Papillary Urothelial Carcinoma Research Articles

Case Report: Urothelial urethral carcinoma in HIV patient underwent total urethrectomy and perineal urethrostomy

Introduction HIV affects over 38 million people worldwide, affecting the immune system and leading to symptoms like fever, lymphadenopathy, and sore throat. High viral loads can lead to opportunistic infections and tumors. The life expectancy of HIV patients has increased due to high-efficiency combination anti-retroviral therapy. Urothelial carcinoma, a malignant development, damages the urinary canal lining. The connection between HIV and urinary cancers is unclear, the aims of this study to report a case of urethral urothelial Carcinoma in HIV patient who underwent total urethrectomy and perineal urethrostomy. Case presentation A 34-year-old male patient with a papilliferous lump on the glans penis for over six months was admitted to the hospital. Preoperative screening revealed HIV and a urethral mass was found. A partial urethrectomy was performed, revealing high grade papillary urothelial Carcinoma. Five months after surgery, the patient developed a recurrent lump, requiring a total urethrectomy, TUR (transurethral resection) of the mass in the prostatic urethra, and perineal urethrostomy. Conclusion Primary carcinoma of the urethra in HIV patient is an extremely rare case. To date, there is no consensus on the primary urethral carcinoma therapy. The treatment of primary urethral carcinoma is tailored specifically to the patient based on the location, histology, and stage of the carcinoma.

Outcome Analysis of a Series of Mixed-Grade, Non-muscle Invasive, Papillary Carcinomas of the Bladder.

Introduction. Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited. Methods. The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers. Results. Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >pT2. Conclusions. The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors.

Spatial Distribution of Macrophage and Lymphocyte Subtypes within Tumor Microenvironment to Predict Recurrence of Non-Muscle-Invasive Papillary Urothelial Carcinoma after BCG Immunotherapy.

Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette-Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial-stromal interface zone compartments and their distribution, represented by an epithelial-stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.

The role of histological subtype and chemotherapy on prognosis of ureteral cancer

ObjectiveTo date, there have been few studies examining the prognostic implications of histological subtypes in ureteral cancer. And chemotherapy plays a crucial role in the treatment of ureteral cancer, while many factors influence the efficacy of chemotherapy. This study aimed to utilize the Surveillance, Epidemiology and End Results database to assess the impact of histological type on ureteral cancer prognostic outcomes and discovered how histological type and T-stage influence the efficacy of chemotherapy.MethodsBased on Surveillance, Epidemiology, and End Results Program, we reviewed 8915 records of patients with primary ureteral cancer from 18 centers between 2000 and 2018. We focused on the overall survival and cancer-specific survival of the records and used Kaplan‒Meier method to calculate survival curves.ResultsIn the comparison of prognostic outcomes, atypical subtypes exhibited a less favorable prognosis compared to typical ureteral carcinoma. Notably, patients diagnosed with papillary urothelial carcinoma demonstrated the most favorable overall survival (p = 0.005). Statistically significant benefits were observed in the prognosis of patients with non-papillary urothelial carcinoma who received chemotherapy (HR = 0.860, 95% CI 0.764–0.966, p = 0.011), while chemotherapy did not yield a statistically significant effect on the prognosis of patients with papillary urothelial carcinoma (HR = 1.055, 95% CI 0.906–1.228, p = 0.493). Chemotherapy had an adverse impact on the prognosis of patients with T1 ureteral cancer (HR = 1.235, 95% CI 1.016–1.502, p = 0.034), whereas it exhibited a positive prognostic effect for T3/T4 cases (HR = 0.739, 95% CI 0.654–0.835, p < 0.001).ConclusionsHistological type affects the prognosis of ureteral cancer. And evaluation of cancer histological type and T stage in ureteral cancer patients prior to chemotherapy is mandatory.

Safety and Diagnostic Efficacy of Image-Guided Biopsy of Small Renal Masses.

Image-guided renal mass biopsy is gaining increased diagnostic acceptance, but there are limited data concerning the safety and diagnostic yield of biopsy for small renal masses (≤4 cm). This study evaluated the safety, diagnostic yield, and management after image-guided percutaneous biopsy for small renal masses. A retrospective IRB-approved study was conducted on patients who underwent renal mass biopsy for histopathologic diagnosis at a single center from 2015 to 2021. Patients with a prior history of malignancy or a renal mass >4 cm were excluded. Descriptive statistics were used to summarize patient demographics, tumor size, the imaging modality used for biopsy, procedure details, complications, pathological diagnosis, and post-biopsy management. A biopsy was considered successful when the specimen was sufficient for diagnosis without need for a repeat biopsy. Complications were graded according to the SIR classification of adverse events. A chi-squared test (significance level set at p ≤ 0.05) was used to compare the success rate of biopsies in different lesion size groups. A total of 167 patients met the inclusion criteria. The median age was 65 years (range: 26-87) and 51% were male. The median renal mass size was 2.6 cm (range: one-four). Ultrasound was solely employed in 60% of procedures, CT in 33%, a combination of US/CT in 6%, and MRI in one case. With on-site cytopathology, the median number of specimens obtained per procedure was four (range: one-nine). The overall complication rate was 5%. Grade A complications were seen in 4% (n = 7), consisting of perinephric hematoma (n = 6) and retroperitoneal hematoma (n = 1). There was one grade B complication (0.5%; pain) and one grade D complication (0.5%; pyelonephritis). There was no patient mortality within 30 days post-biopsy. Biopsy was successful in 88% of cases. A sub-group analysis showed a success rate of 85% in tumors <3 cm and 93% in tumors ≥3 cm (p = 0.01). Pathological diagnoses included renal cell carcinoma (65%), oncocytoma (18%), clear cell papillary renal cell tumors (9%), angiomyolipoma (4%), xanthogranulomatous pyelonephritis (1%), lymphoma (1%), high-grade papillary urothelial carcinoma (1%), and metanephric adenoma (1%), revealing benign diagnosis in 30% of cases. The most common treatment was surgery (40%), followed by percutaneous cryoablation (22%). In total, 37% of patients were managed conservatively, and one patient received chemotherapy. This study demonstrates the safety and diagnostic efficacy of image-guided biopsy of small renal masses. The diagnostic yield was significantly higher for masses 3-4 cm in size compared to those <3 cm. The biopsy results showed a high percentage of benign diagnoses and informed treatment decisions in most patients.

Challenges and technical aspects in the management of muscle invasive bladder cancer as retrograde radical cystectomy with ileal conduit.

To evaluate long-term outcomes in patients homogenously treated with radical cystectomy and ileal conduit for muscle invasive bladder cancer. The retrospective study was conducted at the Urology Department of Pakistan Kidney and Liver Institute and Research Centre, Lahore, Pakistan, and comprised data from December 25, 2017, to January 16, 2023, related to patients who underwent radical cystectomy with ileal conduit with or without neo-adjuvant and adjuvant radiation, chemotherapy, or immunotherapy for papillary urothelial carcinom of the bladder. Clinical trajectory, histopathological characteristics and long-term clinical outcomes were noted. Data was analysed using SPSS 20. In our study of 40 patients with muscle invasive bladder cancer, males predominated (32, 80%), with a median age of 57.4 years (IQR: 29-80). Diagnosis was early in 5 (12.5%) patients with varying haematuria durations, while 34 (85%) patients had a smoking history. Comorbidities included hypertension in 17 (42.5%) patients, diabetes in 1 (2.5%) patient, both hypertension and diabetes in 9 (22.5%) patients and a combination of hypertension, diabetes, and ischaemic heart disease in 3 (7.5%) patients. Transurethral resection was performed once in 13 (32.5%) patients and multiple times in 27 (67.5%) patients. Additionally, 5 (12.5%) patients received immunotherapy, 11 (27.5%) patients underwent non-adjuvant radiation, and 14 (35%) patients received non-adjuvant chemotherapy. Papillary urothelial carcinoma was the predominant histological subtype among 37 (92.5%) patients. Patients receiving chemotherapy had significantly better overall survival (p=0.02). No significant differences were noted in recurrence or survival by therapy modality (p>0.05). These findings highlight the significance of early diagnosis, tailored treatments, and comorbidity management in muscle invasive bladder cancer patients. Age stratification revealed significant survival differences across groups (χ²=10.923, df=3, p= 0.012). Analysis by complications did not show age-related survival variations (χ² =3.978, df = 3, p=0.264). Achieving excellent long-term survival in MIBC patients requires a multidisciplinary approach, emphasizing early diagnosis, tailored treatment, and adherence to guidelines and protocols.

Prediction of Non-Muscle Invasive Papillary Urothelial Carcinoma Relapse from Hematoxylin-Eosin Images Using Deep Multiple Instance Learning in Patients Treated with Bacille Calmette-Guérin Immunotherapy.

The limited reproducibility of the grading of non-muscle invasive papillary urothelial carcinoma (NMIPUC) necessitates the search for more robust image-based predictive factors. In a cohort of 157 NMIPUC patients treated with Bacille Calmette-Guérin (BCG) immunotherapy, we explored the multiple instance learning (MIL)-based classification approach for the prediction of 2-year and 5-year relapse-free survival and the multiple instance survival learning (MISL) framework for survival regression. We used features extracted from image patches sampled from whole slide images of hematoxylin-eosin-stained transurethral resection (TUR) NPMIPUC specimens and tested several patch sampling and feature extraction network variations to optimize the model performance. We selected the model showing the best patient survival stratification for further testing in the context of clinical and pathological variables. MISL with the multiresolution patch sampling technique achieved the best patient risk stratification (concordance index = 0.574, p = 0.010), followed by a 2-year MIL classification. The best-selected model revealed an independent prognostic value in the context of other clinical and pathologic variables (tumor stage, grade, and presence of tumor on the repeated TUR) with statistically significant patient risk stratification. Our findings suggest that MISL-based predictions can improve NMIPUC patient risk stratification, while validation studies are needed to test the generalizability of our models.

[Bladder Cancer Detected Incidentally by Cystoscopy before Radical Prostatectomy].

Radical prostatectomy is the treatment of choice for localized prostate cancer. In our institution, preoperative cystoscopy is performed routinely to clarify the prostate anatomy, including the median lobe and position of ureteral orifices. We conducted a retrospective analysis of 721 patients, from January 2008 to December 2022, our aim being to assess the clinical course of bladder cancer discovered incidentally through cystoscopy prior to radical prostatectomy. We found that bladder cancer was detected in eight of these patients (1.1%), seven of whom had low-grade, non-invasive, papillary urothelial carcinomas ; the remaining patient had a high-grade lesion. Notably, the pathological stage was Ta in all cases. The median duration of follow-up of patients with bladder cancer was initially set at 21 months (12-24 months). During the follow-up period, bladder cancer recurrence was identified in three patients. Patients who remained recurrence-free beyond the follow-up period underwent radical therapy. Importantly, no evidence of prostate cancer progression was detected throughout the follow-up period. Thus, incidental bladder cancer detected prior to radical prostatectomy is predominantly non-invasive, ensuring safe treatment of both the bladder and prostate cancers. Our findings suggest that cystoscopy could be omitted.

Proliferation and immunohistochemistry for p53, CD25 and CK20 in predicting prognosis of non-muscle invasive papillary urothelial carcinomas.

Non-muscle invasive papillary urothelial carcinoma is a prevalent disease with a high recurrence tendency. Good prognostic and reproducible biomarkers for tumor recurrence and disease progression are lacking. Currently, WHO grade and tumor stage are essential in risk stratification and treatment decision-making. Here we present the prognostic value of proliferation markers (Ki67, mitotic activity index (MAI) and PPH3) together with p53, CD25 and CK20 immunohistochemistry (IHC). In this population-based retrospective study, 349 primary non-muscle invasive bladder cancers (NMIBC) were available. MAI and PPH3 were calculated manually according to highly standardized previously described methods, Ki-67 by the semi-automated QPRODIT quantification system, p53 and CD25 by the fully automated digital image analysis program Visipharm® and CK20 with the help of the semi-quantitative immunoreactive score (IRS). Survival analyses with log rank test, as well as univariate and multivariate Cox regression analyses were performed for all investigated variables. Age and multifocality were the only significant variables for tumor recurrence. All investigated variables, except gender, were significantly associated with stage progression. In multivariate analysis, MAI was the only prognostic variable for stage progression (p<0.001).

Urinary Bladder Cancer Induced by N-Butyl-N-(4-Hydroxybutyl)-Nitrosamine.

Urinary bladder cancer is the tenth most common cancer worldwide with high morbidity and mortality. The majority of bladder cancers are urothelial carcinomas. More than half are papillomas or the papillary urothelial carcinomas (stages Ta and T1), which have a relatively good prognosis. Squamous cell carcinomas have a variable survival rate, while carcinomas in situ (Tis) can progress to muscle-invasive urothelial carcinomas (T2) with a poor prognosis. The most challenging feature of bladder cancer is its high recurrence rate, ranging from 50% to 90% of cases. The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model is an invaluable experimental tool for bladder cancer research, as BBN-induced bladder cancer in rodents resembles human bladder cancer in its morphological, biological, and molecular features. We present here a detailed protocol for the treatment of mice and the main expected results.

The transcription factor sex-determining region Y-box 2 (SOX2) in bladder cancer.

Sex-determining region Y-box 2 (SOX2) is a transcription factor with a central role in embryologic development. SOX2 is also an oncogene in several cancer types. Prior work by our group has shown SOX2 activity associates with cell cycle dysregulation in early-stage bladder cancer. The present study was thus undertaken to broadly investigate SOX2 in bladder cancer, with emphasis on associations with tumor stage, clinical outcomes, and tumorigenicity. Gene expression was quantified by immunohistochemistry in an established tissue microarray (n=303 cystectomy specimens, all stages) and whole tissue sections of noninvasive papillary urothelial carcinoma (n=25). Gene expression by RNA sequencing was evaluated in non-muscle invasive and muscle-invasive cohorts from publicly available repositories. By immunohistochemistry, SOX2 was expressed in 40% of whole tissue sections of noninvasive papillary carcinoma, which correlated with SOX2 expression by RNA sequencing (r=0.6, P=0.001, Spearman correlation). Expression tended to be focal (median H-score =6). SOX2 was expressed in only 9% of TMA cases, consistent with focal expression. SOX2 expression was substantially higher in muscle-invasive compared with noninvasive papillary urothelial carcinoma by RNA sequencing (P<0.001, Wilcoxon rank sum test). SOX2 expression associated with stage progression in lamina-propria invasive cancers (hazard ratio =2, P=0.05, Cox model, binary, RNA sequencing) but not noninvasive papillary cancers (P=0.5, Cox model, binary, RNA sequencing). SOX2 expression did not associate with overall survival in muscle-invasive carcinoma. Activity of SOX2 in bladder cancer was tested in vivo using murine allografts created with MB49 cells that express human SOX2 (MB49-SOX). MB49-SOX allografts expressed this protein focally by immunohistochemistry, much like human tumors. Compared with controls, MB49 allografts demonstrated larger tumor size (P=0.03, Wilcoxon rank sum test) and higher tumor burden in mesenteric metastases (P=0.009, Wilcoxon rank sum test). Though SOX2 expression is focal within tumors, it may drive tumorigenesis, increase growth rate, and promote aggressive features of bladder cancer, particularly stage progression of early-stage disease.

Papillary urothelial carcinoma of the ureter - A rare entity.

Papillary urothelial carcinoma of the ureter - A rare entity.

Brenner Tumor Case Report

Brenner tumors are rare transitional cell tumors of the ovary. They are usually benign tumors, but there are rarer borderline and malignant types. Most benign Brenner tumors are small and found incidentally. In our case, a 65-year-old female patient who underwent nephroureterctomy by the urology coincidentally had a mass in the left ovary during the operation. The obstetrics and gynecology department was called for consultation, and bilateral salpingotomy was performed as malignancy might occur. In histopathological examination; The mass found in the nephrectomy material was diagnosed as invasive, low-grade papillary urothelial carcinoma, and the mass in the left ovary was diagnosed as benign Brenner tumor. In our article, the histological findings of this rare case are presented and the literature is reviewed.

Stromal and Epithelial Architectural Alterations Mimicking Invasion (Pseudoinvasion) in Noninvasive Papillary Urothelial Carcinoma.

Retraction artifact, paradoxic maturation/differentiation, desmoplasia, and complex irregular growth are morphologic criteria of invasion in urothelial carcinoma. To describe changes mimicking invasion in noninvasive papillary urothelial carcinoma (NPUC). We reviewed 159 consecutive in-house patients with NPUC for either the presence of pseudoinvasion (irregular carcinoma nests within dense hyalinized stroma in the absence of other criteria of invasion) or precursor findings (stromal hyalinization not yet associated with epithelial architectural alteration). We assessed the correlation of these findings with age, sex, evidence of peripheral vascular disease, tumor grade, tumor infarction, and tumor size. We then followed up the patients clinically for tumor recurrence or progression. We identified 233 separate NPUCs (136 high grade and 97 low grade) in 125 men and 34 women. Of the 233 tumors, 26 (11.2%) had pseudoinvasion and 24 of 233 tumors (10.3%) had precursor findings. Except for complex irregular growth, no other criteria for invasion were seen. Pseudoinvasion and precursor findings were more common in men (47 of 183 [26%] versus 3 of 50 [6%]; P = .003), larger tumors (mean size, 2.6 versus 1.2 cm; P < .001), and tumors with infarction (33 of 50 [66%] versus 29 of 183 [15.8%]; P < .001). In multivariable analysis, tumor size (odds ratio, 1.49; P =.006), male sex (odds ratio, 6.48; P = .007), and the presence of infarction (odds ratio, 6.59; P < .001) were significant variables. Recurrence rates did not differ between patients with and without pseudoinvasion (31% [5 of 16] versus 42% [45 of 107], respectively; P = .41). None of the tumors with pseudoinvasion progressed to invasive carcinoma. Given the correlation with size and presence of infarcted papillae, we suggest the possibility of tumor ischemia/infarction as a plausible etiology of pseudoinvasion. Awareness of this phenomenon is important for the accurate diagnosis of invasion in papillary urothelial carcinoma.

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.

CD4, CD20 and PD-L1 as Markers of Recurrence in Non-Muscle-Invasive Bladder Cancer

Introduction: A tumor microenvironment plays an important role in bladder cancer development and in treatment response. Purpose: The aim of the study was to assess how the components of the microenvironment affect tumor recurrence and to find the potential biomarkers for immunotherapy in NMIBC. Methods: The study group consisted of 55 patients with primary NMIBC. Immunohistochemistry was performed on sections of primary papillary urothelial carcinoma of the bladder. Cox proportional hazard multiple regression analysis was performed to characterize tumors with the highest probability of an unfavorable outcome. Results: Multivariate analysis confirmed that the CD4 (p = 0.001), CD20 (p = 0.008) and PD-L1 expressed on tumor cells (p = 0.01) were independently associated with the risk of recurrence of bladder cancer. Patients with weak CD4+ cell infiltration (&lt;4.6%) and severe CD20+ infiltration (&gt;10%) belong to the group with a lower risk of recurrence. The cancer in this group also frequently recurs after 12 months (p = 0.0005). Conclusions: The evaluation of CD4+ and CD20+ cells in the tumor microenvironment, in addition to PD-L1 on tumor cells, facilitates the determination of a group of patients with a low risk of recurrence.

Nested and Large Nested Subtypes of Urothelial Carcinoma of the Upper Urinary Tract: A Multi-institutional Study

Nested urothelial carcinoma (NUC) and large nested urothelial carcinoma (LNUC) of the upper urinary tract are exceedingly rare. This has contributed to the paucity of information regarding their clinicopathological and molecular characteristics. To address this knowledge gap, we explored the largest cohort to date of these rare tumors, comprising resection specimens of 10 LNUC and 7 NUC, from 7 participating institutions. Clinicopathological data were retrieved and documented. Whole exome sequencing and RNA sequencing were performed on the Illumina NovaSeq 6000 sequencer. The data generated were analyzed using the genome analysis toolkit pipeline. Somatic mutations were annotated using funcotator tool to identify pathogenic/likely pathogenic variants. Tumor mutational burden was calculated using python-based “pyTMB” tool. Microsatellite instability analysis was done using MSIsensor2 and the Idylla platform. Differential expression analysis of genes in LNUC and NUC along with mRNA expression–based molecular subtyping was performed by analyzing expression pattern of markers used in The Cancer Genome Atlas subclassification of bladder carcinoma. Both tumor types were more common in older males, were unifocal, and occurred more commonly mixed with minor components of predominantly conventional urothelial carcinoma. Overlying low-grade papillary urothelial carcinoma was significantly more common in LNUC (P = .034). On follow-up (LNUC: median, 10 months; range, 3-84 months; NUC: median, 9 months; range, 2-48 months), LNUC had better clinical outcomes (P = .031). Pathogenic mutations in FGFR3 and PIK3CA were significantly more common in LNUC (P = .049 and P = .044, respectively), with the latter present exclusively in LNUC. Seventy-five percent of the cases showed tumor mutational burden of <10, and all cases were microsatellite-stable. FGFR3 mutations were also more common in low-stage tumors. This study expands on the clinicopathological spectrum of NUC and LNUC of the upper urinary tract and is the first to comprehensively analyze the molecular profile of these tumors, highlighting pathogenic genetic alterations of potential therapeutic and prognostic value.

Clinicopathologic features and prognostic significance of mixed (Low and high-grade) papillary urothelial carcinoma comparison with low and high-grade papillary urothelial carcinoma.

The World Health Organization/International Society of Urological Pathology (2022 WHO/ISUP) classification categorizes noninvasive carcinomas based on the highest grade observed in a pathology sample. According to this classification, a lesion is classified as mixed-grade (MG) if the highest-grade component comprises less than 5% high-grade (HG) carcinoma [14]. This study included 160 cases of low-grade papillary urothelial carcinoma (LGUC) and 160 cases of HG papillary urothelial carcinoma (HGUC), selected randomly. In addition, 160 consecutive and unselected cases of MG papillary urothelial carcinoma (MGUC) were obtained from all bladder transurethral resection specimens diagnosed with papillary urothelial carcinoma between January 2007 and January 2021. The results of the multivariate analysis showed that histologic grade, invasion of the lamina propria, and the presence of carcinoma in situ at presentation were independent prognostic parameters regarding recurrence-free survival (p = 0.002; hazard ratio (HR) = 1.44, 95% confidence interval (CI) = 1.059-1.956, p = 0.02; and HR = 1.76, 95% CI = 1.159-2.684, p = 0.008, respectively). Histologic grade was the only independent prognostic parameter of disease-specific survival (DSS) (p < 0.001). Comparisons between non-muscle invasive (NMI) MGUC and NMI LGUC, as well as between NMI MGUC and NMI HGUC, revealed statistically significant differences in terms of DSS (HR = 0.07, 95% CI = 0.024-0.252,p< 0.001 and HR = 1.59, 95% CI = 1.023-2.460, p = 0.039, respectively). Our study findings demonstrate statistically significant differences regarding DSS between NMI MGUC and NMI HGUC, as well as between NMI MGUC and NMI LGUC. Therefore, we suggested that considering the presence of less than 5% MGUC as a separate category may be appropriate. However, it is important to validate our results in larger cohorts with longer follow-up periods to establish the clinical significance of MGUC and provide guidance for patient management.

A retrospective study on expression and clinical significance of PHH3, Ki67 and P53 in bladder exophytic papillary urothelial neoplasms.

Exophytic papillary urothelial neoplasms (EPUN) are difficult to diagnose pathologically and are well-known for their heterogeneous prognoses. Thus, searching for an objective and accurate diagnostic marker is of great clinical value in improving the outcomes of EPUN patients. PHH3 was reported to be expressed explicitly in the mitotic phase of the cell cycle, and recent studies have shown that PHH3 expression was associated with the differential diagnosis and prognosis of many tumors. However, its significance in EPUN remains unclear. This study aimed to determine the expression of PHH3 in different EPUN, compare its expression with cell-cycle related proteins Ki67 and P53, and analyze its significance in the differential diagnosis and prognostic value for high-grade papillary urothelial carcinoma (HGPUC), low-grade papillary urothelial carcinoma (LGPUC), papillary urothelial neoplasm of low malignant potential (PUNLMP) and urothelial papilloma (UP). We retrospectively analyzed the pathological diagnosis and clinical features of 26 HGPUC cases, 43 LGPUC cases, 21 PUNLMP cases and 11 UP cases. PHH3, Ki67 and P53 were detected by immunohistochemistry in 101 EPUN cases samples. The cut-off values of PHH3 mitosis count (PHMC), HE mitosis count (HEMC), Ki67 and P53 in the different EPUN were determined using the ROC curve. The distribution of counts in each group and its relationship with clinical parameters and prognosis of EPUN patients were also analyzed. The determination coefficient (R2=0.9980) of PHMC were more potent than those of HEMC (R2=0.9734) in the EPUN mitotic counts microscopically by both pathologists. Of the 101 EPUN cases investigated, significant positive linear correlations were found between PHMC and HEMC, PHMC and Ki67, and HEMC and Ki67 (P<0.0001). In HGPUC, LGPUC, PUNLMP and UP, a decreasing trend was observed in the median and range of PHMC/10HPFs, HEMC/10HPFs, Ki67 (%) and P53 (%). PHMC, HEMC, Ki67 and P53 were associated with different clinical parameters of EPUN. PHMC, HEMC, Ki67 and P53 were found to exhibit substantial diagnostic values among different EPUN and tumor recurrence. Based on the ROC curve, when PHMC was >48.5/10HPFs, a diagnosis of HGPUC was more likely, and when PHMC was >13.5/10HPFs, LGPUC was more likely. In addition, when PHMC was >5.5/10HPFs, the possibility of non-infiltrating LGPUC was greater. Kaplan-Meier survival curve analysis showed that the median recurrence-free survival (RFS) for cases with PHMC > 13.5/10HPFs and HEMC > 14.5/10HPFs were 52.5 and 48 months, respectively, and their respective hazard ratio was significantly higher (Log-rank P<0.05). PHH3 exhibited high specificity and sensitivity in diagnosing EPUN. Combined with HEMC, Ki67 and P53, it can assist in the differential diagnosis of EPUN and estimate its clinical progression with high predictive value to a certain extent.

CD105 and CD34 as Markers of Angiogenesis of Urothelial Carcinoma: A Cross Sectional Study

Background Urothelial carcinoma (UC) of the bladder is a major cause of morbidity and mortality throughout the world. The present study was carried out to see the expression of CD105 and CD34 as marker of angiogenesis in UC and study their relationship with grades and muscle invasion. Methods 50 cases of histopathologically diagnosed UC were included. CD105 and CD34 IHC staining was performed. Microvessel density (MVD) evaluation by CD105 and CD34 was compared. The number of microvessels were counted in high power in three hot spots. The highest value obtained amongst three fields were reported as MVD. Statistical analysis was done by (SPSS 28.00 version for windows) using independent t-test. Results There were 45 high grade cases UC 5 low grade cases of UC. Invasive papillary UC was seen in 25 cases (50%) followed by invasive UC seen in 13 cases (26%). Both Lamina propria (LP) invasion and muscularis propria invasion were noted in 16 cases of high-grade urothelial carcinoma. Only LP invasion was seen in 3 cases of low grade and 25 cases of high-grade UC respectively. Evaluation of MVD CD105 and MVD CD34 did not show any significant association of MVD with grade with a p value of 0.214 &amp; 0.429 respectively. Aso there was no significant association of MVD CD105 (p=0.580) &amp; CD34 (p=0.747) with muscularis propria invasion. Overall mean CD105 and CD34 were similar with no statistical difference between the two markers. Conclusion Both CD105 and CD34 can be used as marker to assess angiogenesis. However, there is no significant association of MVD with grade or muscle invasion in UC.