Transurethral Resection Materials Research Articles

The prognostic value of expressions of STAT3, PD-L1, and PD-L2 in Ta/T1 urothelial carcinoma before and after BCG treatment

IntroductionNonmuscle invasive bladder cancers (NMIBC) are common tumors diagnosed in older individuals and men (median age: 69 years). Immunotherapy is a treatment option in cases resistant to Bacillus-Calmette-Guerin (BCG) therapy. We aimed to evaluate the prognostic role of programmed-cell-death ligand (PD-L)-1 (PD-L1), PD-L2, and signal transducer and activator of transcription 3 (STAT3) expressions, which are closely related to immune mechanisms, in the response to BCG treatment of NMIBC. MethodsThe data of patients at the Ta and T1 stages of the cancer without muscularis propria invasion, who were treated with intravesical BCG therapy between 2017 and 2022 were retrospectively analyzed. Immunohistochemical staining for PD-L1, PD-L2, and STAT3 was performed on transurethral resection materials. ResultsThe mean age of 59 patients was 66.5 ±7.7 and 83.9% were male. The percentage of patients with complete response to BCG treatment was 66.1% and that of BCG refractory patients was 33.9%. Demographic and clinical data did not differ significantly according to BCG treatment response (P> 0.05). The proportion of patients with tumor-infiltrating lymphocytes (TILs) ≥20% were 9.7% among those with Ta-stage tumors and 46.4% among those with T1-stage tumors (P = 0.0014). The percentages of tumor cell scoring (TCS), immune cell scoring (ICS), combined scoring (CS), and expression levels of PD-L1, PD-L2, and H-score of STAT3 did not differ significantly according to tumor stage and treatment response (P > 0.05). However, the median ICS and CS for PD-L1 and median H-score for STAT3 were significantly higher among patients in T1 stage compared to those in Ta stage (P = 0.0487, 0.0462, 0.0112, respectively). Among BCG refractory patients, median STAT3 of patients in T1 stage was significantly higher than those at stage Ta (P = 0.0356) and the rate of TILs was ≥20% in only 3 patients in T1 stage (P = 0.031). Among all patients, significant positive correlation was found between TCS for PD-L1 and H-score for STAT3 (P = 0.0302); and between ICS for PD-L1 and TCS for PD-L2 (P = 0.0053) and TILs ratio (P < 0.0001). Among BCG-refractory cases, pretreatment and post-treatment TCS for PD-L2 and H-scores for STAT3 were significantly correlated (P = 0.0361 and 0.0021, respectively). ConclusionsThe success of BCG treatment in NMIBC was not related to PD-L1, PD-L2, and STAT3 expression status, but PD-L1 expression was correlated with both PD-L2 and STAT3 as well as TILs rate, but this correlation was lost after BCG treatment.

Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. Patient summaryIt is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.

Molecular and immunohistochemical evaluation of BAP-1 antibody in bladder cancer and comparison with luminal-basal subtyping

AimMolecular subtyping has become increasingly important in bladder cancer, and it is mainly divided into “luminal” and “basal” types. Despite the large amount of studies about the molecular pathway of bladder cancer, there are few studies about BAP-1. The aim of this study is to evaluate the BAP-1 expression molecularly and immunohistochemically and compare it with GATA-3 and CK5/6 immunohistochemical stains. Materials and methodA BAP-1 antibody was applied by western blotting to the tumor and normal tissues of 11 patients with known primary bladder tumors. The paraffin blocks of 150 non-invasive and 150 invasive tumor tissues were selected from transurethral resection materials. BAP-1, GATA-3, and CK5/6 immunohistochemical stains were applied to them, and the results were evaluated. ResultsThe protein expression levels of BAP-1 increased more in the tumor tissues compared to the normal tissues. The immunohistochemical BAP-1 expression was strong in the muscle-invasive group. The immunohistochemical GATA-3 expression was higher in the non-invasive group, and the CK5/6 expression was higher in the muscle-invasive group. The GATA-3 and CK5/6 immunohistochemical stains had a negative correlation in the muscle-invasive group. The immunohistochemical expression of BAP-1 had no correlation with GATA-3 and CK5/6 in all groups. ConclusionsMolecular subtyping has become increasingly important in bladder cancer and it is mainly divided into “luminal” and “basal” type. Despite the large amount of studies about molecular pathway of the bladder cancer, there are a few studies about BAP-1. The aim of this study is to evaluate the BAP-1 expression molecularly and immunohistochemically and compare it with GATA-3 and CK5/6 immunohistochemical stains.

Large nested urothelial carcinoma: A clinicopathological study of 22 cases on transurethral resection materials

Large nested urothelial carcinoma (LNUC) is a recently recognized variant of urothelial carcinoma (UC), which is characterized with inverted growth pattern and bland cytology. Diagnosis can be extremely challenging, especially in transurethral resection (TUR) materials.Haematoxylin-eosin stained slides of TUR materials with UC, submitted to our department between 2008 and 2017 were re-examined. Twenty-two LNUC cases were found.LNUC frequency was 0.7%. Mean age was 69.9, 82% were male. Mean tumor diameter was 4.9 cm. Non-invasive UC was present in all cases; low-grade in 6, high-grade in 1, low and high-grade in 15. Five and 16 cases were pT1 and pT2, respectively, no invasion was detected in one case. In addition to medium-large nests, small nests and conventional UC areas was present in 2 and 3 cases, respectively. Stroma-tumor interface was irregular in 19 cases and 3 cases had invasive nests with rounded contours. Fibrous stromal reaction and/or stromal lymphoid infiltration were present in 21 cases. Budding, described as small nests in stromal interface of medium-large nests was found in 16 cases. Follow-up was available for 18 cases with an average of 59 months. Four cases had metastasis, 1 patient died of disease.LNUC causes diagnostic difficulty, especially in TUR materials. Large size of tumor, irregularity of nests, presence of stromal reaction and budding can be clues for correct diagnosis.

Immunohistochemical expression profiles of MUC1 and MUC2 mucins in urothelial tumors of bladder.

Mucins may show aberrant expression, localization, and/or glycosylation in multiple malignancies. However, information regarding expression of these mucins is mostly unknown in urothelial tumors. This study was conducted for examining the expressions of membrane associated and secreted mucin (MUC1) and a secreted gel-forming mucin (MUC2) in urothelial tumors of the urinary bladder. Archival transurethral resection materials of 97 urothelial carcinoma cases were reexamined light microscopically and graded according to the 2004 WHO Classification. Pathological stage was given as pTa, pT1, and pT2. Demonstrative sections were recut for immunohistochemistry for MUC1 and MUC2. The results were statistically analyzed, and P < 0.05 was considered statistically significant. The positivity for MUC1 and MUC2 was 89.7% and 44.3%, respectively. Independent from pathological stage of the tumor, MUC1 expression showed statistically significant correlation with tumor grade (P < 0.05). We did not find any correlation between pathological stage and MUC1 and MUC2 expression (P > 0.05). MUC1 staining pattern in papillary urothelial neoplasm of low malignant potential cases was more commonly apical and superficial (luminal cell layer only). Intermediate cells ± basal cells or isolated cells or islands of tumor cells with cytoplasmic and/or circumferential membrane positivity for MUC1 and MUC2 were more commonly observed in both low- and high-grade carcinomas. The difference between groups in terms of MUC1 and MUC2 staining was statistically significant (P < 0.05). The staining patterns of both mucins are different between urothelial papillary tumors and may be used to make a differentiation, especially for low-grade papillary urothelial lesions. This difference may also be important in the carcinomatous transformation of urothelial neoplastic and preneoplastic lesions.

Foamy Gland Variant of Prostatic Carcinoma

The foamy gland variant (FGV) of prostatic acinar adenocarcinoma was first described by Nelson and Epstein (1) in 1996. Abundant xanthomatous cytoplasm with picnotic nuclei is characteristic for this variant. The FGV is uncommon but its incidence is not clear on transurethral resection materials (2). The age range of affected patients with foamy gland carcinoma does not differ from that of those with the usual prostatic adenocarcinoma.

Immunohistochemical expression of p63, p53 in urinary bladder carcinoma

Urothelial carcinomas (UC) is of the most common cancers urinary bladder. The aim of the study is to assess the immunohistochemical staining differences between p63 and p53 according to the pathological stage and histological grade of the tumor in urinary bladder carcinomas. Totally 62 urinary bladder transurethral resection materials diagnosed with urothelial carcinoma in the pathology department of our hospital were included in the study. On pathological examination, cases were dichotomized as noninvasive and invasive, whereas noninvasive cases were dichotomized as low grade and high grade and invasive cases were dichotomized as pT1 and pT2. Subsequently, the cases were evaluated by means of p63 and p53 immunohistochemical staining. Statistical analyses were performed by SPSS program, and Chi-square and Fisher's exact tests. When pTa was evaluated in terms of p63 immunoreactivity, no statistically significant difference was observed between LGPUC and HGPUC, noninvasive papillary UC, regarding staining percentages ( P > 0.05), whereas statistically significant relation was observed for pT1 and pT2 regarding p63 staining percentages ( P < 0.05). For pTa, no statistically significant relation was observed between LGPUC and HGPUC, noninvasive papillary UC, in terms of p53 staining percentages ( P > 0.05). However, highly significant relationship was observed for pT1 and pT2 in terms of p53 staining percentages ( P < 0.01). No significant relationship was observed between the staining percentages of p53 and p63 ( P > 0.05). The role of p53 and p63 immunoreactivities in the differential diagnosis and prognosis of urinary bladder carcinomas according to the pathological stage and histological grade of the tumor will be understood better with the increasing number of long term investigations performed with large series at a molecular level.

Prognostic Value of DNA Ploidy, bcl-2 and p53 in Localized Prostate Adenocarcinoma Incidentally Discovered at Transurethral Prostatectomy

Discovery of prostatic adenocarcinoma limited to transurethral resection material generates a treatment dilemma. We investigated the usefulness of parameters shown to be associated with prognosis in prostate cancer (p53 and bcl-2 immuno-expression, DNA cell cycle analysis and Gleason score) to stratify these incidentally identified tumors to guide clinical decision making. Paraffin embedded tissues from transurethral prostate resection specimens containing T1a prostate adenocarcinoma from 44 patients who underwent resection between 1980 and 1990 were immunostained for p53 and bcl-2, and subjected to flow cytometry to determine DNA ploidy. Gleason score was determined by 2 pathologists independently. Statistical relationships among these 4 variables, tumor progression and cancer specific survival were analyzed. Six of 44 patients in the study population had cancer progression. Time to clinical progression was 4.5 years (range 7 months to 11 years). Most tumors stained negative for p53 and bcl-2. Only 2 tumors studied were aneuploid and neither of these 2 patients had cancer progression. Only Gleason score was a significant predictor of cancer progression on univariate and multivariate Cox regression analysis (p = 0.045 and 0.046, respectively). No tumor characteristics correlated with time to disease progression, including p53 and bcl-2 immuno-expression, and Gleason score (p = 0.182, 0.563 and 0.346, respectively). Positive immunostaining for p53 and bcl-2 did not occur together in the same tumor in significant fashion (p = 0.334), nor did either significantly occur more with aneuploidy (p = 0.237 and 0.307 respectively). For T1a prostate cancer incidentally detected on transurethral prostate resection p53 and bcl-2 immuno-expression, and DNA ploidy do not predict survival or disease progression.

Gene profiling in transurethral resection samples of patients with hormone-refractory prostate cancer (HRPC)

4641 Background: Patients with metastatic carcinoma of the prostate (CaP) develop after a mean of 15 months resistance to hormone ablation therapy. However, the underlying molecular mechanisms are still unknown. Our goal was to identify the transcriptional changes that are characteristic for the transition to hormone resistant prostate cancer (HRPC) using oligonucleotide microarrays. Here, we report the attempt to profile fresh frozen tissue obtained by palliative transurethral resection (TUR) in patients with HRPC and concomittant urinary obstruction. Methods: Indications for palliative TUR were locally progressive tumors with obstruction and voiding problems. HRPC was defined according to the criteria of Scher et al. 1995. Samples of 8 HRPC patients were compared to tissues from 8 hormone-sensitive CaP patients including biological and technical replicates. All tissue samples had been pathologically evaluated. Only macrodissected prostate samples with at least 70% tumor content were used for RNA extraction. RNA quality was controlled using the Bioanalyzer Nanochip (Agilent Technologies, Palo Alto). Expression analysis was performed on Affymetrix oligonucleotide arrays. Results: We identified 323 genes being significantly deregulated (corrected p-value &lt;0.05, false discovery rate &lt;0.05). These genes were mapped to cellular pathways using the KEGG annotation and the most significantly deregulated pathways were identified. Deregulation of metabolic pathways included fatty acid metabolism as well as oxidative phosphorylation and ATP synthesis. Cell cycle control seems to be further suppressed by the downregulation of JNK-pathway via MEKK4 and JUND, the downregulation of p21 (CDKN1A) and the induction of Cylcin D1. We also present evidence for a significant downregulation of actin cyctoskeleton components. Deregulated genes likely to be specific for the transition from prostate carcinoma to HRPC will be presented. Conclusions: Gene expression profiling has been successfully standardised using fresh TUR material of HRPC patients. Deregulated genes have been mapped to specific signal transduction pathways. On this platform, clinical trials in patients with HRPC using specific inhibitors of cell signalling are being developed. [Table: see text]

Staging bladder carcinoma by three-dimensional ultrasound rendering

Organ-confined staging for bladder cancer has major impact on further treatment. Most imaging techniques for this purpose are insufficient. We, therefore, assessed the value and the limitations of a new diagnostic tool, the 3-D ultrasound (US) rendering, to distinguish invasive from noninvasive bladder cancers. A total of 63 patients underwent 3-D US of the bladder before transurethral resection or radical cystectomy. The US findings were compared with the pathologic stages of the transurethral resection material or the cystectomy specimens. Superficial (pTa) carcinomas were correctly staged in 66% by 3-D US. Lamina propria infiltrating (pT1) were correctly staged in 83% and the quota of correct staging of infiltrating carcinomas (> pT1) by 3-D rendering was 100%. The overall accuracy was 79%. Three-dimensional US rendering is most valuable to discriminate between superficial stages < pT1 and muscle invasive carcinoma > pT1. This new technique might improve staging of bladder cancer. (E-mail: hans-werner.gottfried@medizin.uni-ulm.de)

Expression of PS2 Protein and Its Relation with the Ki–67 Proliferative Indices and Tumor Recurrence in Superficial Bladder Carcinomas

Objective: To investigate the expression and possible role of pS2 protein as a predictor of tumor recurrence in superficial transitional cell carcinoma of the bladder and to determine its relation with tumor stage, grade, size, number, recurrence and proliferative activity. Methods: Paraffin sections of transurethral resection material from 80 patients with superficial transitional cell bladder carcinoma were stained with pS2 and Ki–67 antibodies using the standard streptavidin biotin immunoperoxidase method. Cytoplasmic pS2 staining was scored on a scale of 1–3 and the Ki–67–labelling index was determined as a percentage of positively staining tumor cells. Results: An inverse relationship was found between pS2 expression and Ki–67 index (p<0.001). pS2 expression showed no relation with any clinicopathological prognostic parameters as well as the recurrence rate. The recurrence rate was only associated with increased tumor number (p = 0.05), while the time to first recurrence was significantly related to tumor size, proliferative activity and tumor grade (p = 0.04, p<0.001, and p = 0.03, respectively). On the other hand, higher tumor grade was correlated with increased tumor number, Ki–67 index and tumor stage (p = 0.016, p = 0.006, and p<0.001, respectively). Conclusion: pS2 expression is associated with a low proliferative potential of superficial transitional cell carcinoma of the bladder, while it does not seem to be related to the recurrence rate of the tumor and other prognostic factors. Tumor size and proliferative activity may aid in the estimation of the time to the first recurrence.

AgNOR/P53 expression compared with different grades in bladder carcinoma.

The aim of this study is to assess the relation between silver-strained nucleolar organizer regions (AgNOR)/P53 expression and urothelial neoplasm of the bladder which graded according to the WHO/ISUP tumor grading system. Transurethral resection materials (TUR) and cystectomy specimens from 52 patients with bladder urothelial carcinomas were stained by AgNORs and analyzed immunohistochemically using an avidinbiotin peroxidase method for p53 staining and also silver for AgNORs. Nuclear p53 accumulation was determined in two of 5 LMP cases (%40), in 10 of 22 LGC (%45.4), and in 8 of 25 HGC (%32). Positivity of p53 accumulation was observed in 20 (%57.7) of all cases. There was no statistically significant relationship between AgNOR score of p53(+) and p53(-) cases. There was no correlation between LGC and LMP, also between LGC and HGC (p > 0.05), but a meaningful relationship was found between LMP and HGC (p = 0.03). Association between P53 and grade, AgNOR value and grade, p53 and AgNOR was found statistically insignificant. Although we found a statistically significant correlation between AgNOR count of LMP and HGC, this study did not show a satisfying correlation between AgNOR, p53 and any grade of urothelial carcinoma.

Quantitative assessment of bladder carcinoma by acid labile DNA assay.

Effective noninvasive methods for monitoring patients with bladder carcinoma and screening for bladder carcinoma that show better performance than the methods currently in use would be desirable for detecting urothelial carcinoma at an early, easily treatable stage. A rapidly hydrolyzed component of nuclear DNA has been described, the increase of which has been linked to malignancy. Quantitative determination of acid labile DNA has been applied successfully to detect other neoplasms. This study investigates the potential of this method to detect transitional cell carcinomas. Touch imprints of transurethral resection material from 62 cases of nonmalignant urothelium (control group including reactive changes) and 94 cases of bladder carcinoma were analyzed. The full Feulgen hydrolysis profiles of the nonmalignant and malignant urothelial cells were compared by measuring the staining density of the nuclei using digital image analysis after various hydrolysis times. Twenty cells were sampled randomly from among the cells measured for calculation of the mean optical density (MOD). The MOD of each time was used to build the hydrolysis profile of a case. A hydrolysis time of 10 minutes was found to be the most discriminative between control and carcinoma cases. Applying a single threshold MOD value of 101 resulted in a test sensitivity of 95.7%, a specificity of 94.4%, a positive predictive value of 98.3%, a negative predictive value of 95.9%, and an area under the receiver operating characteristic curve of 0.97. The results of this pilot study suggest that measurement of the rapidly hydrolyzed component of DNA present in the nuclei of bladder urothelium offers a highly sensitive and reliable supplement to the qualitative and subjective cytologic procedures currently in use.

Differential diagnosis of glandular proliferations in the prostate. A conventional and immunohistochemical approach.

A variety of small acinar lesions of the prostate can mimic prostate cancer in punch biopsies and in transurethral resection material. The first part of this review deals with differential diagnostic problems of the central and transition zone, including atypical adenomatous hyperplasia of the prostate, atrophic processes, sclerosing adenosis, basal cell hyperplasia, and low-grade adenocarcinoma. The second part deals with differential diagnostic problems in the peripheral zone: prostatic intraepithelial neoplasia, postatrophic hyperplasia, Cowper's glands, seminal vesicles, and ductal and intraductal carcinoma. Finally, atypical and small acinar proliferations are described. Diagnostic perspectives are discussed. proliferations (ASAP) that cannot be integrated into any of the well-established diagnostic entities [1, 16, 22, 41]. The relevant glandular proliferations of the central, transitional and peripheral zones of the prostate are discussed here with reference to the related carcinomas.

Effect of Combination Endocrine Therapy (LHRH Agonist and Flutamide) on Normal Prostate and Prostatic Adenocarcinoma

The histopathology of 23 radical prostatectomies from patients with prostatic adenocarcinoma pretreated for 3-6 months with combination therapy including a luteinizing hormone-releasing hormone agonist and the antiandrogen drug flutamide was reviewed and compared with the pretreatment biopsies or transurethral resection material. After combination therapy, benign prostatic glands showed marked atrophy with prominent basal-cell layers, basal-cell hyperplasia, and epithelial-cell vacuolization. Immature squamous-cell metaplasia was present in seven cases. Residual carcinoma, on the other hand, was found in 19 of the 23 cases, and in 8 of these, tumor cells were either vacuolated or had scanty cytoplasm. Residual tumor was present as only one focus in 13 cases, and in 3 of these it was composed of single cells with a "hemangiopericytoma-like" pattern. An immunohistochemical study for prostatic acid phosphatase and prostatic-specific antigen could be carried out on paraffin blocks from 19 biopsies and 18 prostatectomies. After combination therapy, a reduction in staining (intensity and number of positive cells) was observed for the two markers in both normal prostate and carcinoma but with more pronounced effects on the latter. The present data show that temporary combination therapy before radical prostatectomy causes marked and very characteristic changes in normal prostatic tissue as well as in the prostatic tumor. These histologic patterns enter the differential diagnosis of a variety of atrophic, metaplastic, and proliferative lesions of the prostate gland. The pathologist must be aware of these histologic changes when looking at biopsy or resection material of treated patients.

Clinical Features and Spectrum of Light Microscopic Changes in Interstitial Cystitis

Transurethral resection material from a series of 64 patients with classical (ulcer) interstitial cystitis (60 women and 4 men, with a mean age of 64 years), 44 with nonulcer interstitial cystitis (40 women and 4 men, with a mean age of 39 years) and 20 control women (mean age 49 years) were studied by light microscopy. Patients with classical disease had mucosal ulceration and hemorrhage, granulation tissue, intense inflammatory infiltrate, elevated mast cell counts and perineural infiltrates. Patients with nonulcer disease, despite the same severe symptoms, had a relatively unaltered mucosa with a sparse inflammatory response, the main feature being multiple, small, mucosal ruptures and suburothelial hemorrhages that were noted in a high proportion of the patients. It is suggested that these features are characteristic, specific and prevalent enough to allow for morphological differentiation of the 2 clinical subtypes of interstitial cystitis.