Morphological markers of secretory activity in prostatic adenocarcinoma

Background/Aim. The vast majority of prostatic tumors developing in adult males are adenocarcinomas (ACP). Histological diagnosis of prostate cancer relies on the infiltrative growth pattern, presence of macronucleoli, and absence of basal cell layer. In the last few years a special attention has been focused on investigation of cancerous glands lumen content. The aim of the study was to determine the presence of intraluminal (crystaloids, blue-tanged mucinous secretions and distension of glands) and extracellular markers of pathological secretions in ACP, as well as the type of intraluminal and extracellular mucinous secretions. Methods. Micromorphological and hystochemical (PAS, HIDAB pH 2.5) analysis was done in 96 patients to detemine differentiation by Gleason and markers of secretory activity. Results. In ACP neoplastic gland`s distension (53.12%), crystalloids (30.2%), basophilic secretions (26.04%) and presence of extracellular mucins (8.3%) were found. All morphological signs were detected in carcinoma of Gleason grade 1-4A. There was significant presence of crystalloids ((G1+G2)/G4 p < 0.05; G3/G4A p < 0.05), basophilic secretions (G3/G2 p < 0.05; G3/G4A p < 0.05) and extracellular mucins (G3/G4A p < 0.001). The association of these morphological features with neutral and acidic mucins secretion was statisticaly significant (p < 0.0001). Conclusion. This study showed that intraluminal and extracellular markers of secretory activity in ACP were significantly more often associated by mixed type of mucin secretion with predominace of sialomucins.

Stromal reaction and prognosis in acinic cell carcinoma of the salivary gland

Introduction. Primary acinic cell carcinoma (ACC) is an uncommon malignant neoplasm of the salivary gland (SG), which usually presents as slow growing tumor. Case report. We reported a 69-year-old woman with tumor in the right parotid gland with a 5-year progress. Biopsy sections revealed a hybrid form of ACC with a low- and high-grade component and prominent lymphoid tissue in tumor stroma. Immunohistochemistry was performed to define the molecular profile of this unusual ACC, with special interest for stromal influence on to the proliferative activity of ACC with dedifferentiation. We detected that the level and the type of stromal lymphoid reaction (particularly CD8+/CD4+ ratio) had a significant influence on to Ki-67 index in the high-grade component of ACC, as well as the involvement of the CXCR4 signaling axis in the stromal reaction influence. Conclusion. We suggest that tumor stroma may be a source of potential new tumor biomarkers which can determine the aggressivity of this tumor.[Projekat Ministarstva nauke Republike Srbije, br. 175092

The association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients

Disrupted NOTCH activity is a driving event in urothelial bladder cancer (UBC). After activation by hypoxia, the NOTCH3 receptor participates in tumor cell proliferation, acquisition of the epithelial-mesenchymal transition phenotype, and angiogenesis. The aim was to analyze the association of NOTCH3 expression with histopathological and clinical parameters, and to determine its predictive impact on the clinical outcome in UBC patients. The present research included 614 UBC samples incorporated in paraffin tissue microarrays, evaluated by immunohistochemistry for NOTCH3 expression. The accrual period was four years, while the follow-up period was two years. The membranous expression was semi-quantified (0-3), and the mean degree was 1.81±0.94. Criteria for semi-quantification the NOTCH3 expression were the intensity of the staining and the percentage of positive cells. The samples with negative (0) and weak (1) NOTCH3 immunohistochemical (IHC) score were considered negative, while the samples that showed moderate (2) and strong (3) expression were considered positive. Higher degree of positivity was associated with higher risk of cancer-specific mortality (p<0.001). Independent predictors for cancer-specific mortality were NOTCH3 expression and high stage (p<0.001). NOTCH3 expression was not a statistically significant predictor of recurrence-free survival (p=0.816). This study indicated that NOTCH3 is a predictor of poor outcome, suggesting that the NOTCH3 could be potentially reliable IHC marker for selecting the UBC patients that would require more intensive follow-up, especially if they diagnosed in higher stage, with divergent differentiation in pathological report, and without recurrences which would lead them to more frequent medical assessments

Prognostic value of apoptotic activity in muscle-invasive bladder cancer

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Expression of nuclear Ki-67 antigen in prostatic high grade intraepithelial neoplasia and prostatic carcinoma

Background/Aim. Prostatic intraepithelial high grade neoplasia (PINHG) is accepted as preneoplastic lesion in prostatic carcinoma. One of the fundamental events in early oncogenesis is the disruption of proliferative activity. One of the numerous regulatory proteins is Ki-67 expressed in all proliferating cells. Index Ki-67 is considered to have prognostic significance. The aim of the study was to compare the level of proliferation in hyperplastic epithelium, prostatic carcinoma (Gleason score &gt; 6) and PINHG. Methods. Micromorphological examination was done in 85 patients. Pathohistological analysis was performed on standard histologic specimens with the estimation of Gleason score and the presence of PINHG in its surroundings. Nuclear proliferative activity was analyzed immunohistochemically in 19 cases, using a monoclonal anti-Ki-67 antibody. Results. PINHG was found in prostatic carcinoma surrounding in 30% of the patients. In hyperplastic epithelia Ki-67 proliferative activity was 1,08, in PINHG 2,25 (p &lt; 0,05), while in prostatic cancer, Ki-67 index was 17,64. Proliferative activity in prostatic carcinoma was significantly higher than in PINHG (p &lt; 0,001) and hyperplasia (p &lt; 0,001). Conclusion. This study confirmed that high grade PIN lesion predominately appears in the surrounding of poor or moderately differentiated prostate carcinoma, and that it represents progressive disorder of proliferation in preneoplastic and neoplastic prostatic epithelium.

Malakoplakia mimics urinary bladder cancer: A case report

Introduction. Malakoplakia is an unusual and very rare chronic inflammatory disease. In bladder especially it can mimic malignancy and lead to serious misdiagnosis. Case report. We presented a case of a middle-aged woman with persistent macrohematuria and cystoscopically polypoid bladder mass that resembled a neoplastic process. The final diagnosis was based on cystoscopic biopsy and microscopic findings of acidophilic, foamy histiocytes with the presence of Michaelis-Gutmann inclusions which are characteristic for diagnosis of malakoplakia. Immunohistochemistry confirmed diagnosis by demonstrating CD68-positive macrophages. Conclusion. Urinary bladder malakoplakia should be considered in patients with persistent urinary tract infections and tumor mass at cystoscopy. Early identification with prompt antibiotic treatment can be helpful in avoiding unnecessary surgical interventions and in preventing development of possible complications. [Projekat Ministarstva nauke Republike Srbije, br. 175092

Urachal adenocarcinoma - case report and literature review

Introduction. Urachal adenocarcinoma is extremely rare and comprises from 0.35% to 0.7% of all bladder tumors. The most common histologic subtype of urachal tumors is adenocarcinoma which can be associated with intestinal metaplasia and mucin production. Case report. We report a case of a 53-year-old patient who attented a urologist because of an intermittent haematuria lasting for three months. The ultrasound examination detected infiltration of the bladder at the fundus, 24 × 29 mm in diameter. By the same wall, next to the tumor, there was an oval hypoechoic lesion about 40 mm in diameter. Computed tomography scan showed a solid, echogenic, strictly limited tumor at the fundus of the bladder, anteriorly, 32 × 35 × 22 mm in diameter which was positive after contrast application. The patient underwent partial cystectomy with complete excision of the tumor lesion 1.5 cm in healthy tissue. Histopathological analysis showed diagnosis of Adenocarcinoma mucinosum vesicae urinariae infiltrans. Patohistological findings detected a part of the urachal wall with a thin layer of fibromuscular tissue, chronic inflammation, microcalcifications in the lumen, flattened and desquamated epithelium. One year after the surgery, there were no signs of primary disease or metastases in other organs. Conclusion. Urachal adenocarcinoma is extremely rare. Long term survival could be achieved by surgical treatment in the early stage of the disease which consists of complete resection of urachal carcinoma and partial or total cystectomy

Template-Independent Poly(A)-Tail Decay and RNASEL as Potential Cellular Biomarkers for Prostate Cancer Development

The post-transcriptional messenger RNA (mRNA) decay and turnover rate of the template-independent poly(A) tail, localized at the 3′-untranslated region (3′UTR) of mRNA, have been documented among subtle mechanisms of uncontrolled cancer tissue growth. The activity of Poly(A) deadenylase and the expression pattern of RNASEL have been examined. A total of 138 prostate tissue specimens from 46 PC patients (cancer specimens, corresponding adjacent surgically healthy tissues, and in their normal counterparts, at least 2 cm from carcinoma) were used. For the stratification prediction of healthy tissue transition into malignant phenotype, the enzyme activity of tumor-adjacent tissue was considered in relation to the presence of microfocal carcinoma. More than a four-times increase in specific enzyme activity (U/L g.prot) was registered in PC on account of both the dissociation of its inhibitor and genome reprogramming. The obtained ROC curve and Youden index showed that Poly(A) deadenylase identified PC with a sensitivity of 93.5% and a specificity of 94.6%. The RNASEL expression profile was raised significantly in PC, but the sensitivity was 40.5% and specificity was 86.9%. A significantly negative correlation between PC and control tissue counterparts with a higher expression pattern in lymphocyte-infiltrated samples were reported. In conclusion, significantly upregulated Poly(A) deadenylase activity may be a checkpoint for the transition of precancerous lesion to malignancy, while RNASEL may predict chronic inflammation

Expression of regulatory proteins and proliferative activity in relation to phenotypic characteristics of upper urothelial carcinoma

Background/Aim. Deregulation of the normal cell cycle is common in upper urothelial carcinoma (UUC). The aim of this study was to investigate the expression of regulatory proteins of the cell cycle (p53, p16, cyclin D1, HER-2) and proliferative Ki-67 activity in UUC, and to determine their interaction and influence on the phenotypic characteristics of UUC. Methods. In 44 patients with UUC, histopathological and immunohistochemical analyses (p53, p16, cyclin D1, HER-2, and Ki-67) of tumors were done. Results. Overexpression/ altered expression of p53, p16, cyclin D1 or HER-2 was detected in 20%, 57%, 64%, and 57% of tumors, respectively. Eleven (25%) UUC had a high proliferative Ki-67 index. Forty patients (91%) had at least one marker altered, while four (9%) tumors had a wild-type status. Analysis of relationship between expressions of molecular markers showed that only high expression of p53 was significantly associated with altered p16 activity (p &lt; 0.05). High Ki-67 index was associated with the high stage (p &lt; 0.005), solid growth (p &lt; 0.01), high grade (p &lt; 0.05), and multifocality p &lt; 0.05) of UUC, while high expression of p53 was associated with the solid growth (p &lt; 0.05). In regression models that included all molecular markers and phenotypic characteristics, only Ki-67 correlated with the growth (p &lt; 0.0001), stage (p &lt; 0.01), grade (p &lt; 0.05) and multifocality (p &lt; 0.05) of UUC; Ki-67 and HER-2 expression correlated with the lymphovascular invasion (p &lt; 0.05). Conclusions. This investigation showed that only negative regulatory proteins of the cell cycle, p53 and p16, were significantly associated in UUC, while proliferative marker Ki-67 was in relation to the key phenotypic characteristics of UUC in the best way

Xanthine Oxidase/Dehydrogenase Activity as a Source of Oxidative Stress in Prostate Cancer Tissue

Prostate cancer (PC) is one of the most frequent malignancies. Better biomarkers are constantly wanted, such as those which can help with the prediction of cancer behavior. What is also needed is a marker which may serve as a possible therapeutic target. Oxidative stress (OS), which is a hallmark of cancer, is included in the pathogenesis and progression of PC. We have conducted the present study to determine whether xanthine oxidase/dehydrogenase activity is the source of OS in prostate tissue. We have also determined the concentration of TBA-reactive substances (TBARS) and advanced oxidation protein products (AOPP), as well as the activity of catalase. Xanthine oxidase (XO) activity is significantly higher (p &lt; 0.001) in tumor tissue when compared to the control healthy tissue. The concentration of TBARS (p &lt; 0.001) and AOPP (p &lt; 0.05) are also higher in tumor tissue. Catalase has raised its activity (p &lt; 0.05) versus the control. There is also a strong correlation between XO activity and prostate-specific antigen (PSA) levels in the serum. These results indicate a significant role of XO activity in OS in prostate carcinogenesis, and it could be a possible theranostic biomarker, which can be important for a better understanding of the disease, its evolution, and prognosis. A promising treatment may be using XO inhibitors such as allopurinol as adjuvant therapy