Low-grade Papillary Urothelial Carcinoma Research Articles

Low-Grade Urothelial Neoplasia

This chapter reviews the clinical, histopathologic, and cytologic features of low-grade urothelial neoplasia, including urothelial papilloma, papillary urothelial neoplasm of low malignant potential, and low-grade papillary urothelial carcinomas. An overview of various surgical pathology and cytology classification systems, diagnostic criteria, and common molecular alterations will be reviewed.

Cytomorphological characteristics of low-grade papillary urothelial carcinoma in voided urine samples: Distinction from benign and high-grade papillary urothelial carcinoma.

Given its frequent recurrence and the potential for high-grade transformation, accurate diagnosis of low-grade papillary urothelial carcinoma (LGPUC) in urine cytology is clinically important. We attempted to identify cytomorphologic features in urine samples, which could be helpful for the identification of LGPUC. We conducted a retrospective review of voided urine specimens collected from patients with histopathologic diagnoses of LGPUC. Their cytomorphological features were compared with those from patients with benign conditions and high-grade papillary urothelial carcinoma (HGPUC). A total of 115 voided urine specimens were evaluated, including 30 benign, 41 LGPUC, and 44 HGPUC cases. In LGPUC, 18 cases (44%) were diagnosed as atypical, a proportion significantly higher than that observed in benign cases (4 cases, 13%), while the remaining 23 cases (56%) were diagnosed as negative. LGPUC urine samples tended to have higher cellularity than benign cases, but the difference was not statistically significant. Three cytological features, namely nuclear enlargement, higher nuclear-to-cytoplasmic (N/C) ratio, and presence of small cell clusters, were statistically more prevalent in LGPUC compared to benign cases, although the changes were relatively subtle. In contrast, cytomorphological distinction between LGPUC and HGPUC was evident, as high cellularity, nuclear enlargement, hyperchromasia, high N/C ratio, irregular nuclear membrane, and apoptosis were significantly more prevalent in HGPUC cases. Several cytomorphologic features in voided urine samples were more prevalent in cases with LGPUC, albeit not observed in all instances. Since these alterations were relatively subtle, meticulous attention to these cytomorphologic details is crucial to suggest the possibility of LGPUC.

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.

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.

Clinicopathologic Features of Noninvasive Inverted Urothelial Papillary Tumor.

Clinicopathologic features and recurrence rates of inverted noninvasive urothelial papillary tumors have been poorly characterized to date with few larger studies evaluating long-term outcomes. The spectrum of histomorphology, clinical features, and prognosis of inverted lesions of the urinary bladder are retrospectively reviewed. Archived paraffin-embedded urothelial tumor samples from patients diagnosed with inverted urothelial papillary lesions between January 2005 and June 2020 were collated. A matched control population of patients with exophytic papillary lesions of the urothelium diagnosed during the same time period was randomly selected. The conventional clinicopathologic features of inverted urothelial papillary tumor were evaluated retrospectively and patient demographics, tumor characteristics, recurrence, and survival information were recorded. Lower recurrence rates were observed for inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP) relative to papillary urothelial neoplasms of low malignant potential and for low-grade papillary urothelial carcinoma with an inverted growth pattern (LG-PUCI) relative to low-grade papillary urothelial carcinomas. No recurrence was found among the inverted urothelial papilloma cases. The 2- and 5-year disease-free survival rates were 100.0% and 85.2% for IPUNLMP patients; 94.4% and 80.4% for papillary urothelial neoplasms of low malignant potential; 89.5% and 82.0% for LG-PUCI; 73.7% and 54.6% for low-grade papillary urothelial carcinoma; 40.0% and 20.0% for high-grade papillary urothelial carcinoma with an inverted growth pattern patients and 26.7% and 26.7% for high-grade papillary urothelial carcinoma. Multivariate Cox regression analysis of IPUNLMP and LG-PUCI/high-grade papillary urothelial carcinoma with an inverted growth pattern indicated that tumor number (hazard ratio=4.356; 95% CI: 1.145-16.570; P =0.031) was a powerful prognostic factor for disease-free survival. Noninvasive, papillary urothelial lesions of the bladder tend to have lower recurrence and a better outcome if an inverted growth pattern is shown.

Recent Advances in the Classification of Bladder Cancer - Updates from the 5th Edition of the World Health Organization Classification of the Urinary and Male Genital Tumors.

The World Health Organization Classification (WHO) of Urinary and Male Genital Tumors has recently been updated to its 5th edition. The new edition presents a comprehensive approach to the classification of urinary and male genital tumors with an incorporation of morphologic, clinical, and genomic data. This review aims to update the new classification of bladder cancer in the 5th edition and to highlight important changes in nomenclatures, diagnostic criteria, and molecular characterization, as compared to the 4th edition. The pathologic classification of bladder cancer in the 5th edition of WHO Classification of Urinary and Male Genital Tumours was compared to that in the 4th edition. PubMed was searched using key words, including bladder cancer, WHO 1973, WHO 1998, WHO 2004, WHO 2016, histology, pathology, genomics, and molecular classification in the time frame from 1973 to August of 2022. Other relevant papers were also consulted, resulting in the selection of 81 papers as references. The binary grading of papillary urothelial carcinoma (UC) is practical, but it may be oversimplified and contribute to "grade migration" in recent years. An arbitrary cutoff (5%) has been proposed for bladder cancers with mixed grades. The diagnosis of papillary urothelial neoplasm with low malignant potential has been dramatically reduced in recent years because of overlapping morphology and treatment with low-grade papillary UC. An inverted growth pattern should be distinguished from true (or destructive) stromal invasion in papillary UC. Several methods have been proposed for pT1 tumor substaging, but it is often challenging to substage pT1 tumors in small biopsy specimens. Bladder UC shows a high tendency for divergent differentiation, leading to several distinct histologic subtypes associated with an aggressive clinical behavior. Molecular classification based on the genomic analysis may be a useful tool in the stratification of patients for optimal treatment. The 5th edition of WHO Classification of Urinary and Male Genital Tumours has made several significant changes in the classification of bladder cancer. It is important to be aware of these changes and to incorporate them into routine clinical practice.

PREVALANCE OF UROTHELIAL CARCINOMA, ITS HISTOLOGICAL GRADE AND TYPE IN URINARY BLADDER OVER A PERIOD OF 2 YEARS: A STUDY IN A TERTIARY HOSPITAL IN CENTRAL INDIA

BACKGROUND:-Urinary bladder carcinoma is well known to show many histological divergent differentiation. The histological variants have important diagnostic, prognostic and therapeutic implications. The aim of the study was to find the prevalence of urothelial carcinoma in a tertiary care centre and to find the proportion of different histological grades and types of urothelial carcinoma. MATERIAL AND METHODS:- A retrospective monocentric study was done between April 2020 and April 2022 which includes 37 bladder biopsies which were received in the histopathology section of the Department of Pathology, Gajra raja medical college. Patients who refuse to give consent and those having cystitis were excluded from the study. RESULTS AND OBSERVATIONS :- Out of total 37 cases which were reviewed, the mean age was 62 years, with a male predominance (M:F ratio-3.16). Out of 37 cases, there were 8 cases each of highgrade urothelial carcinoma(21.6 %), high grade urothelial carcinoma with invasion ( 21.6 %) and high grade papillary urothelial carcinoma with invasion ( 21.6 %). There were 4 cases of high grade urothelial carcinoma with invasion with squamous differentiation ( 10.8 %), one case each of recurrent high grade urothelial carcinoma with invasion ( 2.7 %), well differentiated invasive glandular adenocarcinoma NOS (2.7%) and invasive micropapillary urothelial carcinoma with squamous differentiation ( 2.7 % ), two cases each of low grade urothelial carcinoma - 2 cases ( 5.4 %), low grade papillary urothelial carcinoma ( 5.4%) and papillary urothelial neoplasm of low malignant potential ( PUNLMP) ( 5.4 %). CONCLUSION Urinary bladder carcinoma is more common in male than females. Average age of presentation is 62 years in present study. High grade urothelial carcinoma ( 83.8 %) is more common compared to low grade ( 10.8% ). H&amp;E staining with ancillary techniques like immunohistochemistry or molecular it can be very effective in to analyse histological variants to better understand this invasive disease hence aiding in further management of patients.

HISTOPATHOLOGICAL PATTERN OF URINARY BLADDER TUMOURS IN TERTIARY CARE HOSPITAL, KASHMIR

Urinary bladder cancer is one of the most common cancers worldwide, with the highest incidence in industrialized countries. A total of 225 cases of urinary bladder tumours were studied at the Department of Pathology, Government medical college Srinagar, Kashmir, India over a period of 4 years (Jan 2015 to Dec 2018). Tumours were evaluated as per Age, Sex, Histological type, grade of tumour and clinical features. Males were more commonly affected than females. Low grade Papillary urothelial carcinomas (PUC) were more common (66.4%) than high grade (28.5%). Peak age of incidence was 7th decade of life. Painless hematuria was the commonest symptom in high grade tumours and pain abdomen was mostly seen in high grade tumours. A denitive correlation between advancing grade of tumour and detrusor muscle invasion was observed

Nested Subtype of Urothelial Carcinoma in the Upper Urinary Tract: A Series of 15 Cases.

Nested subtype of urothelial carcinoma (NVUC) of the upper urinary tract is rare. While this subtype has an aggressive behavior in the urinary bladder, little is known about this subtype in the renal pelvis and ureter. In addition, due to NVUC's bland morphology and resemblance to von Brunn nests proliferation, which can be florid in the renal pelvis and ureter, establishing a diagnosis of NVUC in these sites can be difficult, especially on small biopsies. Nineteen cases of NVUC of the renal pelvis and the ureter were identified. One was in-house and 18 cases were sent to the genitourinary pathology consult service. Four cases were excluded due to difficulty in obtaining the slides from other institutions. In all, 8/15 (53.33%) cases showed large nested morphology, 4/15 (26.66%) cases showed mixed large and small nested morphology, and only 3/15 (20%) cases showed predominantly small nested morphology. In all cases, the invasive component was pure nested subtype, and tumors were all unifocal. In 8/15 cases, there was the presence of an overlying low-grade papillary urothelial carcinoma. An associated desmoplastic stromal reaction was none/minimal in 12/15 (80%) cases, with a prominent reaction in the remaining 3/15 (20%) cases. Pathologic stages for the resections were pT1 (n=1), pT2 (n=3), pT3 (n=8), and pT4 (n=1). There was only 1 case with a lymph node metastasis at the time of resection who had pT4 disease. Follow-up was available in 10/15 cases, 7/10 cases showed no recurrences or metastases, and the remaining 3/10 cases later developed urothelial carcinoma of the bladder. In 5/15 cases, follow-up could not be obtained. Similar to NVUC in the urinary bladder, NVUC in the upper tract typically lacks an associated desmoplastic reaction and has by definition bland cytology. In contrast to NVUC of the urinary bladder, NVUC in the upper urothelial tract is: (1) more frequently associated with an overlying papillary urothelial carcinoma; (2) more commonly has a large nested pattern; and (3) appears to behave less aggressively.

Diagnosis of Upper Urinary Tract Urothelial Cell Carcinoma by Urine Cytology in a Patient with Valvular Heart Disease: A Case Report

A 58-year-old male was admitted to the hospital with severe gross hematuria and many comorbidities such as rheumatic heart disease and severe mitral valve stenosis. Because of atrial fibrillation, the patient took anticoagulant drug for stroke prevention. The patient was requested to stop anticoagulant agents and received blood replacement therapy for blood loss after hospitalization. Ureterorenoscopy was unable to visualize or biopsy the mass due to a massive blood clot. Urine cytology of left and right ureter showed high-grade urothelial carcinoma (HGUC) and few suspicious cells, respectively. Computed tomography angiography (CTA) of the whole abdomen revealed blood clot in the upper pole calyx and renal pelvis of the left kidney as well as the urinary bladder, but no abnormal enhancing lesion. The patient underwent the standard treatment for upper tract urothelial carcinoma (UTUC) with laparoscopic radical nephroureterectomy (RNU) with bladder cuff excision because the consulted cardiologist suggested to start anticoagulant agents as soon as possible. Surgical pathology analysis revealed high-risk tumors with multiple low grade papillary urothelial carcinoma. The patient required long term follow-up. Here, the authors reported a case of UTUC with valvular heart disease, earlier diagnosed by using only positive urinary cytology, rather than by radiological examinations and/or related symptoms before definite treatment. Keywords: Urine Cytology; Upper tract; Ureter; Ureteroscopy; Urothelial carcinoma; False positive; Nephroureterectomy

PSUN250 Empagliflozin Induced Bladder Cancer in an Adult Patient With Latent Autoimmune Diabetes

Abstract Sodium glucose cotransporter type 2 (SGLT2) inhibitor is a novel class of antidiabetic agent. The association of SGLT2 inhibitors and incidence of bladder cancer has not been well established due to few numbers of cases and not enough length of exposure. Here we describe a case of bladder cancer developed one year after empagliflozin exposure in a patient with latent autoimmune diabetes. Case description A 51-year-old man presented to our endocrine clinic with a one-year diagnosis of type 2 diabetes mellitus. His glycosylated hemoglobin (HbA1c) was 8% on maximum dose metformin and well adherence to diet. The patient had no significant past medical history and his body mass index was 23.6 kg/m2. Empagliflozin 25 mg daily was added to his regimen, in addition to sulfonylurea and dipeptidyl peptidase-4 (DPP-4) inhibitor drugs. The patient continued to have persistent hyperglycemia despite medical therapy with HbA1c ranged between 7.5-7.9%. After one year, he presented with fatigue, unintentional 7-kg weight loss and perianal pain. A transrectal ultrasound of the pelvis showed a 10-mm solid lesion in the urinary bladder. He underwent transurethral resection of bladder tumor; pathology showed a low grade papillary urothelial carcinoma with focal areas of high grade. Empagliflozin was discontinued and due to persistent hyperglycemia, further labs were requested. Fasting blood glucose of 265 mg/dl, HA1c of 7.9%, anti-GAD antibody was positive 37.52 u/ml (&amp;lt;10.0), C-peptide of 0.51 ng/ml (0.37-1.47), insulin of 2.0 mu/ml (2.6-24.9). These findings suggested latent autoimmune diabetes with mild pancreatic reserve. Patient was then started on insulin therapy of Glargine and Aspart. Conclusion The use of SGLT2 inhibitors in patients with autoimmune diabetes may have a higher risk of bladder cancer as compared to patients with type 2 diabetes. An individualized selection of antidiabetic agent with consideration of proper diagnosis is recommended to prevent a serious consequence. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Clinicopathological analysis of recurrence and progression of low-grade papillary urothelial carcinoma of the urinary bladder: Predicting the outcome

BackgroundUrothelial carcinoma of the urinary bladder is the most common malignancy of the urinary system. Patients with low grade papillary urothelial carcinoma (LGPUC) usually have a low risk for tumor recurrence and progression; yet a subset of patients develop recurrence or grade/stage progression to high-grade papillary urothelial carcinoma (HGPUC). The clinicopathological and molecular factors that contribute to this progression are yet to be determined. ObjectivesIn our study, we aimed to assess the incidence and clinicopathological factors associated with tumor recurrence/progression of LGPUC. MethodsUsing a pathological database of surgical specimens from patients who underwent bladder biopsies and/or transurethral resection of bladder tumors (TURBTs) between August 01, 2011, and July 31, 2021, at a large academic medical center, a single-center retrospective cohort analysis was performed, and medical charts of patients were reviewed. ResultsOf the total 258 patients included, 157 (60.9 %) had “no recurrence”, 85 (32.9 %) had ≥1 “recurrence of LGPUC”, and 16 (6.2 %) had “grade progression to HGPUC”. The mean follow-up time was 31.5 ± 32 months. Patients with “grade progression” and “recurrence of LGPUC” had larger mean tumor size on initial biopsy and multiple lesions on initial cystoscopy compared to those with “no recurrence.” Interestingly, former smokers had 2.5- and 8.5-times higher risk of recurrence of LGPUC and grade progression, respectively. ConclusionSince the majority of our patients did not develop recurrence, we question whether there is tendency to overclassify the papillomas as LGPUC based on the 2004 WHO/ISUP consensus grading classification.

Proteomic-Based Machine Learning Analysis Reveals PYGB as a Novel Immunohistochemical Biomarker to Distinguish Inverted Urothelial Papilloma From Low-Grade Papillary Urothelial Carcinoma With Inverted Growth.

BackgroundThe molecular biology of inverted urothelial papilloma (IUP) as a precursor disease of urothelial carcinoma is poorly understood. Furthermore, the overlapping histology between IUP and papillary urothelial carcinoma (PUC) with inverted growth is a diagnostic pitfall leading to frequent misdiagnoses.MethodsTo identify the oncologic significance of IUP and discover a novel biomarker for its diagnosis, we employed mass spectrometry-based proteomic analysis of IUP, PUC, and normal urothelium (NU). Machine learning analysis shortlisted candidate proteins, while subsequent immunohistochemical validation was performed in an independent sample cohort.ResultsFrom the overall proteomic landscape, we found divergent ‘NU-like’ (low-risk) and ‘PUC-like’ (high-risk) signatures in IUP. The latter were characterized by altered metabolism, biosynthesis, and cell–cell interaction functions, indicating oncologic significance. Further machine learning-based analysis revealed SERPINH1, PKP2, and PYGB as potential diagnostic biomarkers discriminating IUP from PUC. The immunohistochemical validation confirmed PYGB as a specific biomarker to distinguish between IUP and PUC with inverted growth.ConclusionIn conclusion, we suggest PYGB as a promising immunohistochemical marker for IUP diagnosis in routine practice.

Dysfunctional Voiding- Presentation of a Rare Case of Pediatric Non Muscle Invasive Urothelial Bladder Carcinoma

Bladder cancer is rare in children, with 86.8% of pediatric patients diagnosed not carrying any of the common risk factors commonly seen in adults. Here, a 16-year-old female presented to the ED with in urinary retention. A renal bladder ultrasound revealed an echogenic focus in the bladder wall. On diagnostic cystoscopy a small papillary bladder lesion was appreciated and resected. Final pathology of the bladder mass resulted as non-invasive low grade papillary urothelial carcinoma (pTa). This report demonstrates bladder cancer in the pediatric age group, and should be considered as a possible differential diagnosis in patients with dysfunctional voiding.

Significance of Ki67, BCL 2 Immunoexpression in Urothelial Carcinoma and their Association with Grading and Staging: A Descriptive Cross-sectional Study

Introduction: Urinary bladder is the most common site of malignancy in the urinary tract and the most common type of cancer of urothelial origin is urothelial cell carcinoma. This subtype constitutes more than 90% of bladder cancer. Histological grade of tumour is one of the most important predictive parameter for prognosis and biological behavior of urothelial carcinoma. As some crucial discordances may arise between pathologists because of subjectivity, so immunohistochemistry can be used for accurate diagnosis and prediction of prognosis. Aim: To study the immununohistochemical expression of B-Cell Lymphoma 2 (BCL 2) and Ki(Kiel)-67 markers and their association with tumour grade and stage in urothelial carcinomas. Materials and Methods: A descriptive cross-sectional study was conducted in the Department of Pathology of a tertiary care R G Kar Medical College and Hospital, Kolkata, West Bengal, India. West Bengal, India, on a total of 75 cases from January 2018 to June 2019. The study population comprised of cases of urothelial lesions as diagnosed by cystoscopy, who underwent standardized operative procedures. Relevant sections were taken from different parts of the fixed specimens. Histopathological Examination (HPE) was done to confirm the presence or absence of non-invasive and invasive carcinoma, and the depth of invasive tumour cells for pathological staging. Evaluation of the level of cytological and architectural disorder at low and medium magnification (100X and 200X) were done for grading. Cytological disorder were defined as abnormalities in nuclear size, shape, and chromatin, while architectural disorder were defined as abnormalities in the orientation of the cells in relation to each other and to the basement membrane of the papillae. Immunohistochemical analysis was done for Ki67 and BCL 2 expression in paraffin embedded sections in all the cases. In this study, chi-square test was done with International Business Management(IBM) Statistical Package for Social Sciences (SPSS), as per which, the association between two variables is statistically significant if p value is &lt;0.05. Results: Out of total 75 cases(mean age: 67.3 years) analysed, 58 cases (77.3%) had Invasive type of bladder neoplasm, followed by low grade papillary urothelial carcinoma 10 (13.3%), and papillary urothelial neoplasm of low malignant potential 07 (9.3%). Ki67 expression in urothelial carcinoma has more significance because 59 cases (78.7%) showed high level expression (&gt;20%) out of 75 cases, whereas only 12 (16%) cases show high level expression (4+) of BCL 2 marker. Conclusion: Ki67 overexpression is seen more commonly, than BCL 2, in high grade tumours as well as in advanced stage. So Ki67 may be used as a marker to predict aggressive behavior and to differentiate low grade and high grade tumours also.

Nitrosamine (and/or Irbesartan) Induced Large Plaque Parapsoriasis and Urothelial Carcinoma: First Report in the Medical Literature!

A presenting case of a 64-year-old gentleman with a complaint of disseminated skin rash on the trunk, upper and lower limbs. He was diagnosed with type II hypertension in January 2017 and was started on irbesartan 150 mg one oral tablet daily (1-0-0). After 6 months, this dose was reduced to half a tablet which he continues to take to this day. He was also diagnosed with type two diabetes mellitus for which he is actively treated with metformin 1500 mg (1-1-1) daily. The patient noticed subtle skin changes in 2019 and upon seeking medical advice, he was diagnosed with an incidental finding of low grade papillary urothelial carcinoma, (T1 N0 M0). He was subsequently treated with transurethral surgical interventions and hospitalised for four different sessions before being sent to our dermatological clinic for evaluation of the skin condition. On examination, multiple large psoriasiform plaques were observed bilaterally, predominantly on the trunk, upper and lower extremities (Figure A-D), the greatest measuring approximately 6 cm in diameter. The plaques were variable in size and polymorphic in nature exhibiting a salmon-pink discoloration. There were no signs of pruritis or poikilodermatous changes. Based on the clinical data, a drug-induced parapsoriasis was suspected. Histopathological examination revealed generalised parakeratosis with perivascular lymphocytic infiltrations in the upper dermis. No signs of mycosis fungoides was noted, keeping in line with a clinicopathological diagnosis of large plaque parapsoriasis.

Tumour Behaviour of Low-Grade Papillary Urothelial Carcinoma: A Single-Centre Retrospective Study

Background and objectiveCarcinoma of the urinary bladder is the most common urological cancer, and it accounts for 3.9% of all cancer cases in men. Patients with the subset of noninvasive low-grade papillary urothelial carcinoma (LG-UrCa) are at higher risk for tumour recurrence. In this study, we aimed to analyse the histopathological features of LG-UrCa and to correlate those with recurrence potential as well as disease stage and grade progression.Materials and methodsWe conducted a retrospective study from January 2016 to December 2018. All cases with presenting biopsy initially reported as LG-UrCa were included in the study. All cases with initial biopsy reported as high-grade papillary urothelial carcinoma (HG-UrCa) were excluded from the study. We used the 2016 World Health Organization/International Society of Urological Pathology (WHO/ISUP) guidelines for the classification of papillary urothelial neoplasm.ResultsA total of 48 initially diagnosed cases of LG-UrCa were identified. Two out of 48 cases were reclassified as high-grade urothelial carcinoma and were excluded from the study. The mean age of patients at presentation was 56.7 years. The mean duration of follow-up was 19.8 months. The mean size of initial tumours was 3.4 cm. Tumour recurrence was encountered in 14 (30.4%) of 46 patients. Out of the four patients who had high-grade progression (8.7%), two also developed TNM stage progression. These two patients eventually underwent radical cystectomy. Patients with larger initial tumour sizes were found to have an increased tumour recurrence rate (p=0.009). Patients with multiple lesions at initial diagnosis had a significantly higher tumour recurrence rate than those with a single tumour (p=0.02). There was no significant difference with regard to intravesical Bacillus Calmette-Guérin (BCG) and tumour recurrence (p=0.065). None of the clinicopathological parameters were significantly associated with the grade and/or stage progression.ConclusionBased on our findings, patients with larger initial tumour size and tumour multiplicity at presentation had an increased tumour recurrence rate.

Noninvasive low-grade papillary urothelial carcinoma with degenerative nuclear atypia: a grading pitfall

Noninvasive low-grade papillary urothelial carcinoma is a papillary neoplasm with orderly appearance and mild nuclear pleomorphism. Some cases show significant nuclear pleomorphism with degenerative atypia leading to grading difficulties. A retrospective review of the pathology files identified 16 cases diagnosed as noninvasive low-grade papillary urothelial carcinoma with degenerative atypia. Fifteen cases were consults. The average age was 46 years (range 19-78). The average size was 1.7cm (range: 0.3-3.5). The submitting diagnoses in consults were noninvasive high-grade papillary urothelial carcinoma (n=6), condyloma (n=1), atypical papillary lesion (n=1), prominent umbrella cells (n=1), and not given (n=6). Ki-67 proliferation rate was <5% in 10 of 10cases (100%), and the cells with large atypical nuclei were negative. Microscopically, there were scattered cells with nuclei larger than 5 times the size of stromal lymphocytes but displayed smudgy chromatin and occasional multinucleation and intranuclear vacuoles. Next-generation sequencing identified the following mutations: HRAS (n=4), FGFR3 (n=3), KRAS (n=3), BRAF (n=1), PDGFRA (n=1), and PIK3CA (n=1). Other deleterious mutations were identified, but none in genes characteristic of high-grade tumors. Follow-up was available in 6 patients (median 32 months). One patient recurred with a noninvasive low-grade papillary urothelial carcinoma 20 months after the index case. All the remaining patients had no evidence of disease at the last follow-up. No patient died or had disease progression. The combination of preservation of polarity, low mitotic activity, Ki-67<5% with the larger atypical nuclei negative for Ki-67, along with nuclear atypia that is degenerative are features used to classify these tumors as low grade.