Papillary Urothelial Carcinoma Research Articles

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.

Chemoprevention of Urothelial Cell Carcinoma Tumorigenesis by Dietary Flavokawain A in UPII-Mutant Ha-ras Transgenic Mice.

Non-muscle-invasive bladder cancer (NMIBC) has one of the highest recurrence rates among all solid cancers and the highest lifetime treatment cost per patient. Therefore, the development of chemoprevention strategies for reducing the occurrence and recurrence of NMIBC as well as its burdens on the healthcare system is valuable. Our aim was to determine whether flavokawain A (FKA), a kava chalcone isolated from the kava plant, can target the in vivo activated Ha-ras pathway for prevention and treatment of NMIBC. UPII-mutant Ha-ras transgenic mice that develop papillary urothelial cell carcinoma were fed orally with vehicle control or FKA-formulated food for 6 months starting at 6 weeks of age. Seventy-nine percent (15/19) of male mice fed with 6 g FKA per kilogram (kg) of food survived beyond the 6 months of treatment, while 31.6% (6/19) of control food-fed male mice survived the 6-month treatment period (p = 0.02). The mean bladder weights in FKA vs. control food-fed mice were 0.216 ± 0.033 vs. 0.342 ± 0.039 g in male mice (p = 0.0413) and 0.043 ± 0.004 vs. 0.073 ± 0.004 g in female mice (p < 0.0001); FKA reduced bladder weight by 37% and 41%, respectively. The tumor burdens, determined by the wet bladder weight, in these mice were inversely related to plasma FKA concentrations. In addition to decreased bladder weight, FKA treatment significantly reduced the incidences of hydronephrosis and hematuria. FKA-treated mice exhibited more well-differentiated tumors in the bladder and ureter. Immunohistochemical analysis of FKA-treated tumors compared to those in the control group revealed fewer Ki-67- and survivin-positive cells and an increased number of p27- and TUNEL-positive cells, indicating that FKA inhibits proliferation and induces apoptosis. Overall, the results suggest that FKA can target the in vivo activated Ha-ras pathway for the prevention and treatment of NMIBC.

Dermatomiositis amiopática como primera manifestación de cáncer de uréter

Resumen Descripción del caso clínico: Varón de 79 años, consultó por episodio de angioedema facial sin otra sintomatología. A la exploración física presentaba eritema en cara y cuello, angioedema peripalpebral y máculas eritematosas en el dorso de las manos. Se realizó biopsia de lesión cutánea compatible con pápula de Gottron y para descartar enfermedad sistémica urografía por tomografía computarizada observando ureterohidronefrosis izquierda grado III por posible neoplasia ureteral. Estudio de extensión negativo. Se realizó nefroureterectomía izquierda laparoscópica e instilación endovesical de Mitomicina C, con resultados anatomo-patológicos de carcinoma papilar urotelial de alto grado multifocal. El paciente presentó una evolución posquirúrgica favorable, con mejoría de las lesiones dérmicas, pero a los 7 meses desarrolló múltiples metástasis siendo éxitus. Relevancia: La asociación de dermatomiositis con neoplasias es bien conocida, pero son pocos los casos descritos con malignidad urológica. El cáncer ureteral con dermatomiositis amiopática es extremadamente raro. Implicaciones clínicas: Es importante realizar un tamizaje de cáncer en pacientes que cursan con dermatomiositis para así tratarlos y mejorar su pronóstico. Conclusión: La dermatomiositis es un síndrome paraneoplásico raro que se asocia al cáncer ureteral de manera muy infrecuente. El tamizaje de cáncer en estos pacientes es muy importante para mejorar el pronóstico. El tratamiento quirúrgico de este tumor supuso la desaparición de las alteraciones cutáneas.

A 5 Year Analysis of Different Types of Urothelial Malignancies with Special Reference to The Expression Of EGFR in These Tumours

Background:&#x0D; Urothelial neoplasms are a heterogenous group of neoplasms with high propensity for recurrence. EGFR is a novel and potential biological marker for predicting the prognosis of urothelial malignancies. This study highlights the diagnostic and prognostic usefulness of EGFR as a phenotypic marker in urothelial malignancies. Thus, it warrants for anti-tumour therapy and prevention of recurrence of urothelial cancers by anti-EGFR therapy.&#x0D; Methods:&#x0D; Current study includes 500 cases of urothelial tumours received in a major tertiary center in South Kerala. Based on the histopathological features these tumours were classified according to the WHO-2016 criteria. Proportion in each class of urothelial tumours during the study period was calculated. In addition to that, we also studied relation between EGFR expression and tumour grade and recurrence. Inclusion criteria: All consecutive cystoscopy biopsies, transurethral resection of bladder tumour (TURBT) and radical cystectomy specimens histologically diagnosed as urothelial malignancies of bladder. Exclusion criteria: All benign urothelial cases.&#x0D; Result:&#x0D; Out of the 500 cases of urothelial malignancies included in the study, the non-invasive papillary urothelial carcinoma, low grade constituted the major part, the second being invasive urothelial carcinoma, high grade, followed by noninvasive urothelial carcinoma, high grade. A strong expression of EGFR was found to be significantly associated with higher tumour grade (P = 0.001) and recurrence (P = 0.010).&#x0D; Conclusion: &#x0D; Histopathology supported by immunohistochemistry is a helpful tool in subtyping the various urothelial malignancies. EGFR can be considered as an adverse prognostic factor, the expression of which increases with tumour grade and stage. EGFR positivity may favor the use of targeted therapy in urothelial malignancies.

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.

Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder.

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

Utility of GATA-3 and Cytokeratin 5/6 Immunostains in Separating Condyloma Acuminatum Arising in the Urinary Tract From Non-Invasive Papillary Urothelial Carcinoma.

Background Condyloma acuminatum is a squamous epithelial lesion which uncommonly involves the urinary tract. In this location, non-invasive papillary urothelial carcinoma constitutes one of the main differential diagnoses with significant prognostic and therapeutic implications. To date, no ancillary immunohistochemical stain has been described to differentiate these two entities. We assess the utility of cytokeratin 5/6 (CK5/6) and GATA-3 immunohistochemistry in distinguishing condyloma acuminatum from non-invasive papillary urothelial carcinoma. Design We reviewed 9 condylomata acuminata involving the urinary tract, 12 low-grade and 8 high-grade non-invasive papillary urothelial carcinomas. CK5/6 immunostaining was performed in all cases. GATA-3 immunostaining and low-risk human papilloma virus (HPV) chromogenic in situ hybridization was performed in all condyloma cases and 2 urothelial carcinomas with squamous differentiation. Results 8/9 condylomata acuminata were positive for low-risk HPV. All condylomata acuminata exhibited strong full-thickness cytoplasmic staining for CK5/6. In 10 of 12 low-grade non-invasive papillary urothelial carcinomas, CK5/6 expression was continuous and limited to the basal cell layer, while it was patchy and limited to the basal cell layer in all 8 high-grade non-invasive papillary urothelial carcinomas. Two low-grade non-invasive papillary urothelial carcinomas showed focal full-thickness CK5/6 expression in the areas of squamous differentiation. These 2 cases were negative for low-risk HPV. GATA-3 immunostaining was positive in all condylomata acuminata. Conclusions CK5/6 immunostaining is a useful and simple tool that can help separate low-grade and high-grade non-invasive papillary urothelial carcinomas from condyloma acuminatum involving the urothelium-lined organs. GATA-3 has no discriminatory role between condyloma acuminatum and papillary urothelial carcinomas.

Expression of GATA3 and Cytokeratin 14 in Urinary Bladder Carcinoma (Histopathological and Immunohistochemical Study)

BACKGROUND: Urothelial carcinoma (UC) with squamous differentiation (SD) is the most common histologic variant of bladder carcinoma and its presence is associated with poor prognosis which may need early radical cystectomy to avoid progression and recurrence. It is difficult to detect few foci of SD, especially nonkeratinizing or early switch from urothelial to squamous epithelium on only morphological basis. Combination of GATA3 and Cytokeratin 14 (CK14) could be helpful in differentiating pure UC, UC with SD and pure squamous cell carcinoma (SCC). AIM: Assessment of GATA3 and CK14 expression in urinary bladder carcinoma and correlation with clinical and histopathological variables, for both diagnostic and prognostic purposes. MATERIALS AND METHODS: Sixty cases of archived paraffin blocks of urinary bladder carcinoma were tested for GATA3 and CK14 expression by immunohistochemistry using a rabbit monoclonal antibody against human CK 14 and mouse monoclonal antibody against GATA3, respectively. RESULTS: There is a significant correlation between GATA3 immunohistochemical expression and histological tumor subtypes of bladder carcinoma (p &lt; 0.001), i.e. the GATA3 is a useful marker for urothelial origin especially in papillary UC. There is a significant correlation between GATA3 immunohistochemical expression and UC grade (p &lt; 0.001). CK14 showed positive cytoplasmic staining in 9/14 (64.3%) cases of UC with SD and (13/13) (100%) cases of pure SCC and negative in 33/33(100%) cases of UC other than UC with SD. CK14 had sensitivity (64.3%) and specificity (100%) for areas of SD. CONCLUSION: GATA3 is a specific immunohistochemical marker for urothelial origin. CK14 is a highly specific and sensitive immunohistochemical marker of squamous cell carcinoma.

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.

Unusual Cervical Lymph Node Metastasis of Papillary Urothelial Carcinoma.

Papillary urothelial carcinoma is aggressive and characterized by frequent metastasis to distant sites at an early stage. Papillary urothelial carcinoma of the urinary bladder usually metastasizes to the local lymph nodes, liver, lungs, bone, and mediastinum. Urogenital tract carcinoma of the head and neck metastasis is uncommon and rarely reported to the cervical lymph nodes. We present a case of cervical lymph node metastasis of papillary urothelial carcinoma of the urinary bladder.

Calcaneal metastases, urothelial origin

Our patient is a 78-year-old lady with known metastatic papillary urothelial carcinoma that presented for evaluation of left foot pain. Imaging studies revealed an aggressive appearing mass measuring approximately 4.8 cm that was subsequently biopsied with pathology consistent with her known diagnosis of urothelial carcinoma.

Evaluation of P53 and CK20 Immunohistochemical Markers in Comparison with Morphologic Findings in Low- and High-grade Urothelial Carcinomas.

Background & Objective:Urothelial carcinoma is the seventh most common cancer in the world. The histological classification of papillary carcinoma is one of the most important determinants for its prognosis. Sometimes there is an overlap in the extent of the tumor, and the accurate microscopic diagnosis of the tumor is not always easy. The aim of this study was to evaluate P53 and CK20 immunohistochemical markers in comparison with morphologic findings in low- and high-grade urothelial carcinomas.Methods:For this descriptive study, urinary bladder samples were collected from 50 cancer patients who had undergone biopsy and surgery in Shohaday-e Tajrish Hospital of Tehran, Iran, during the years 2015-2016. P53 and CK20 were studied, and the demographic and histopathological characteristics of the tumor were also analysed.Results:The mean age of patients enrolled in this study (48 males and 2 females) was 65.8±11.9. Twenty-five cases presented with low-grade and 25 cases presented with high-grade papillary urothelial carcinomas. Sensitivity, specificity, and positive and negative predictive values for P53 were 48%, 80%, 70.5%, and 60.6%, respectively, while the same values for CK20 were 44%, 92%, 84.6%, and 62.2%, respectively. Immunohistochemical results were also positively correlated with the extent of the tumor. Conclusion:Based on the results, P53 and CK20 may serve as specific markers for diagnosis of low- and high-grade papillary urothelial carcinoma but not sensitive. P53 and ck20 staining have also a high specificity as 80% and 92% and low sensitivity compared to the low and high morphology of papillary carcinoma, thus their positive and their staining intensity are valuable for diagnosis, but their negative results are not determinant.

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.

Первично-множественные синхронные злокачественные новообразования лоханки почки и обоих мочеточников

Introduction. Urothelial carcinoma of the upper urinary tract in Western countries of Erope and USA occurs in 1-2 cases per 100,000 populations. Nephroretrectomy remains the main method of treatment of this pathology, however, the role of organ-sparing surgeries increases with the bilateral localization of the tumor process. Due to the rarity of bilateral upper urinary tract lesions with urothelial cancer and the lack of data evaluating the results of organ-sparing surgeries in such situations, each clinical case is of interest. Materials and methods. The article describes a case of surgical treatment of a patient with non-invasive papillary urothelial carcinomas of both ureters and the pelvis of the right kidney, which were manifested by macrohematuria. Results. The diagnosis was confirmed by computer tomography (CT) and ureteroscopy with tumor biopsy, which revealed a neoplasm of the right kidney pelvis, multiple tumors of the distal part of the right ureter and a solitary neoplasm of the middle part of left ureter. The patient underwent laparoscopic nephrureterectomy on the right with transurethral resection of the bladder wall in the area of the mouth of the right ureter and endoscopic removal of the neoplasm in the middle third of the left ureter using laser energy. At the control examination 1,5 months after the surgical treatment, according to the results of CT, cystoscopy with biopsy of the bladder and ureteroscopy, as well as histological examination of the biopsies, no data for tumor growth were found. At CT 6 months after the surgery, no data for the recurrence of cancer were obtained. Сonclusions. This clinical observation demonstrates the technical feasibility and oncological feasibility of using organ-preserving surgical treatment for bilateral localization of low-grade urothelial carcinoma.

GATA3 expression in human tumours: a tissue microarray study on 13,204 tumours

GATA3 is a critical transcription factor for embryonic development of various tissues including breast and urothelium and is commonly used as a diagnostic marker for breast and urothelial cancer although it can also occur in other neoplasms. To comprehensively evaluate GATA3 expression tumour tissues, a tissue microarray containing 17,646 samples from 135 different tumour types was analysed by immunohistochemistry. GATA3 positivity was found in 69 different tumour types including 48 (35%) with at least one moderately positive and 25 tumour types (18%) with at least one strongly positive tumour. The highest positivity rates occurred in non-invasive papillary urothelial carcinoma (100%), lobular carcinoma (98%) and carcinoma of no special type of the breast (92%), basal cell carcinoma of the skin (97%), and invasive urothelial carcinoma (73%). In breast cancer, low GATA3 staining was linked to high pT stage (p=0.03), low BRE grade (p<0.0001), HER2 overexpression (p=0.0085), oestrogen and progesterone receptor negativity (p<0.0001 each) and reduced survival (p=0.03). In summary, our data demonstrate that GATA3 positivity can occur in various tumour entities. Particularly high frequency and levels of GATA3 occur in breast and urothelial carcinoma. A reduced level of GATA3 reflects cancer progression and poor patient prognosis in these tumour entities.

Urothelial carcinoma of the graft kidney with molecular analyses: a rare case report

BackgroundMalignancy after transplantation is a leading cause of death among kidney transplant recipients. However, donor-derived malignancies are rare. We report a case of a high grade papillary urothelial carcinoma arising in a transplanted kidney.Case presentationA 62-year-old female who received a kidney transplantation more than 30 years ago presented with urinary tract infection, acute renal failure, and hydronephrosis of the transplant kidney. Anterograde nephrostogram showed a large filling defect in the lower pole of the transplant kidney and in the proximal 3–4 cm of the ureter. A biopsy from the renal pelvic mass showed a high grade urothelial carcinoma. She underwent an anterior exenteration, resection of both transplant and native kidneys and bilateral pelvic lymph node dissection. Pathologic examination showed a high grade papillary urothelial carcinoma which appeared to arise in the pelvis of the graft kidney, involve the graft ureter and native urinary bladder. The tumor had metastasized to one left obturator lymph node but spared the two native kidneys and ureters. Short tandem repeat (STR) analysis confirmed the tumor to be of donor origin. Next-generation sequencing identified amplification of TERT and loss of CDKN2A/CDKN2B in the primary tumor.ConclusionWhile it is known that transplant recipients have an increased risk of urothelial carcinoma compared to the general population, the lack of the well-documented risk factors, such as older age at transplantation, BK polyomavirus infection, and prolonged post-transplantation history and dissemination of the tumor in this case shed light on the de novo tumorigenesis of the graft kidney within the host microenvironment. Amplification of Telomerase reverse transcriptase (TERT) and loss of cyclin dependent kinase inhibitor 2A/2B (CDKN2A/CDKN2B) detected in the tumor by next gene sequencing suggests that they may play an important role in this case.

A histopathological study of urinary bladder neoplasms

The present study was carried out to describe the Histopathological features of various neoplasms in the urinary bladder biopsies and to categorize the neoplastic lesions according to W.H.O (2016)/ISUP classification of urinary bladder tumors.A total of 37 cases, 28 urinary bladder biopsies (TURBT) and 9 cystectomy specimens of urinary bladder neoplasia [histologically proved] of patients were studied retrospectively over the period from June 2016- Oct 2018 in Pathology department of Smt. N.H.L. medical college. All cases of urothelial carcinomas were graded histologically according to WHO (2016)/ISUP classification.Maximum numbers of patients are in age group 60-69 years. Males (78.37%) are more frequently affected as compared to female. The most frequent Neoplastic findings in Urinary bladder is Invasive Papillary Urothelial carcinoma (81.06%); Low grade (37.8%) being more common than High grade (35.14%). A large percentage (80%) of high grade invasive urothelial cell carcinomas presented with muscle invasion.Invasion to the muscle propria layer correlates with high grade tumor. In 18.5% cases detrusor muscle was absent, hence the importance of including detrusor muscle in the biopsy specimens needs to be emphasized. We must accept the fact that grading is highly subjective and that in future various molecular and immunohistochemical studies will provide better reproducibility.

Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes.

The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients including 83 with nonmuscle invasive bladder cancer and 86 patients with muscle invasive bladder cancer. Staining was scored for intensity (0 to 3) and extent (% positive cells) using the histological score system, where >15 was considered positive. Overall, 72/83 (87%) samples of nonmuscle invasive urothelial carcinoma were positive, including 29/30 (97%) noninvasive papillary urothelial carcinomas, 7/8 (87.5%) carcinomas in situ, 36/45 (80%) papillary urothelial carcinomas invading the lamina propria. Overall, 50/86 muscle invasive tumors were positive, including 15/22 (68.2%) urothelial carcinomas, 7/10 (70%) squamous cell carcinomas, 3/11 (28%) micropapillary tumors, 4/6 (66%) adenocarcinomas, 2/4 (50%) nested carcinomas, 5/8 (63%) plasmacytoid, 1/10 (10%) sarcomatoid carcinomas, and 0/15 (0%) small cell carcinomas. Whole transcriptome RNA sequencing revealed that compared with conventional urothelial carcinomas, most sarcomatoid carcinomas and all but 2 small cell carcinomas expressed very low levels of nectin-4 mRNA but expressed significant levels of either trop2 or ERBB2, which are the molecular targets of 2 other antibody-drug conjugates-sacituzumab gavitecan (trop2) or trastuzumab deruxtecan (ERBB2/HER2). In summary, our study demonstrates that there is heterogeneity of expression of nectin-4 in morphologic variants of urothelial cancer and nonurothelial histotypes, and suggests that testing expression of nectin-4 should be considered in morphologic variants or nonurothelial histotypes found to have lower expression.

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.