Nested Variant Of Urothelial Carcinoma Research Articles

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

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. 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. 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. 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.

Large nested variant of urothelial carcinoma of urinary bladder: a clinicopathological analysis of five cases

Objective: To investigate the clinicopathologic features, diagnosis and differential diagnosis of large nested variant of urothelial carcinoma (LNUC) of urinary bladder. Methods: The clinical and pathologic data of five cases of LNUC of urinary bladder diagnosed between January 2014 and December 2018 at the Department of Pathology, Zhejiang Provincial People's Hospital were analyzed by immunohistochemistry (IHC) and Sanger sequencing. The relevant literature was reviewed. Results: All five patients were male with a mean age of 63 years (range, 48 to 81 years). The mean tumor size was 3.4 cm (range, 1.7 to 4.7 cm). Histologically, the invasive LNUC tumor cells formed medium to large sized nests of varying shapes, from regular round, bulbous, oval to irregularly fused, branched, dumbbell shaped glands, with mild stromal reaction. In all five cases, focal central necrosis and microcystic changes in the tumor nests were identified. Cytologically, the tumor cells were low grade in four cases; the remaining case was overall low grade with focal high grade areas. Mitoses were scarce. All cases possessed surface urothelial tumors, including three low-grade papillary carcinomas, one high-grade papillary carcinoma and one carcinoma in situ. Three of the LNUC were accompanied by small nested variant of urothelial carcinoma and two by conventional high grade invasive urothelial carcinoma. Perineural involvement and angiolymphatic invasion were each noted in four tumors. Radical cystectomy was performed in four cases with TNM stages as followings: pT3aN0M0 in two cases, pT4aN0M0 and pT4aN1M0 in one case each. The remaining case had transurethral bladder resection and was of pT2 stage. By IHC, all five cases were positive for CK7 and p40; four were positive for GATA3; two were positive for CK20; and the mean Ki-67 proliferation index was 18%. TERT promoter mutation status were successfully performed in three cases, with one showing mutation (C228T) and two were wild type. All patients received postoperative chemotherapy. At a follow-up of 2 to 11 months, one patient died of unrelated causes, two patients developed metastases, and two were alive with no evidence of disease. Conclusions: LNUC is a histologic subtype of urothelial carcinoma with deceptively benign features but aggressive behavior, and appreciation of its unique infiltration patterns can aid in diagnosis and differential diagnosis. LNUC tends to coexist with small nested variant of urothelial carcinoma, suggesting these may represent different manifestations of the same urothelial carcinoma subtype.

PAX8 positivity in nested variant of urothelial carcinoma: a potential diagnostic pitfall

Nested variant of urothelial carcinoma is a rare variant of urothelial carcinoma morphologically characterized by infiltrative nests of cytologically bland urothelial cells. It is widely recognized that nested variant of urothelial carcinoma can closely mimic von Brunn nests. However, nested variant of urothelial carcinoma with tubule formation can also resemble nephrogenic adenoma, where immunohistochemical positivity for PAX8 has been used to establish the diagnosis of nephrogenic adenoma. Following anecdotal examples of PAX8 positive nested variant of urothelial carcinoma, we formally evaluated 23 cases of nested variant of urothelial carcinoma from 2011 to 2018. Cases were collected from our institution and evaluated for their architectural pattern and PAX8 expression. Except for 1 case from the renal pelvis, cases were located in the bladder. The majority (14/23 [61%]) showed solid nests with at least focal tubular differentiation. PAX8 immunoreactivity was strong (3+) in 7 (30%), moderate (2+) in 6 (26%), and negative in 10 (44%) cases. Four (57%) of the cases with strong expression and 3 (50%) of those with moderate staining showed diffuse immunoreactivity. Moderate-strong immunoreactivity was seen in 4/6 (66.7%) cases with solid nests, 8/14 (57.1%) with solid nests and tubules, and 1/3 (33.3%) with large nests. In conclusion, PAX8 can be positive in a significant proportion of nested variant of urothelial carcinoma cases, and recognition of this finding is important to avoid misdiagnosis of nested variant of urothelial carcinoma as nephrogenic adenoma based on PAX8 expression, particularly in cases with tubular differentiation and limited sampling.

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

Nested variant of urothelial carcinoma (NVUC) is rare, and only a few small series exist. Molecular characteristics and the classifying marker profile as well as therapeutic targets of this specific variant are mostly unknown. The aim of this study was to characterise NVUC at the molecular level in one of the largest cohorts to date. In addition, we applied an immunohistochemical marker panel in order to define the molecular subtype. Sixty NVUC cases were collected from different departments. TERT promoter mutation analysis was carried out in all samples using SNaPshot analysis. Targeted sequencing of 48 cancer-related genes by next-generation sequencing (NGS) analysis was performed in a subset of 26 cases. Immunohistochemical markers CD44, CK5, CK14, EGFR, p63, FOXA1, GATA3, CD24 and CK20 were used to elucidate the molecular subtype. A total of 62.5% of NVUC cases harboured a mutation of the TERT promoter. Additionally, TP53, JAK3 and CTNNB1 were among the most frequently mutated genes identified by NGS analysis. Subtyping revealed that all NVUC express luminal markers such as CD24, FOXA1, GATA3 and CK20. In summary, NVUC belong to the luminal molecular subtype. Moreover, a subset of NVUC seems to be characterised by mutations of the Wnt and inflammatory pathways, including JAK3 mutations, indicating a different biological background compared to conventional urothelial bladder cancer.

Nested Variant of Urothelial Carcinoma of the Renal Pelvis and Ureter: A Case Report

The nested variant of urothelial carcinoma (NVUC) is a rare form of bladder cancer with a reported prevalence of 0.3%. It is even more rare in the renal pelvis and the ureter. NVUC is characterized by a bland morphology but an aggressive clinical behavior. We report a case of an 87-year-old lady with a history of colon …

Large Nested Variant of Urothelial Carcinoma - A Case Report: Do Not Judge This Book by Its Cover - This Tumor Is a Wolf in Sheep's Clothing

Large nested variant of urothelial carcinoma (LNVUC) is a rare and relatively recently described subtype of urothelial carcinoma by Cox et al (2011), with …

Nested variant of urothelial carcinoma of urinary bladder strongly expressing NSE, KIT and PDGFRA

The nested variant of urothelial carcinoma (NVUC) of urinary bladder (UB) is very rare and is characterized by the presence of benign-appearing urothelial carcinoma cells in lamina propria, sparing surface urothelial involvement. It shows aggressive clinical course despite the benign-looking histology. A 72-year-old woman presented with dysuria. Cystscopy revealed papillary infiltrative tumor, and transurethral resection of UB tumor (TUR-BT) was performed. It was composed of small three fragments, two of which showed urothelial carcinoma (UC) of low grade (G1) atypia. In one section, NVUC was seen. The nested areas showed small clusters of UC of mild atypia. They were remote from surface urothelium. The tumor was mildly invasive, and the pathological stage was pT1. Immunohistochemically, tumor cells were positive for various types of cytokeratins, EMA, p63, p53, MUC1, NSE, KIT, PDGFRA, Ki-67 (43%), NCAM and synaptophysin. This is the first case of NVUC of UV with neuroendocrine features and expressions of KIT and PDGFRA.

Case Report: Large nested variant urothelial carcinoma –invasive malignancy masquerading as low grade disease

Introduction The large nested variant of urothelial carcinoma (LNVUC) is a newly described and rare subtype of urothelial carcinoma. It is characterised by bland cytological features and a large nested architecture similar in appearance to low grade urothelial carcinoma with an inverted growth pattern. To date only 23 cases in a single series have been described. Case Report We describe the case of a 59 year old male with LNVUC whose tumour was initially misdiagnosed as a non-invasive low grade urothelial carcinoma. At a subsequent re-resection, his tumour was correctly re-classified as LNVUC with extensive invasion of the muscularis propria. Radical cystectomy and formation of an ileal conduit was performed. His operative specimen revealed invasion of prostatic stroma and perivesical fat, with all surgical margins clear. He is currently free from clinical recurrence 12 months after his cystectomy. Conclusion LNVUC is a newly described and rare urothelial carcinoma subtype. It characteristically possesses bland cytological features and may mimic low grade urothelial cancer. Despite its bland appearance it behaves aggressively with invasion, metastasis and death being common.

Nested variant of urothelial carcinoma of the urinary bladder

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.