Search Results (53)

Background/Objectives: Aberrant expression of high-mobility group protein B1 (HMGB1) has been linked to cancer development and progression. Methods: To better comprehend the role of HMGB1 expression in cancer, a tissue microarray containing 14,966 samples from 134 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: Strong HMGB1 staining occurred in almost all normal cell types and in most cancers. Of 11,808 evaluable cancers, only 7.8% showed complete absence of HMGB1 staining (HMGB1 deficiency) while 9.9% showed 1+, 25.0% showed 2+, and 57.2% showed 3+ HMGB1 positivity. Absence of HMGB1 staining mostly occurred in pheochromocytoma (90.0%), seminoma (72.4%), gastrointestinal stromal tumor (28.6%), adrenal cortical carcinoma (25.0%), and Hodgkin’s lymphoma (25.0%). Low HMGB1 staining was linked to poor histologic grade (p < 0.0001), advanced pT stage (p < 0.0001), high UICC stage (p < 0.0001), and distant metastasis (p = 0.0413) in clear cell renal cell carcinoma, invasive tumor growth in urothelial carcinoma (pTa vs. pT2–4, p < 0.0001), mismatch repair deficiency (p = 0.0167) in colorectal cancers, and advanced pT stage in invasive breast carcinoma of no special type (p = 0.0038). Strong HMGB1 staining was linked to nodal metastases in high-grade serous ovarian carcinomas (p = 0.0213) and colorectal adenocarcinomas (p = 0.0137), as well as to poor histological grade in squamous cell carcinomas (p = 0.0010). Conclusions: HMGB1 deficiency and reduced HMGB1 expression occur in a broad range of different tumor entities. Low rather than strong HMGB1 staining is often linked to an aggressive tumor phenotype. Whether HMGB1 deficiency renders cells susceptible to specific drugs remains to be determined. Full article

Background: The glucocorticoid receptor (GR) regulates the transcription of thousands of genes. In cancer, both oncogenic and tumor suppressive roles of GR have been proposed. Methods: A tissue microarray containing 18,527 samples from 147 tumor (sub-)types and 608 samples from 76 normal tissue types was analyzed for GR expression by immunohistochemistry. Results: GR positivity was found in 76.4% of 14,349 interpretable cancers, including 18.5% with weak, 19.6% with moderate, and 38.3% with strong positivity. GR positivity appeared in all 147 tumor types, with at least one strongly positive tumor in 136 types. Of out tumor entities, 77 of the 147 showed GR positivity in 100% of the cases analyzed. Only six tumor types had less than 50% GR-positive cases, including adenomas with low-/high-grade dysplasia (32.5%/21.7%), adenocarcinomas (17%) and neuroendocrine carcinomas (45.5%) of the colorectum, endometrial carcinomas (25.6%), and rhabdoid tumors (25%). Reduced GR staining was associated with grade progression in pTa (p < 0.0001) and with nodal metastasis in pT2-4 (p = 0.0051) urothelial bladder carcinoma, advanced pT stage (p = 0.0006) in breast carcinomas of no special type (NST), and high grade (p = 0.0066), advanced pT stage (p < 0.0001), and distant metastasis (p = 0.0081) in clear cell renal cell carcinoma. GR expression was unrelated to clinico-pathological parameters in gastric, pancreatic, and colorectal adenocarcinoma, and in serous high-grade carcinoma of the ovary. Conclusions: GR expression is frequent across all cancer types. Associations between reduced GR expression and unfavorable tumor features in certain cancers suggest that the functional importance of GR-regulated genes in cancer progression depends on the cell of tumor origin. Full article

Background: The diagnosis of upper urinary tract urothelial carcinoma (UTUC) in cytological specimens is challenging, particularly the designation of atypical urothelial cells (AUC). The application of the Paris System for Reporting Urinary Cytology (TPS) has improved the performance of lower tract urothelial carcinoma specimens but has shown variable results in upper tract specimens, which are frequently instrumented. Methods: This retrospective study analysed upper tract selective cytology samples from January to December 2023. Samples were classified under TPS 2.0 categories. Histological specimens were used where available as the gold standard to calculate statistical metrics including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Out of 122 samples, 12.2% were considered non-diagnostic or insufficient, with 13.1% designated as Non-high-grade urothelial carcinoma (N-HGUC), 53.3% as atypical urothelial cells (AUC) and 21.3% as positive/suspicious for HGUC. Histopathological correlation was available for 48.7% of cases. The risk of malignancy was: NHGUC (0%), AUC (47%) and HGUC (77.7%). The highest PPV was for HGUC (78%), with a diagnostic accuracy of 81.3% and specificity of 88%. In contrast, AUC had a PPV of 47% in instrumented and non-instrumented samples, rising to 58% in combination with the HGUC category. Conclusion: TPS 2.0 is an effective tool with excellent diagnostic accuracy for HGUC and in excluding malignancies in the N-HGUC category, but in our hands, the high rates of the AUC category, together with the low PPV, remain a major challenge and an obstacle to the correct stratification of patients with UTUC. Full article

Background and Objectives: This study aimed to evaluate the recurrence rates at three years for upper tract urothelial carcinoma (UTUC) cases managed conservatively, using Narrow Band Imaging (NBI)-assisted flexible ureteroscopy and Holmium laser vaporization. Materials and Methods: The study group included 61 patients who were diagnosed with NBI-assisted visualization with superficial pyelo-calyceal urothelial tumor lesions, treated conservatively by the flexible ureteroscopic approach and Holmium laser vaporization, also assisted by NBI. This was compared with a control group with the same number of cases, which underwent the same procedure, but without NBI technology. Recurrence rates, the rate of patients who underwent nephroureterectomy, and cancer-specific survival were compared. Results: The relapse rate at 1 year was 3.3% in the study group, and respectively 8.2% in the control group (p < 0.05). Depending on the histological characteristics, at 1 year the relapse rates in the study group were 1.8% in patients with low-grade tumors and 20% in those with high-grade tumors. At 3 years, the relapse rate was 11.5% in the study group versus 18% in the control group, (p < 0.05): 7.1% in patients with low-grade lesions and 40% in patients with high-grade lesions versus 21.4% in patients with low-grade lesions and 100% in patients with high-grade lesions (both arms with statistically significant differences, p < 0.05). Cancer-specific survival was 93.4% in the study group versus 86.9% in the control group (p < 0.05). Conclusions: The recurrence rates at three years for the UTUC cases managed conservatively, using NBI-assisted flexible ureteroscopy and Holmium laser vaporization, were lower than in patients treated by the same technique without NBI assistance, both in low- and high-grade tumors. Cancer-specific survival was also significantly improved by the association of NBI visualization during diagnosis and laser vaporization. Full article

Background: Upper urinary tract urothelial tumors are mostly treated with the use of endoscopic laser ablation. The treatment is recommended when the tumor is low grade and non-invasive. Objective: The aim of the present study was to investigate the oncological outcome of patients treated endoscopically for low-grade (LG) upper tract urothelial carcinoma (UTUC). Methods: One hundred and eighteen consecutive patients with pTa LG UTUC initially treated with laser ablation from 2012–2022 at a single university hospital were included. Patient and tumor characteristics, treatment, and oncological outcomes were retrospectively registered from electronic medical journals. Survival analysis was performed using Kaplan–Meier and Nelson–Aalen plots. Results: The median number of local recurrences was 2 with a median time to first recurrence of 5 months (IQR: 2–46). The 2-year share of patients having no recurrence was 28.8%. The risk of recurrence was highest within the first 3 years following initial treatment. Two-year survival function with no progression and preserved renal unit was 67.9%. The two-year overall survival (OS) and disease-specific survival (DSS) were 84.2% and 97.1%. The 5-year OS and DSS were 59.1% and 94.1%. The median follow-up time for OS was 36 months (IQR: 20.3–58.8). Conclusions: In the patient series, we found that the risk of recurrence following laser ablation of LG UTUC was high; however, it was associated with a low risk of progression and high OS and DSS. Therefore, we conclude that treatment with laser ablation in patients with LG UTUC is safe, although frequent follow-up is needed to detect recurrence. Full article

Upper tract urothelial carcinoma (UTUC) accounts for 5–10% of urothelial cancers and is associated with high morbidity and mortality. Increasing incidence of UTUC has been observed since the 1970’s, alongside the evolution of advance imaging techniques, precision biopsy equipment, and risk stratification models. The high morbidity of radical nephroureterectomy (RNU) which is still the gold-standard treatment for high-risk UTUC, has driven the development of kidney-sparing surgery alternatives for low-risk UTUC. Now, several treatment approaches have outcomes comparable to RNU for low-risk UTUC and guidelines are recommending kidney-sparing surgery for favorable low-risk disease. The main categories of kidney-sparing surgery include segmental ureterectomy, endoscopic ablation, chemoablation, and vascular-targeted phototherapy. These treatments are highly nuanced making them difficult to compare, but for most cases of favorable low-grade disease, we recommend endoscopic laser ablation with optional adjuvant intracavitary therapy. Adverse events associated with kidney-sparing surgery include ureteral stricture, bleeding requiring transfusion, and bladder recurrence of UTUC. Limitations of kidney-sparing surgery include appropriate tissue sampling (contributing to under-grading and under-staging), higher rates of ipsilateral recurrence, and potential for grade and stage progression. Collectively, these may subsequently necessitate RNU. Here, we review the technical variations and evidence behind kidney-sparing therapies as well as their practicality in the real world. Full article

Background/Objectives: Immunohistochemical expression of TRPS1 (trichorhinophalangeal syndrome type 1) protein is usually used by pathologists to confirm breast origin for triple-negative breast cancers (TNBC) or metastatic carcinomas of unknown primary. However, recent studies have reported TRPS1 expression in a variety of non-breast lesions. This review aims to provide a comprehensive evaluation of TRPS1 expression across various tumor types, highlighting both its diagnostic utility and potential pitfalls that may arise in clinical practice. Methods: A thorough search of the PubMed database on TRPS1 immunoexpression in tumor pathology was conducted. While the gene itself has been known for several decades, most studies regarding its use in immunohistochemistry emerged in the late 2010s. Particular emphasis was placed on case reports and cohort studies that examined the implications of TRPS1 expression in non-breast tissues, as well as variations in the results between commercially available TRPS1 clones, which may influence the staining intensity and specificity. Results: TRPS1 demonstrated a strong diagnostic utility in identifying primary breast lesions, particularly in TNBC cases. However, its expression in a growing number of non-breast cancers, such as lung adenocarcinoma, prostate adenocarcinoma, urothelial carcinoma, ovarian high-grade serous carcinoma, and endometrial adenocarcinoma, as well as up to 96% of synovial sarcomas with SS18-SSX fusion, emphasizes the need for caution when interpreting TRPS1 positivity and suggests a multi-marker approach in order to increase the diagnostic accuracy. Conclusions: While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility. Full article

Background/Objectives: Bladder cancer, predominantly urothelial carcinoma, is an important malignancy of the urinary system. Despite the same histologic grade and stage, some patients seem to have a worse prognosis. In this context, the epithelial–mesenchymal transition (EMT), characterized by the loss of E-cadherin and gain of vimentin expression, is an important process in tumor progression. Galectin-3, a lactose-binding protein involved in various cellular processes, has been associated with increased tumor cell migration, invasion, and treatment resistance. Methods: In this study, 223 bladder cancer cases were examined, and E-cadherin, vimentin, and galectin-3 expression was evaluated by immunohistochemical staining in tumor budding areas and invasive components. These markers were also correlated with clinicopathological parameters, including tumor grade and stage. Results: The results indicated a significant decrease in E-cadherin expression and an increase in vimentin staining in higher-grade and higher-stage tumors, supporting EMT involvement. Galectin-3 expression was notably higher in T1 high-grade tumors but decreased in T2 stage tumors. Despite this, no significant correlation was found between galectin-3 and E-cadherin or vimentin, suggesting a complex role of galectin-3 in EMT. Conclusions: High galectin-3 expression in T1 high-grade tumors highlights its potential role in early tumor progression and as a therapeutic target. However, the decrease in its expression in advanced stages underscores the need for further research to understand its multifaceted involvement in bladder cancer. These findings suggest that while galectin-3 may contribute to the EMT and early tumor progression, its exact role and potential as a therapeutic target require more detailed investigation. Full article

Background/Objectives: Trefoil factor 1 (TFF1) plays a role in the mucus barrier. Methods: To evaluate the prevalence of TFF1 expression in cancer, a tissue microarray containing 18,878 samples from 149 tumor types and 608 samples of 76 normal tissue types was analyzed through immunohistochemistry (IHC). Results: TFF1 staining was detectable in 65 of 149 tumor categories. The highest rates of TFF1 positivity were found in mucinous ovarian carcinomas (76.2%), colorectal adenomas and adenocarcinomas (47.1–75%), breast neoplasms (up to 72.9%), bilio-pancreatic adenocarcinomas (42.1–62.5%), gastro-esophageal adenocarcinomas (40.4–50.0%), neuroendocrine neoplasms (up to 45.5%), cervical adenocarcinomas (39.1%), and urothelial neoplasms (up to 24.3%). High TFF1 expression was related to a low grade of malignancy in non-invasive urothelial carcinomas of the bladder (p = 0.0225), low grade of malignancy (p = 0.0003), estrogen and progesterone receptor expression (p < 0.0001), non-triple negativity (p = 0.0005) in invasive breast cancer of no special type, and right-sided tumor location (p = 0.0021) in colorectal adenocarcinomas. Conclusions: TFF1 IHC has only limited utility for the discrimination of different tumor entities given its expression in many tumor entities. The link between TFF1 expression and parameters of malignancy argues for a relevant biological role of TFF1 in cancer. TFF1 may represent a suitable therapeutic target due to its expression in only a few normal cell types. Full article

Background: Urothelial carcinoma presents as non-muscle-invasive bladder cancer (NMIBC) in ~75% of primary cases. Addressing the limitations of the TNM and WHO04/16 classification systems, this study investigates genetic alterations, the mitotic activity index (MAI), and immunohistochemistry (IHC) markers CK20, p53, and CD25 as better prognostic biomarkers in NMIBC. Methods: Using the Oncomine™ Focus Assay for targeted next-generation sequencing (NGS), 409 single-nucleotide variations (SNVs) and 193 copy number variations (CNVs) were identified across 287 patients with TaT1 tumors. Results: FGFR3 and PIK3CA alterations were significantly more prevalent in Ta tumors, while T1 tumors had significant ERBB2 alterations. Low-grade (LG) tumors were enriched with FGFR3 alterations, while high-grade (HG) tumors were significantly associated with ERBB2 alterations, as well as FGFR1 and CCND1 amplifications. FGFR3 alterations were linked to shorter recurrence-free survival (RFS; p = 0.033) but improved progression-free survival (PFS; p < 0.001). Conversely, ERBB2 alterations (p < 0.001), ERBB3 mutations (p = 0.044), and both MYC (p < 0.001) and MYCN (p = 0.011) amplifications were associated with shorter PFS. Survival analysis of gene sets revealed inverse associations between PIK3CA and ERBB2 (p = 0.003), as well as PIK3CA and MYC (p = 0.005), with PFS. Conclusions: In multivariate Cox regression, MAI was the strongest predictor for PFS. Integrating genetic alterations and histopathological features may improve risk stratification in NMIBC. Full article

Background/Objectives: Bladder cancer is a prevalent urinary system malignancy and urinary cytology is widely used for its screening and follow-up. A novel diagnostic tool called Bladder Epicheck^® (BE) is increasingly being used for monitoring the recurrence of non-muscle-invasive bladder cancer (NMIBC). The simultaneous use of BE and urinary cytology can increase the diagnostic performances in the follow-up of bladder neoplasms. Methods: In this multicenter study, we retrospectively evaluated the data of 322 patients in follow-up for a high-grade bladder carcinoma over a six-year period (from January 2018 to March 2024). The diagnostic performances of both cytology and BE and their combination were calculated using histology as gold standard. Results: Recurrences were diagnosed as high-grade urothelial carcinoma NMIBC in 18 cases, low-grade papillary NMIBC in 8 cases, and carcinoma in situ (CIS) in 4 cases. Cytological analysis correctly identified 26 out of 30 carcinomas, while 286 were correctly diagnosed as negative results. BE correctly identified 25 out of 30 carcinomas, 285 were correctly diagnosed as negative results. The combination of BE and urinary cytology correctly identified 29 out of 30 carcinomas, while 289 were correctly diagnosed as negative results. Conclusions: The combination of BE and cytology could be the most effective approach for follow-up diagnosis in patients with high-grade NMIBC, reducing unnecessary invasive procedures. Full article

Contrast-enhanced ultrasound (CEUS) is an advanced imaging technique that integrates conventional US with the intravenous injection of specific US contrast agents (UCAs), combining the non-invasiveness of US with the higher accuracy of contrast-enhanced imaging. In contrast with magnetic resonance imaging (MRI), computed tomography (CT) and cystoscopy, CEUS has few contraindications, and UCAs are non-nephrotoxic agents that can be safely used in patients with kidney failure. CEUS is a well-established method for the detection of liver lesions and for echocardiography, and its indications are expanding. The updated 2018 WFUMB-EFSUMB guidelines have added the urinary bladder under non-hepatic applications of CEUS. The technique is able to distinguish between benign tissue, such as clots or hematoma, and malignant lesions by perfusing the mass with contrast agent. Thanks to the different perfusion rates of the various layers of the bladder wall, CEUS is also able to predict tumor invasion depth and stage. Despite that, current urological guidelines do not include CEUS as a plausible imaging technique for bladder urothelial carcinoma. The main reason for this omission might be the presence of scarce randomized evidence and the absence of large validated series. In this review, we describe the rationale behind the use of CEUS in bladder cancer and the added value of this imaging technique in the detection and staging of bladder lesions. In addition, we researched the available literature on the topic and then described the results of randomized clinical trials and a meta-analysis investigating the accuracy of CEUS in bladder cancer diagnosis and staging. The reported studies show that CEUS is a highly accurate diagnostic and staging tool for BC, reaching levels of specificity and sensitivity in differentiating between Ta-T1, or low-grade BC, and T2, or high-grade BC, that are comparable to those shown by the reference standard methods. Nonetheless, several limitations were found and are highlighted in this review. The aim of this study is to further validate and promote the use of CEUS as a quick, economic and effective diagnostic tool for this high-impact disease. Full article

Stimulator of interferon genes protein (STING) activates the immune response in inflammatory cells. STING expression in cancer cells is less well characterized, but STING agonists are currently being evaluated as anticancer drugs. A tissue microarray containing 18,001 samples from 139 different tumor types was analyzed for STING by immunohistochemistry. STING-positive tumor cells were found in 130 (93.5%) of 139 tumor entities. The highest STING positivity rates occurred in squamous cell carcinomas (up to 96%); malignant mesothelioma (88.5%–95.7%); adenocarcinoma of the pancreas (94.9%), lung (90.3%), cervix (90.0%), colorectum (75.2%), and gallbladder (68.8%); and serous high-grade ovarian cancer (86.0%). High STING expression was linked to adverse phenotypes in breast cancer, clear cell renal cell carcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and papillary carcinoma of the thyroid (p < 0.05). In pTa urothelial carcinomas, STING expression was associated with low-grade carcinoma (p = 0.0002). Across all tumors, STING expression paralleled PD-L1 positivity of tumor and inflammatory cells (p < 0.0001 each) but was unrelated to the density of CD8+ lymphocytes. STING expression is variable across tumor types and may be related to aggressive tumor phenotype and PD-L1 positivity. The lack of relationship with tumor-infiltrating CD8+ lymphocytes argues against a significant IFN production by STING positive tumor cells. Full article

Bladder cancer (BC) is a malignant tumor of the urinary system with high mortality and recurrence rates. Proteasome subunit type 4 (PSMB4) is highly expressed and has been identified as having oncogenic properties in a variety of cancer types. This study aimed to explore the effect of PSMB4 knockdown on the survival, migration, and angiogenesis of human bladder cancer cells with different degrees of malignancy. We analyzed the effects of PSMB4 knockdown in bladder cancer cells and endothelial cells in the tumor microenvironment. PSMB4 was highly expressed in patients with low- and high-grade urothelial carcinoma. Inhibition of PSMB4 reduced protein expression of focal adhesion kinase (FAK) and myosin light chain (MLC), leading to reduced migration. Furthermore, the suppression of PSMB4 decreased the levels of vascular endothelial factor B (VEGF-B), resulting in lower angiogenic abilities in human bladder cancer cells. PSMB4 inhibition affected the migratory ability of HUVECs and reduced VEGFR2 expression, consequently downregulating angiogenesis. In the metastatic animal model, PSMB4 knockdown reduced the relative volumes of lung tumors. Our findings suggest the role of PSMB4 as a potential target for therapeutic strategies against human bladder cancer. Full article

Background: In the EV-301 trial, enfortumab vedotin prolonged survival in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum-based therapy and programmed cell death 1/programmed death-ligand 1 inhibitor. However, real-world Asian data are limited, and potential prognostic markers are non-existent. We aimed to investigate potential prognostic markers for enfortumab vedotin therapy in Asian patients. Methods: We retrospectively enrolled 61 Japanese patients treated with enfortumab vedotin therapy at our hospital and affiliated hospitals between January 2019 and September 2023. Results: Enrolled patients (38 men, 23 women; median age 74 [IQR: 68–79] years) had bladder cancer (26 patients) or upper-tract urothelial carcinoma (35 patients). Fifty-four patients reported adverse events (grade >3 in 12). Skin disorders, pruritus, and neuropathy were common adverse effects. The median overall survival was 17.1 months (95% confidence interval: 10.0–not applicable). In multivariate analysis, the C-reactive protein level was an independent marker predicting favorable overall survival with enfortumab vedotin. Patient characteristics did not differ between C-reactive protein-high and -low groups. Conclusions: Our study provides real-world data showing that enfortumab vedotin prolonged survival in Asian patients similar to the EV-301 trial. Additionally, the C-reactive protein level might be considered a prognostic marker of enfortumab vedotin therapy in such patients. Full article