining could aid to reduce false positivities. Future studies with large groups including different subtypes of prostate cancer would be important for the use of Claudin-3 in daily pathology practise.
Acknowledgement
This study was supported by grant from Commission of Scientific Research of Ankara Dışkapı Research and Training Hospital.
Ethical Standards
This study have been approved by the appropriate ethics commitee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.