Alma Demirović

Expression and prognostic role of syndecan-2 in prostate cancer

Syndecans are a four-member family of transmembrane heparan sulphate proteoglycans that have different functions in cell signalling, adhesion, cytoskeleton organization, migration, proliferation, and angiogenesis. Several studies investigated the role of syndecan-2 (SDC2) in different carcinomas; however, only one being focused on SDC2 in prostate cancer. SDC2 expression and relationship with established prognostic features were assessed in a cohort of 86 patients treated with radical prostatectomy for clinically localized prostate adenocarcinoma. SDC2 expression was present in the majority of prostate cancers and absent in only 11.6% of cases. SDC2 expression was also recorded in cells of prostatic intraepithelial neoplasia, whereas normal prostatic epithelial tissue and stroma did not express SDC2. SDC2 overexpression in prostate cancer was significantly associated with established features indicative of worse prognosis such as higher preoperative PSA (P=0.011), higher Gleason score (P<0.001), positive surgical margins (P<0.003), and extraprostatic extension of disease (P<0.003). Moreover, expression of SDC2 was also associated with biochemical disease progression on univariate analysis (P<0.001). Study results supported the potential role of SDC2 in prostatic carcinogenesis and cancer progression. Moreover, SDC2 could serve as an additional prognostic marker that might help in further stratifying the risk of disease progression in patients with prostate cancer.

Prognostic value of connexin43 expression in patients with clinically localized prostate cancer.

Connexins (Cxs) are a family of transmembrane proteins that build cell-to-cell channels in gap junctions. Gap junctions composed of Cxs have an essential role in intercellular communication, adhesion and cell differentiation. Several studies investigated the role of connexin43 (Cx43) in different carcinomas; however, none investigated its prognostic role in prostate cancer. Cx43 expression and relationship with established prognostic features were assessed in a cohort of 102 patients treated with radical prostatectomy for clinically localized prostate adenocarcinoma. Cx43 expression in prostate cancer was significantly associated with established features indicative of worse prognosis, such as follow-up time (P<0.001) and preoperative PSA (P<0.007). Patients with lower Cx43 expressions in tumours have shorter follow-up time, which indicated shorter disease-free survival and higher preoperative PSA values. Furthermore, tumours with positive surgical margins (P<0.001) showed significantly lower Cx43 expression compared with tumours without this feature. In univariate (P<0.001) and multivariate (P=0.014) analyses, decreased Cx43 expression was found to be a significant predictor of biochemical recurrence free-survival. Study results show the association of decreased Cx43 expression with prostate cancer progression. Moreover, Cx43 could serve as an additional prognostic marker and used together with traditional prognostic markers might help in further stratifying the risk of disease progression in patients with prostate cancer.

Intensity of stromal changes predicts biochemical recurrence-free survival in prostatic carcinoma

Abstract Objective. The reactive stroma of prostate cancer contains a mixture of myofibroblasts and fibroblasts, while fully differentiated smooth-muscle cells are very rare or absent. In experimental prostate cancer models, prostatic stromal cells promote angiogenesis and stimulate prostate tumorigenesis. The aim of this study is to analyse whether the intensity of stromal changes can predict survival in patients with prostatic carcinoma. Material and methods. Stromal reaction was quantified histochemically and imunohistochemically in 50 patients treated with radical prostatectomy for clinically localized prostate carcinoma and its relationship with established prognostic factors was assessed. Results. Kaplan–Meier analysis showed a significant association between the pattern of vimentin and desmin expression and the length of disease-free period; patients with a higher vimentin or lower desmin expression had a shorter disease-free period. On multivariate analysis only vimentin expression (odds ratio 4.06, 95% confidence interval 1.01–16.26, p = 0.049) was a significant predictor of biochemical recurrence. In patients with identical Gleason pattern and Gleason score the level of vimentin expression could identify patients with a higher risk of disease recurrence. Conclusions. Intensity of stromal changes could serve as an independent prognostic factor in the assessment of biochemical recurrence-free survival. Among prostate cancer patients with an identical Gleason score, it could identify patients with a higher risk of biochemical recurrence. Thus, stromal changes and their intensity could serve as a novel marker for the recognition of patients with an increased risk of disease recurrence.

Immunohistochemical expression of tumor antigens MAGE-A3/4 and NY-ESO-1 in renal oncocytoma and chromophobe renal cell carcinoma

The distinction between renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC), especially the eosinophilic variant, can often be difficult. Our study has documented for the first time the expression of MAGE-A3/4 and NY-ESO-1 cancer testis antigens (CTAs) in these tumors. A total of 35 patients (17 ROs and 18 ChRCCs) were included in the study. Two antibodies were used for immunohistochemical staining: 57B recognizing multiple MAGE-A and D8.38 recognizing NY-ESO-1 CTAs. Fifteen (88.2%) samples of RO stained positively for both MAGE-A3/4 and NY-ESO-1 antigens. Regarding ChRCC, seven (38.9%) stained positively for MAGE-A3/4 and six (33.3%) for NY-ESO-1 antigens. Median MAGE-A3/4 expression was moderately positive in RO and negative in ChRCC. The difference in MAGE-A3/4 expression between two tumor groups was significant (P=0.0013). Median NY-ESO-1 expression was strongly positive in RO and negative in ChRCC. The difference in NY-ESO-1 expression between two tumor groups was also significant (P=0.0008). Our study has shown that RO had a significantly higher expression of both CTAs. However, additional research is needed to clarify their potential diagnostic implications.

Extensive retraction artefact predicts biochemical recurrence‐free survival in prostatic carcinoma

Tomas D, Spajić B, Milošević M, Demirović A, Marušić Z & Krušlin B
(2011) Histopathology58, 447–454
Extensive retraction artefact predicts biochemical recurrence‐free survival in prostatic carcinoma

CD138-positive plasmacytoid urothelial carcinoma of urinary bladder with focal micropapillary features

Both the plasmacytoid and micropapillary types of urothelial carcinoma of the urinary bladder are uncommon, distinct clinical and pathological findings. To date, several reports in the English medical literature have been published on either of these variants. CD138 is commonly used as a marker for tumors of plasma cell origin. However, few authors have described positive immunoreactivity of plasmacytoid cells in urothelial carcinoma. Mixed histological differentiation is thought to be a phenotype of locally aggressive and advanced urothelial carcinoma. Therefore, a precise histopathological diagnosis should be made and awareness of all the entities is crucial. We report a case of CD138-positive plasmacytoid urothelial carcinoma of the bladder with focal micropapillary features. To our knowledge this is the first case of these two rare subtypes of urothelial carcinoma combined in a single cystectomy specimen.

Pleomorphic ductal carcinoma of the breast with predominant micropapillary features

An 83‐year‐old woman with long‐standing chronic ischemic cardiac and obstructive pulmonary disease, presented with a painless tumor in her right breast. Microscopically the tumor consisted of micropapillary formations and loosely cohesive nests and strands of large, highly pleomorphic cells. Micropapillary formations were surrounded by peritumoral retraction clefting, and the papillae lacked a true fibrovascular core. Multinucleated giant and bizarre tumor cells were also present and numerous. Within the tumor a high‐grade intraductal component with the same cell morphology and necrosis and mucin production was found. Micropapillary pattern occupied approximately 60% of the tumor mass, loosely cohesive nests and strands approximately 20% and an intraductal component was noted in approximately 20% of the tumor mass. On immunohistochemistry the tumor cells were positive for pan‐cytokeratin, epithelial membrane antigen (EMA), S100 protein and E‐cadherin while estrogen and progesterone receptors, HER2‐neu and Bcl2 were negative. EMA staining was diffuse and observed in the outer and inner margins of neoplastic nests. The diagnosis of pleomorphic breast carcinoma with predominant micropapillary features was established. In summary, micropapillary carcinoma can be distinguished from other types of breast carcinoma with micropapillary growth pattern on the basis of reverse cell polarity, which is easily confirmed on immunohistochemistry.

TGF-β1 Expression in Chromophobe Renal Cell Carcinoma and Renal Oncocytoma

Distinguishing renal oncocytoma (RO) from the eosinophilic variant of chromophobe renal cell carcinoma (ChRCC) under the light microscope is a common diagnostic problem. Our recent research has shown significant difference between the presence of tumor fibrous capsule in ChRCCs and ROs. Transforming growth factor beta 1 (TGF-β1) is a potent cytokine involved in regulating a number of cellular processes. Two main purposes of this research were to investigate whether the TGF-β1 staining could be related to the presence of tumor fibrous capsule and if it could be used in the differential diagnosis between ChRCC and RO. We investigated 34 cases: 16 ChRCCs (8 eosinophilic and 8 classic) and 18 ROs. All available slides of each tumor, routinely stained with hematoxylin and eosin (H&E) were first analyzed to note the presence of tumor fibrous capsule. One paraffin embedded tissue block matching the representative H&E slide was selected for the immunohistochemical analysis. TGF-β1 expression was analyzed semiquantitatively in the tumor tissue, the tumor fibrous capsule, if present and the peritumoral renal parenchyma. Intensity of TGF-β1 expression was weaker in ChRCCs than the one observed in ROs (P<0.05). The type of reaction in ChRCCs was predominantly membranous unlike in ROs, which exhibited a predominantly cytoplasmic reaction (P<0.05). Moreover, none of the ROs showed membranous type of reaction for TGF-β1. In the group of ChRCCs, tumors with capsule had statistically significant higher quantity of TGF-β1 expression in tumor tissue and in peritumoral renal parenchyma compared to the tumors without capsule (P<0.05). Our results showed different types of TGF-β1 expression in ChRCCs and ROs: ChRCCs had predominantly membranous type of reaction, and ROs predominantly cytoplasmic. Furthermore, ChRCCs with capsule had statistically significant higher quantity of TGF-β1 expression in tumor tissue and in peritumoral renal parenchyma compared to the tumors without capsule. Based on these findings we can speculate that it could be possible that TGF-β1 plays a role in the formation of fibrous capsule in ChRCCs.

Correlation of vascular endothelial growth factor and hypoxia-inducible factor-1α expression with pathological renal artery changes in patients with renal cell carcinoma

Abstract Objective. The aim of this study was to correlate the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) with pathological renal artery changes in patients with renal cell carcinoma (RCC). A further aim was to correlate intratumoral microvessel density (MVD) with VEGF and HIF-1α expression and prognostic factors for RCC, including tumour necrosis. Material and methods. Formalin-fixed and paraffin-embedded tissue blocks from 150 patients with RCC and 50 patients with non-tumorous kidney diseases were analysed. The control group consisted of specimens from both renal arteries obtained from 25 decedents at routine autopsy (50 cases in total). Immunohistochemistry was performed using primary antibodies to VEGF, HIF-1α and CD31. Results.Pathological renal artery changes were more common in patients with RCC and non-tumorous kidney diseases than in the control group. MVD was higher in the RCCs of patients with pathological renal artery changes. Tumours with higher HIF-1α expression had higher MVD; however, VEGF expression was not associated with MVD. A significant association was also found between MVD and the extent of tumour necrosis, in that less necrotic tumours had higher MVD. No association between renal artery changes and VEGF and HIF-1α expression was established. Conclusion. Considering the results of this study, the evaluation of renal artery changes in forthcoming research on RCC would be helpful for several reasons: to estimate their incidence in a larger number of patients, to clarify their connection with RCC and to reveal their relationship with MVD in RCC.