High-grade Urothelial Carcinoma Research Articles

Significance of TERT promoter mutation in differential diagnosis of non-invasive inverted urothelial lesions of bladder

Objective: To investigate the gene mutation of telomerase reverse transcriptase (TERT) promoter in inverted urothelial lesions of the bladder and its significance in differential diagnosis. Methods: From March 2016 to February 2022, a total of 32 patients with inverted urothelial lesions diagnosed in Department of Pathology at Qingdao Chengyang People's Hospital and 24 patients at the Affiliated Hospital of Qingdao University were collected, including 7 cases of florid glandular cystitis, 13 cases of inverted urothelial papilloma, 8 cases of inverted urothelial neoplasm with low malignant potential, 17 cases of low-grade non-invasive inverted urothelial carcinoma, 5 cases of high-grade non-invasive inverted urothelial carcinoma, and 6 cases of nested subtype of urothelial carcinoma were retrospectively analyzed for their clinical data and histopathological features. TERT promoter mutations were analyzed by Sanger sequencing in all the cases. Results: No mutations in the TERT promoter were found in the florid glandular cystitis and inverted urothelial papilloma. The mutation rates of the TERT promoter in inverted urothelial neoplasm with low malignant potential, low grade non-invasive inverter urothelial carcinoma, high grade non-invasive inverted urothelial carcinoma and nested subtype urothelial carcinoma were 1/8, 8/17, 2/5 and 6/6, respectively. There was no significant difference in the mutation rate of TERT promoter among inverted urothelial neoplasm with low malignant potential, low-grade non-invasive inverted urothelial carcinoma, and high-grade non-invasive inverted urothelial carcinoma (P>0.05). All 6 cases of nested subtype of urothelial carcinoma were found to harbor the mutation, which was significantly different from inverted urothelial neoplasm with low malignant potential and non-invasive inverted urothelial carcinoma (P<0.05). In terms of mutation pattern, 13/17 of TERT promoter mutations were C228T, 4/17 were C250T. Conclusions: The morphology combined with TERT promoter mutation detection is helpful for the differential diagnosis of bladder non-invasive inverted urothelial lesions.

A Fully Automated Artificial Intelligence System to Assist Pathologists’ Diagnosis to Predict Histologically High-grade Urothelial Carcinoma from Digitized Urine Cytology Slides Using Deep Learning

BackgroundUrine cytology, although a useful screening method for urothelial carcinoma, lacks sensitivity. As an emerging technology, artificial intelligence (AI) improved image analysis accuracy significantly. ObjectiveTo develop a fully automated AI system to assist pathologists in the histological prediction of high-grade urothelial carcinoma (HGUC) from digitized urine cytology slides. Design, setting, and participantsWe digitized 535 consecutive urine cytology slides for AI use. Among these slides, 181 were used for AI development, 39 were used as AI test data to identify HGUC by cell-level classification, and 315 were used as AI test data for slide-level classification. Outcome measurements and statistical analysisOut of the 315 slides, 171 were collected immediately prior to bladder biopsy or transurethral resection of bladder tumor, and then outcomes were compared with the histological presence of HGUC in the surgical specimen. The primary aim was to compare AI prediction of the histological presence of HGUC with the pathologist’s histological diagnosis of HGUC. Secondary aims were to compare the time required for AI evaluation and concordance between the AI's classification and pathologist’s cytology diagnosis. Results and limitationsThe AI capability for predicting the histological presence of HGUC was 0.78 for the area under the curve. Comparing the AI predictive performance with pathologists' diagnosis, the AI sensitivity of 63% for histological HGUC prediction was superior to a pathologists' cytology sensitivity of 46% (p = 0.0037). On the contrary, there was no significant difference between the AI specificity of 83% and pathologists' specificity of 89% (p = 0.13), and AI accuracy of 74% and pathologists' accuracy of 68% (p = 0.08). The time required for AI evaluation was 139 s. With respect to the concordance between the AI prediction and pathologist’s cytology diagnosis, the accuracy was 86%. Agreements with positive and negative findings were 92% and 84%, respectively. ConclusionsWe developed a fully automated AI system to assist pathologists’ histological diagnosis of HGUC using digitized slides. This AI system showed significantly higher sensitivity than a board-certified cytopathologist and may assist pathologists in making urine cytology diagnoses, reducing their workload. Patient summaryIn this study, we present a deep learning–based artificial intelligence (AI) system that classifies urine cytology slides according to the Paris system. An automated AI system was developed and validated with 535 consecutive urine cytology slides. The AI predicted histological high-grade urothelial carcinoma from digitized urine cytology slides with superior sensitivity than pathologists, while maintaining comparable specificity and accuracy.

Sensitivity of urine cytology in detecting high-grade urothelial carcinoma in patients with neoplastic urinary bladder diverticula: A major cancer center experience.

Bladder diverticula are herniations of bladder urothelium and mucosa through the muscularis propria. The reported incidence of neoplasia arising in bladder diverticula is widely variable. The authors' objective was to study the characteristics and sensitivity of urine cytology in these patients with emphasis on primary intradiverticular bladder cancer (IDBC). A 17-year, retrospective review of all resected bladder diverticula associated with bladder carcinoma was performed. Cases that had complete diverticular resections and preresection urine samples were included in this study. The cases were divided into either primary IDBC or primary extradiverticular bladder cancer (EDBC). Demographic data and urine cytology characteristics were recorded, and sensitivity was calculated. For IDBC, a comparison between voided and cystoscopic urines was done for cases that had both collection methods performed. Of 70 patients with IDBC, 47 patients had urine cytology results that were either positive for high grade-urothelial carcinoma (HG-UC) or suspicious for HG-UC. The sensitivity for HG-UC in IDBC samples was 80%, compared with 82% in EDBC samples (p>.05). Also, 28 patients in the IDBC group had both voided and cystoscopic urine samples for comparisons; in seven patients, the voided urine sample yielded a more definitive diagnosis; in 10 patients, the cystoscopic urine sample yielded a more definitive diagnosis; and, in 11 patients, both samples were equally diagnostic (p>.05). The characteristics and sensitivity of urine cytology in bladder diverticula were investigated in association with neoplasia, with an emphasis on primary intradiverticular bladder cancer. The results indicated that urine cytology remains a reliable screening and diagnostic test for detecting IDBC, with sensitivity similar to that for detecting EDBC, and no significant difference was noted between voided and cystoscopic samples.

A case of large-cell undifferentiated carcinoma of the bladder

Abstract Large-cell undifferentiated carcinoma of the urinary bladder is an extremely rare and aggressive neoplasm. We present a unique case of painless gross hematuria and a past surgical history of cystolithotomy. The patient underwent transurethral resection of the bladder tumor, which revealed high-grade urothelial cell carcinoma with lamina propria involvement. Subsequent radical cystoprostatectomy with orthotopic neobladder urinary diversion and pelvic lymphadenectomy was performed, and the postoperative pathologic examination indicated large-cell undifferentiated. This case report highlights the importance of accurate diagnosis and management for this rare malignancy and adds to the limited existing literature on Large-cell undifferentiated carcinoma.

High-Grade Urothelial Carcinoma with Divergent Prostatic Differentiation Mimicking a Collision Tumor

Abstract Introduction/Objective High-grade urothelial carcinoma (HGUC) shows marked morphologic plasticity with many recognized histologic subtypes that may coexist within the same tumor. These pose a diagnostic challenge and should be distinguished from collision tumors, defined by the coexistence of morphologically and genotypically distinct tumors at the same anatomic site. Herein, we present the first case of HGUC with malignant prostatic differentiation mimicking a collision tumor in a bladder diverticulum. Methods/Case Report 68 yo male presented with gross hematuria and was found to have a 2.2 cm tumor in a posterior bladder diverticulum. Initial transurethral resection (TUR) suggested HGUC, while re-TUR showed prostatic adenocarcinoma. Subsequent diverticulectomy specimen revealed two morphologically and immunohistochemically distinct tumor components: 1) a papillary component associated with urothelial carcinoma in situ, positive for CK903 and GATA3, and compatible with HGUC of the bladder, and 2) a distinct and intimately admixed malignant glandular component, which was GATA3 negative, but positive for markers of prostatic differentiation such as NKX3.1, PSA and PSAP and displayed prostatic duct adenocarcinoma features. Accurate diagnosis of this lesion is crucial, and a few possibilities exist: 1) a collision process between urothelial carcinoma of the bladder and a previously undiagnosed duct carcinoma of the prostate metastatic to the bladder diverticulum; 2) prostate cancer arising from an ectopic prostatic epithelium located in the bladder submucosa; 3) HGUC with malignant divergent prostatic differentiation. To this end, papillary and glandular tumor components were macrodissected and subjected to targeted massively parallel sequencing. Disease-associated variants in EGFR, DDR2, KMT2D, and RB1 were identified and were identical and shared among the two histologically distinct components. These findings suggest that the two components are part of the same neoplastic process and represent a urothelial carcinoma with divergent prostatic differentiation. Of note, the patient’s initial and subsequent PSA levels were within normal limits, and magnetic resonance imaging of the prostate was unremarkable. Results (if a Case Study enter NA) NA Conclusion Awareness of divergent differentiation in urothelial carcinomas has important diagnostic, prognostic and therapeutic implications and can be resolved with the use of ancillary and molecular studies.

INCIDENTAL BLADDER MELANOSIS WITH CHRONIC CYSTITIS

Abstract Introduction/Objective Melanosis is a black or brown discoloration due to melanin deposition in the skin or on the mucosa of body organs such as conjunctiva, lips, mouth, genitalia, colon, and rectum. For example, melanosis coli is associated with chronic laxative use. However, melanosis on the bladder mucosa is an extremely rare, incidental, and benign finding which is commonly associated with bladder cancer or melanoma. We report an unusual case of incidental bladder melanosis with chronic cystitis in a patient diagnosed with bladder cancer. Methods/Case Report A 77-year-old male current smoker presented for a follow-up of recurrent bladder cancer (high-grade T1 Transitional Cell Carcinoma, TCC) diagnosed in 2016 with currently no symptoms. His past medical history included high blood pressure, papillary thyroid carcinoma status post thyroid lobectomy, and Type 2 diabetes mellitus. He had completed two cycles of treatment of Bacillus Calmette-Guerin (BCG) and BCG/Interferon for 6 weeks each. He had multiple transurethral bladder resections and biopsies in the past which revealed invasive high- grade papillary urothelial carcinoma, not invading muscularis propria. A recent computerized tomography scan of the abdomen and pelvis revealed diffuse bladder wall thickening and trabeculation along the dome and posterior urinary bladder. His lab workup including urinalysis, complete blood count, and chemistry were within normal limits. This time, the patient underwent urinary bladder midline and back wall cystoscopic biopsies and transurethral resection of the right lateral wall. The biopsies showed mild chronic cystitis with melanosis, however, the resection showed non- invasive high-grade papillary urothelial carcinoma. Results (if a Case Study enter NA) NA Conclusion Bladder melanosis has been reported less than 25 times in the literature worldwide. The etiology of melanosis is still unknown. No specific symptoms or treatment guidelines have been established for bladder melanosis so far due to decreased number of cases reported and therefore, reduced follow-up surveillance. Nonetheless, the general behavior of bladder melanosis alone seems to be benign. To the best of our knowledge, this is the first report of bladder melanosis with chronic cystitis. Further studies are required to establish the association of bladder melanosis with chronic cystitis and to probe its clinicopathologic course, and implications.

Cytologic evaluation of upper urinary tract specimens: An institutional retrospective study using The Paris System for Reporting Urine Cytology second edition with histopathologic follow-up.

Cytologic evaluation of the upper urinary tract (UUT) can be challenging due to instrumentation artefacts. This study retrospectively reviewed UUT specimens using The Paris System for Reporting Urinary Cytopathology, second edition (TPS 2.0), compared it with the original reporting system (ORS) and correlated it with histopathologic follow-up. An institutional database was reviewed for the UUT biopsy/resection histopathologic specimens, and we included 52 UUT cytology specimens pertinent to these cases in the study. These specimens were blindly reviewed and reclassified using TPS 2.0. The correlation between TPS 2.0, ORS and histopathologic follow-up was assessed. The UUT cytology specimens corresponded to 21 (40.4%) high-grade urothelial carcinoma (HGUC), 27 (51.9%) low-grade urothelial carcinoma (LGUC) and 4 (7.7%) benign cases on follow-up. For HGGC cases, the associated TPS categories included unsatisfactory (n = 1, 4.8%), negative for HGUC (NHGUC; n = 3, 14.3%), atypical urothelial cells (AUC; n = 6, 28.6%), suspicious for HGUC (SHGUC; n = 3, 14.3%) and HGUC (n = 8, 38.1%), while ORS categorised the specimens as unsatisfactory (n = 1, 4.8%), negative for malignant cells (NFMC; n = 3, 14.3%), AUC (n = 5, 23.8%), low-grade urothelial carcinoma (LGUC; n = 0, 0%), SHGUC (n = 5, 23.8%) and HGUC (n = 7, 33.3%). The risks of high-grade malignancy among cytologic categories were similar between ORS and TPS (p > 0.05). The majority of LGUC were classified as AUC similarly by ORS and TPS (55.6% vs. 59.3%). Our study demonstrated comparable performance between TPS 2.0 and ORS for UUT cytology specimens. Cytological diagnosis of UUT specimens remains challenging, especially for LGUC.

Urinary tract cytology showing variant morphology and divergent differentiation.

Urothelial carcinoma represents a diverse group of tumours with distinct histologic subtypes, each exhibiting unique cytomorphologic features, architectural growth patterns, and/or well-developed aberrant differentiation. In fact, there are more than 13 subtypes of urothelial carcinoma recognized in the 2022 WHO classification of tumours in the urinary tract. The identification of these subtypes is crucial for an accurate diagnosis of urothelial carcinoma, and many have important clinical implications. Variant/divergent features may coexist with conventional high-grade urothelial carcinoma (HGUC) or present with 100% variant morphology. In urinary tract cytology (UTC), urothelial carcinoma can display divergent differentiation, such as squamous, glandular, or small cell carcinoma differentiation. The use of cell block preparations and immunohistochemistry with available residual urine can enhance diagnostic accuracy. On the other hand, identifying urothelial carcinoma variants, including nested, micropapillary, and plasmacytoid subtypes, poses significant challenges in UTC. Many cases of these variants are only detected retrospectively after variant histology has been established from resection specimens. Moreover, some variants exhibit features inconsistent with the diagnostic criteria for HGUC according to the Paris System for Reporting Urinary Tract Cytology. Nevertheless, the rarity of pure variant morphology and the occurrence of some false negatives for these variant cases are essential to maintain the specificity of UTC overall. This review covers the histology, cytomorphology, and important clinical aspects observed in urothelial carcinoma exhibiting divergent differentiation and various urothelial carcinoma variants detected in UTC.

LB02 - RETRACTED: Grade heterogeneity in high grade urothelial carcinomas: Does it have an impact on the survival of patients with intermediate/high risk NMIBCr who received adequate adjuvan BCG therapy?

LB02 - RETRACTED: Grade heterogeneity in high grade urothelial carcinomas: Does it have an impact on the survival of patients with intermediate/high risk NMIBCr who received adequate adjuvan BCG therapy?

The First Ever Robotic-Assisted Laparoscopic Radical Nephrectomy with Inferior Vena Cava Thrombectomy Performed in Thailand: A Case Report of Atypical Presentation of Urothelial Carcinoma with Tumor Thrombus

Background: Robotic-assisted surgery was proposed as an alternative to open surgery for management of inferior vena cava (IVC) thrombus together with radical nephrectomy in complex renal mass. Here, the authors reported the first case of this type to be managed via this surgical technique in Thailand. Case Report: A 76-year-old Thai female presented with right renal mass with tumor thrombus in the IVC extending 3 cm above the level of the renal vein. The presumed diagnosis was renal cell carcinoma of the right kidney with level 2 tumor thrombus in IVC, clinical staging T3bN0M0. The patient underwent robotic-assisted laparoscopic IVC thrombectomy together with right radical nephrectomy at Siriraj Hospital (Bangkok, Thailand) in May 2020. Results: The operation proceeded uneventfully without immediate complication. The postoperative reduction of IVC diameter was approximately 30%. Total IVC clamp time was 50 minutes, operative time was five hours, with docking time of 20 minutes and console time of 250 minutes, estimated intraoperative blood loss was 2,600 mL, and length of hospital stay was four days. At 30-days and 90-days postoperation, no thromboembolic event or compromising lower extremity venous return was detected. The pathological report revealed high-grade urothelial cell carcinoma with invasion into perinephric fat. Carcinoma involvement was observed in the tumor thrombus and IVC wall (T4N0M0). Conclusion: Robotic-assisted surgery of the IVC is a complex operation that requires robotic surgical proficiency and a highly experienced team. The observed success in the present case demonstrated the feasibly of this procedure in Thailand. Additional benefits include less postoperative pain, reduced blood loss, smaller surgical wound size, and shorter length of hospital stay. Keywords: Robotic-assisted laparoscopic radical nephrectomy; Inferior vena cava thrombectomy; Thailand

Urinary IL-6 and IL-8 as predictive markers in bladder urothelial carcinoma: A pilot study.

Cytokines are known to be a key a factor in numerous malignancies and to exert an important regulatory role in the tumor microenvironment. Interest has grown in understanding how cytokines modulate the tumor microenvironment and which cytokines may serve as markers of the tumor process; however, a complete picture of the cytokine landscape in bladder cancer remains unclear. Fresh urine specimens with sufficient volume were collected at random intervals. The urine concentrations of IL-8 (CXCL8), CCL18, and CXCL9 were determined using the standard commercially available enzyme immunoassay. The urine concentrations of IL-6 were determined using the high sensitivity enzyme immunoassay kit. Urinary cytokine concentrations were normalized with urinary creatinine concentrations. Significantly elevated concentrations of IL-6 and IL-8 were detected in the urine from patients with urothelial carcinoma on follow-up compared to patients with benign follow-up. The presence of both IL-6 and IL-8 in the urine samples from the high grade urothelial carcinoma (HGUC) cohort revealed a clear discrimination when compared to samples from patients with benign follow-up. The presence of the combination of both IL-6 and IL-8 had a sensitivity of 90.0% and a specificity of 81.25%. Similar data were obtained when receiver operating characteristic analysis was performed on both IL-6 and IL-8 concentrations in the urine from patients with HGUC vs. the hematuria cohort. The presence of IL-6 and IL-8 in urine specimens may have predictive value for urothelial carcinoma. However, a large longitudinal study is required to statistically eliminate confounding factors and support this theory.

Sequential endoluminal gemcitabine and docetaxel for the treatment of clinically non-invasive high-grade upper tract urothelial carcinoma

PurposeThere is an unmet need for effective renal sparing treatments for upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown favorable efficacy in nonmuscle invasive bladder cancer. We report the outcomes of patients treated with endoluminal Gem/Doce for noninvasive high-grade UTUC. MethodsA retrospective review of patients treated with Gem/Doce for clinically noninvasive high-grade UTUC with no radiographic or endoscopically visible disease, either at diagnosis or following ablation, was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks, followed by 6 monthly instillations if disease-free. Recurrence was defined as biopsy-proven disease or high-grade (HG) cytology. Progression was defined by development of muscle invasion, metastases, or death due to cancer. Survival was assessed with the Kaplan-Meier method. ResultsThe final cohort included 31 patients with 41 upper tract units, 51% of which would have been dialysis dependent with nephroureterectomy. Median (IQR) age was 74 years (68–81). Median follow-up was 29 months (IQR 20–58). Prior to treatment, 37 (90%) units presented with a localizing HG cytology (presumed occult CIS), and 4 (9.8%) with HG biopsy-proven disease. Sixteen (52%) patients reported any side effects; 5 were Grade 3 and 1 was Grade 5. Recurrence-free survival was 76%, 54%, and 40% at 1, 2, and 3 years, respectively. Five patients died from urothelial carcinoma. The 3-year progression-free and overall survival were 75% and 75%, respectively. ConclusionsGem/Doce demonstrates promising safety and efficacy as a renal-sparing treatment option for high-grade UTUC in appropriately selected patients.

A Novel Approach to Intraluminal Mitomycin C Instillation for Treatment of High Grade Nonmuscle Invasive Upper Tract Urothelial Carcinoma

Abstract Introduction and Objective: We present a novel technique for intrapelvicalyceal mitomycin C (MMC) instillation mixed with a contrast agent for treatment of high-grade nonmuscle invasive upper tract urothelial carcinoma in patients in whom nephroureterectomy would render them dialysis-dependent. Methods: After incomplete endoscopic resection, the patient underwent 3 intrapelvicalyceal instillations of MMC mixed with iopamidol, each 2 weeks apart. Results: Treatment has had a durable response for over 2 years after treatment. Conclusions: Intraluminal MMC mixed with iopamidol is an approach which helps to avoid pyelovenous backflow and provides visual confirmation that the drug is in adequate contact with the tumor.

Clinicopathological profile of urothelial carcinoma of the bladder: A five-year retrospective study

Background and Objectives. Urothelial carcinoma of the bladder is more common than urothelial carcinoma of the upper urinary tract. Carcinoma of the bladder is the tenth most common cancer in the world, with 570,000 new cases and 213,000 deaths annually. Men are significantly more likely than women to develop bladder cancer, with an incidence of 9.5 per 100,000 and a mortality of 3.3 per 100,000, which are rates approximately four times those seen among women globally. Clinicopathological profiling is highly significant in bladder carcinoma because the majority of specimens are received through TURBT. Materials and Methods. This observational descriptive study takes a retrospective approach. The population of this study consists of paraffin blocks obtained from biopsy, transurethral resection of bladder tumor, and cystectomy that were used to diagnose urothelial carcinoma of the bladder through histopathological analysis in the Dr. Soetomo General Academic Hospital between January 2018 and December 2022. The demographic and histopathological data were taken from the patients’ medical records. Results. The majority of patients were men (88%). The average age of the patients was 58.65 years, with a range of 21–80 years and peak incidence occurring at 51–60 years (39%). The procedure most frequently employed was TURBT (68.48%), and squamous differentiation was the most frequent histologic finding (87.5%). The most common type of urothelial carcinoma of the bladder found on urine cytopathology examination was negative for high-grade urothelial carcinoma (81%). Conclusions. The clinicopathological profile is very important in determining the prognostic factor in urothelial carcinoma of the bladder. Most patients herein were men in the age group of 51–60 years. The procedure most frequently employed was TURBT. Most tumors comprised urothelial carcinoma with squamous differentiation, and the majority was negative for high-grade urothelial carcinoma on urine cytopathological examination.

A Case Report: High-Grade Urothelial Carcinoma in the Renal Pelvis with Complete Kidney and Ureter Duplication Featuring Heterologous Differentiation

This report describes a considerably rare case of high-grade urothelial carcinoma of the renal pelvis and ureter, presenting with heterologous differentiation, in a patient with bilateral duplicated kidneys. A 73-year-old male experienced intermittent gross hematuria for 5 months, accompanied by lower back and abdominal pain. Ultrasound and computed tomography scans revealed bilateral renal and ureteral duplication with multiple tumors in the left renal pelvis. A total nephroterectomy and bladder cuff resection were performed on the left two nephrons. Multiple space-occupying lesions were identified in the left renal pelvis and ureter. Histopathological examination showed poorly differentiated and diverse tumor cells, manifesting as sarcomatoid carcinoma, papillary adenocarcinoma, and infiltrating high-grade urothelial carcinoma. The tumor infiltrated the subcutaneous fibrous connective tissue of the renal pelvis and the full thickness of the ureter. Given the rarity of recurrent renal urothelial carcinoma with heterogeneous differentiation, comprehensive imaging and pathological assessments are vital to delineate the nature of the lesion and the direction of tissue pathological heterologous differentiation. These evaluations guide early radical surgical interventions, improving survival rates.

MCM4 expression is associated with high-grade histology, tumor progression and poor prognosis in urothelial carcinoma

BackgroundWe previously reported Minichromosome maintenance 4 (MCM4) overexpression in gastric cancer. However, the clinicopathological significance of MCM4 in urothelial carcinoma (UC) has not been investigated. To clarify the clinicopathological significance of MCM4 in UC, we investigated MCM4 expression with immunohistochemistry (IHC).MethodsWe analyzed the expression and distribution of MCM4 in 124 upper tract urothelial carcinoma (UTUC) samples by IHC. Additionally, using 108 urine samples, we analyzed MCM4 Immunocytochemistry (ICC) expression in urine cytology.ResultsIn normal urothelium, MCM4 expression was weak or absent. Meanwhile, the strong nuclear expression of MCM4 was observed in UTUC tissues, and it was detected in 77 (62%) of a total of 124 UTUC cases. MCM4-positive UTUC cases were associated with nodular/flat morphology, high grade, high T stage, and poor prognosis. Moreover, MCM4 expression was significantly higher in the invasive front than in the tumor surface. Similar results were also obtained in TCGA bladder cancer cohort. Additionally, MCM4 expression was associated with high expression of Ki-67, HER2, EGFR, and p53 in UTUC. Among representative cancer-related molecules, MCM4 had an independent predictive value for progression-free survival and high-grade UC. ICC for MCM4 was also performed on urine cytology slides and showed that the nuclear expression of MCM4 was more frequently found in UC cells than in non-neoplastic cells. The diagnostic accuracy of urine cytology was improved by combining MCM4 immunostaining with cytology.ConclusionThese results suggest that MCM4 might be a useful predictive biomarker for high-grade histology, tumor progression and poor prognosis in UC. Moreover, ICC for MCM4 might be helpful for UC detection as additional markers in the cytomorphology-based diagnosis.

Role of GATA3 in Early-Stage Urothelial Bladder Carcinoma Local Recurrence.

Background One of the most characteristic features of non-invasive urothelial carcinoma (UC) is its high recurrence rate. Guanine-adenine-thymine-adenine nucleotide sequence-binding protein 3 (GATA3), as a transcription factor, correlates with urothelial differentiation and has been reported with poor prognosis in high-grade UC and recurrence in breast malignancies. As such, we set out to study the specifics of GATA3 in non-invasive UC, emphasizing on prediction for recurrence. Methods The cohort comprised 163 patients, with a follow-up period of five years, including 109 pTa cases and 54 pT1 cases. Immunohistochemical expression of GATA3 was assessed using a histo score (H-score). Kaplan-Meier test was conducted for the time to recurrence, according to the level of expression of GATA3 and the indicators studied. Receiver operating characteristic (ROC) curve analysis was done to determine the role of accuracy and specificity of predictability of the indicators. Results Recurrence within the follow-up period was noted in 41.72% of cases. No recurrence relationship was established for age and gender. GATA3 expression showed a varying H-score. Using ROC curve analysis, a cut-off value of 155 divided UC expression levels into low and high, with a sensitivity of 72.7% and specificity of 78.7% (area under the curve=0.800, 95% confidence interval: 0.696-0.904, p<0.001), further showing an association between high levels of nuclear expression and risk of local recurrence (p<0.0001). Conclusion Herein we have described the sensitivity of high GATA3 expression in non-invasive UC of the urinary bladder and its relation to local recurrence, independent of gender, age, tumor differentiation, and stage.

PD-L1 protein expression by Combined Positive Score (CPS) in patients with muscle invasive or advanced urothelial carcinoma: a single institution experience

IntroductionImmune checkpoint inhibitors have revolutionized the treatment of patients with advanced urothelial carcinoma (UC) in the frontline and relapsed settings. Lebanon has one of the highest incidence of UC worldwide, yet no data exists regarding the expression of PD-L1 by Combined Positive Score (CPS) in advanced disease.MethodsWe reviewed all patients treated at our institution for high grade UC, stage pT2 and above, between January 2017 and March 2021. We assessed the expression of PD-L1 by immunohistochemistry using 22C3 clone, and analyzed the association between PD-L1 expression and clinicopathological characteristics. PD-L1 positivity was defined as CPS score ≥ 10.ResultsA total of 101 patients with advanced UC were included, with a median age of 71 years (range, 38 to 96 years); 78% were ever-smokers. Ninety-three of 101 patients (92%) had conventional UC and 43 patients (43%) had positive PD-L1 expression, with 12 patients having CPS of 100. The analysis by molecular subtype showed that patients with maximal CPS of 100 were enriched in “basal” molecular subtype. However, no association was found between PD-L1 expression (positive versus negative) and clinicopathological characteristics.ConclusionThe positivity of PD-L1 expression as assessed by CPS using the 22C3 clone in our population was almost comparable to the results reported in the occidental literature. Therefore, PD-L1 expression, as a potential predictor of response to immunotherapy, concerns the same percentage of the Lebanese UC patients.

Variants of High-Grade Urothelial Carcinoma: Can We Catch Them in Urine Cytology Using The Paris System?

Variants of High-Grade Urothelial Carcinoma: Can We Catch Them in Urine Cytology Using The Paris System?

High grade urothelial carcinoma in kidney transplant patients with a history of BK viremia - Just a coincidence?

Kidney transplant recipients (KTR) have a three-to-four-fold increased risk of developing urothelial carcinoma (UC) compared to the general population. BK polyoma virus (BKV) infection is known to affect approximately 15% of KTR. In vitro models support a potential pathogenic role for BKV in the development of UC. We describe a series of UC in kidney transplant recipients. Electronic patient records were searched to identify KTR with UC who had undergone kidney only or simultaneous kidney and pancreas transplantation in a single UK center between 2009 and 2015. Where available, stored pathological samples were retrieved, re-examined and stained for SV40 as a marker of BKV using standard staining protocols for kidney biopsy samples. Fourteen KTR had developed UC post-transplant. Of these, 10 KTR had a history of BKV infection post-transplant. Six of these 10 KTR developed a rare micropapillary tumor subtype of UC which is typically only found in <1% of UC cases. All six micropapillary tumor samples stained positive for SV40, including samples from metastases. Three tumor samples were available from the four KTR with no history of BKV infection and were not micropapillary subtype and were negative for SV40. Three micropapillary tumors from immunocompetent patients were examined as controls and were negative for SV40. These findings would support a pathogenic role for BK virus in the development of rare micropapillary subtype urothelial tumors in the kidney transplant population.