Nested Variant of Urothelial Carcinoma Is a Luminal Bladder Tumor With Distinct Coexpression of the Basal Marker Cytokeratin 5/6

Abstract Objectives The nested variant of urothelial carcinoma (NVUC) is a rare bladder tumor that may possess a luminal molecular phenotype. We sought to determine whether a small immunohistochemical (IHC) panel using common surrogates for molecular phenotypes would reliably classify a cohort of pure NVUC cases. Methods IHC staining with a panel composed of markers for basal subtypes (CK5/6, CK14) and luminal subtypes (FOXA1, GATA3) was performed on pure small NVUC cases (n = 23) and 5 large NVUC cases (n = 5). Scoring of IHC stains was performed semiquantitatively. Individual cases were analyzed using previously reported IHC-based surrogates for molecular subtype. Results The phenotype of NVUC was classified as luminal from 60.1% (FOXA1+/CK5/6−) to 100% (GATA3+/CK14−) of cases using composite phenotypes. No cases possessed a basal or squamous cell carcinoma–like phenotype. The majority of small NVUC cases (69.5%) showed subset CK5/6 expression distinctly localized to the basal layers of tumor cell nests. Intratumoral heterogeneity was also noted in CK5/6 (21.7% of small NVUC cases) but no other markers. Conclusions NVUC appears to express markers of both basal and luminal bladder tumors. Definitive gene expression profiling may be valuable to further characterize this unique histologic variant.

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Nested variant of urothelial carcinoma of the urinary bladder

Rare Tumors ◽

10.4081/rt.2011.e42 ◽

2011 ◽

Vol 3 (4) ◽

pp. 132-134 ◽

Cited By ~ 6

Author(s):

Tadashi Terada

Keyword(s):

Urothelial Carcinoma ◽

Lamina Propria ◽

Bladder Tumor ◽

Clinical Course ◽

Carcinoma Cells ◽

Ki 67 ◽

Atypical Cells ◽

Nested Variant ◽

Aggressive Clinical Course ◽

Nephrogenic Metaplasia

The nested variant of urothelial carcinoma (NVUC) is characterized by the presence of benign-appearing urothelial carcinoma cells in the lamina propria, sparing the surface urothelial involvement. NVUC shows aggressive clinical course despite of benign-looking histology. Herein reported are two cases of NVUC. One is 80-year-old woman, and another is 78-year-old man. In both cases, atypical cells forming nests and tubules were seen in the lamina propria without surface urothelial involvement. One case resembled nephrogenic metaplasia and another proliferated Brunn's nest or inverted papilloma. Immunohistochemically, both cases showed positive p53 and high Ki67 labeling, suggesting that both cases are malignant. Immunohistochemically, one case was characterized by positive cytokeratins, EMA, p53, Ki-67 (labeling=15%), α-methylacyl CoA racemase, CA19-9, and MUC1, and another case by positive cytokeratins, EMA, p63, p53, Ki-67 (lebeling=30%), CD10, CEA, and MUC1. Cyto keratin immunoprofiles were described and other antigens’ expressions were shown. The patients are now free of tumor 6 and 15 months after the resection of the bladder tumor.

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Distinct genetic alterations and luminal molecular subtype in nested variant of urothelial carcinoma

Histopathology ◽

10.1111/his.13958 ◽

2019 ◽

Vol 75 (6) ◽

pp. 865-875 ◽

Cited By ~ 9

Author(s):

Veronika Weyerer ◽

Rebecca Weisser ◽

Evgeny A Moskalev ◽

Florian Haller ◽

Robert Stoehr ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Molecular Subtype ◽

Genetic Alterations ◽

Nested Variant

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Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype

Cancers ◽

10.3390/cancers12030763 ◽

2020 ◽

Vol 12 (3) ◽

pp. 763 ◽

Cited By ~ 2

Author(s):

Veronika Weyerer ◽

Markus Eckstein ◽

Eva Compérat ◽

Hendrik Juette ◽

Nadine T. Gaisa ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Molecular Subtype ◽

Tumor Development ◽

Case Series ◽

Tert Promoter ◽

Mutational Status ◽

Tert Promoter Mutations ◽

Fgfr3 Mutation ◽

Nested Variant ◽

Promoter Mutations

Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.

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The Nested Variant of Urothelial Carcinoma: Clinicopathology of 2 Cases

Archives of Pathology & Laboratory Medicine ◽

10.5858/2003-127-e333-tnvouc ◽

2003 ◽

Vol 127 (8) ◽

pp. e333-e336 ◽

Cited By ~ 1

Author(s):

Guang-Qian Xiao ◽

Stephen J. Savage ◽

Michael E. Gribetz ◽

David E. Burstein ◽

Lorraine K. Miller ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Tumor Cells ◽

Immunohistochemical Staining ◽

Bladder Tumor ◽

Low Grade ◽

Elderly Men ◽

Ki 67 ◽

Tumor Entity ◽

Nested Variant ◽

Nuclear Features

Abstract The nested variant of urothelial carcinoma is a recently described bladder tumor entity with a rare incidence. Two cases of this disease are presented in this report; the patients in both cases were elderly men, with a predominant involvement of the trigone region. Histologically, the tumor cells were arranged in ill-defined nests and had low-grade nuclear features. Both cases had a diffusely infiltrating growth pattern with widespread local disease at cystectomy. Strong immunohistochemical staining for p63 in the neoplastic cells supports the urothelial cell nature of this neoplasm. High p53 and Ki-67 indices of this tumor correlate with the aggressiveness of this subtype.

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Role of immunohistochemistry in diagnosis of a rare bladder tumor

Journal of Laboratory Physicians ◽

10.4103/jlp.jlp_119_18 ◽

2019 ◽

Vol 11 (01) ◽

pp. 091-093

Author(s):

Manjari Kishore ◽

Purnima Malhotra ◽

Minakshi Bhardwaj

Keyword(s):

Gastrointestinal Tract ◽

Urinary Bladder ◽

Urothelial Carcinoma ◽

Neuroendocrine Tumors ◽

Adult Female ◽

Bladder Tumor ◽

Accurate Diagnosis ◽

Bladder Tumors ◽

History Of

AbstractNeuroendocrine tumors (NETs) are commonly located in the respiratory and gastrointestinal tract; however, these tumors can rarely be found in the urinary bladder. NETs comprise <1% of all bladder tumors; usually intermixed with urothelial carcinoma and its variants. We report a case of primary neuroendocrine carcinoma of urinary bladder in an adult female with a history of smoking and hematuria. The present case highlights the importance of immunohistochemistry in arriving at an accurate diagnosis and thereby differentiating this tumor from other clinical mimics.

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Comparison of Endoscopic Versus Percutaneous Approach (Blind) to Control the Obturator Jerk in Patients Undergoing Transurethral Resection of Bladder Tumors Under Spinal Anesthesia

Bangladesh Journal of Urology ◽

10.3329/bju.v21i2.49885 ◽

2020 ◽

Vol 21 (2) ◽

pp. 120-126

Author(s):

Alamgir Md ◽

Karim Km Monwarul ◽

Nandy SP ◽

Md Monwar Ul Haque ◽

Sakhawat Mahmud Khan

Keyword(s):

Statistical Analysis ◽

Spinal Anesthesia ◽

Transurethral Resection ◽

Bladder Tumor ◽

Complete Resection ◽

Satisfaction Level ◽

Bladder Tumors ◽

Percutaneous Approach ◽

Group A ◽

Group B

Objective: The aim of the study was to compare the endoscopic versus percutaneous approach (blind) to control the obturator jerk in patients undergoing transurethral resection of bladder tumors under spinal anesthesia. Materials and methods: A prospective observational study was performed in Department of Urology, Chittagong Medical College, Chittagong and some Private Hospitals (Ltd.) in Chittagong city during the period from January 2016 to June 2016. Total 100 patients were grouped into two, on alternate basis. Fifty(50) patients in group- A conducted with endoscopic infiltration with 20ml of injection 2% lignocaine at the bladder tumor base and another 50 patients in group-B, conducted with blind percutaneous technique with same drug and volume ( 20ml inj.2% lignocaine) to control obturator jerk. Severity of obturator jerk in both procedure, percentage of complete resection, ONB procedure related time, ONB procedure related complications and surgeon’s satisfaction level were recorded and compared between two approaches. Chi-square analysis was performed to compare the ease of approach and outcome of the two techniques. A value of P<0.05 was considered statistically significant. Results: The mean age of the patients were 59.44+7.681. In group-A, 50 patients were given inj. 2% lignocaine endoscopically at the bladder tumor base to control obturator jerk. Twenty five patients (50%) had no jerk, 20 patients(40%) developed mild jerk and 5 patients (10%) developed moderate jerk and no patients developed severe jerk. Second attempt was taken in moderate jerk patients (5 patients) and succeeded in 3(6%) patients. So, in this group, complete resection of bladder tumor was possible in 96%. In group B, complete resection of bladder tumor was possible in 84%. Statistical analysis was done and result is significant in case of endoscopic procedure to control obturator jerk(p<0.05). ONB Procedure related time was <20 mins. in 32(64%) patients in group-A and 45 (90%) patients in group- B. 20 mins. or more time was required for 18 (36%) patients in group-A and 5 (10%) patients in group-B. Statistical analysis was done and result is significant in percutaneous (blind) technique (p<0.05). ONB procedure related complications in group-A and Group –B were noted. Statistical analysis was done and result is insignificant (p>0.05). Surgeons satisfaction level were recorded on the basis of obturator jerk block and complete resection and which was statistically significant in favour of endoscopy group (p<0.05). Conclusion: It is concluded that endoscopic injection of 2% lignocaine into the bladder tumor base is better in case of jerk elimination and complete resection than blind percutaneous approach. Though, ONB procedure related time was significantly less in percutaneous group. Bangladesh Journal of Urology, Vol. 21, No. 2, July 2018 p.120-126

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GCT-73. EXPRESSION PROFILING OF INTRACRANIAL GERM CELL TUMORS REVEALS UPREGULATION OF RAS THROUGH mRNA-microRNA SIGNALING PATHWAY

Neuro-Oncology ◽

10.1093/neuonc/noaa222.289 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii343-iii343

Author(s):

Aaron M Taylor ◽

Jianhe Shen ◽

Lingzhao Ren ◽

Keita Terashima ◽

Lei Huang ◽

...

Keyword(s):

Gene Expression ◽

Germ Cell ◽

Expression Profiling ◽

Model Building ◽

Rna Binding ◽

Molecular Subtype ◽

Germ Cell Tumors ◽

Cell Renewal ◽

Data Set ◽

Intracranial Germ Cell Tumors

Abstract Intracranial germ cell tumors (IGCTs) account for 3% of CNS tumors in children in the U.S. and 11% in Japan and East Asian countries. IGCTs are separated into two distinct subtypes based on histology: germinomas and non-germinomatous germ cell tumors (NGGCTs). The deep central location of IGCTs makes surgical resection and therefore molecular subtype classification difficult, and previous gene expression studies are limited. We performed mRNA expression profiling (Human Genome U133 Plus 2.0) and microRNA expression profiling (ABI TaqMan) with 36 and 49 IGCTs, respectively. Sample stratification using non-negative matrix factorization clustering of gene expression revealed two distinct subgroups that delineated germinomas from NGGCTs. Employing stepwise model building in each data set separately, we were able to separate these groups using only mRNA probes for the LIN28B and L1TD1 genes, and two microRNA, microRNA-26a and microRNA-373. MicroRNA26a suppresses the LIN28B gene and is down-regulated in germinoma. LIN28B directly binds and suppresses the let-7 microRNA family, which suppress the KRAS oncogene, previously found to be mutated in ~19% of IGCTs. L1TD1 is required for human stem cell renewal and directly interacts with LIN28B for its RNA binding function. LIN28B and L1TD1 are both known to be upregulated in other systemic germ cell tumors, but this has not yet been documented in IGCTs. In conclusion, these results show that intracranial germinomas have similar gene expression compared to systemic seminoma, and suggest a mechanism by which activation of LIN28B and L1TD1 downregulates the let-7 microRNA and subsequently upregulates KRAS.

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Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed

Bladder Cancer ◽

10.3233/blc-201523 ◽

2021 ◽

pp. 1-17

Author(s):

Breann C. Sommer ◽

Deepika Dhawan ◽

Audrey Ruple ◽

José A. Ramos-Vara ◽

Noah M. Hahn ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Cancer Progression ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Clinical Stage ◽

Tumor Characteristics ◽

Rna Seq ◽

Advanced Clinical Stage ◽

Naturally Occurring ◽

Immune Signatures

BACKGROUND: Improved therapies are needed for patients with invasive urothelial carcinoma (InvUC). Tailoring treatment to molecular subtypes holds promise, but requires further study, including studies in pre-clinical animal models. Naturally-occurring canine InvUC harbors luminal and basal subtypes, mimicking those observed in humans, and could offer a relevant model for the disease in people. OBJECTIVE: To further validate the canine InvUC model, clinical and tumor characteristics associated with luminal and basal subtypes in dogs were determined, with comparison to findings from humans. METHODS: RNA sequencing (RNA-seq) analyses were performed on 56 canine InvUC tissues and bladder mucosa from four normal dogs. Data were aligned to CanFam 3.1, and differentially expressed genes identified. Data were interrogated with panels of genes defining luminal and basal subtypes, immune signatures, and other tumor features. Subject and tumor characteristics, and outcome data were obtained from medical records. RESULTS: Twenty-nine tumors were classified as luminal and 27 tumors as basal subtype. Basal tumors were strongly associated with immune infiltration (OR 52.22, 95%CI 4.68–582.38, P = 0.001) and cancer progression signatures in RNA-seq analyses, more advanced clinical stage, and earlier onset of distant metastases in exploratory analyses (P = 0.0113). Luminal tumors were strongly associated with breeds at high risk for InvUC (OR 0.06, 95%CI 0.01 –0.37, P = 0.002), non-immune infiltrative signatures, and less advanced clinical stage. CONCLUSIONS: Dogs with InvUC could provide a valuable model for testing new treatment strategies in the context of molecular subtype and immune status, and the search for germline variants impacting InvUC onset and subtype.

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