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The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including 6 cases diagnosed with LNVUC and 32 with metastatic invasive urothelial carcinoma (UC). Initially, six formalin-fixed paraffin-embedded (FFPE) tissue samples of the LNVUC were subjected to whole-exome sequencing (WES), and then we performed targeted sequencing on 32 cases of metastatic invasive UC of various morphological subtypes, which were interrogated for the FGFR3. Our results revealed 3/6 (50%) LNVUC cases evaluated by WES in our study showed an activating mutation in FGFR-3, 33% showed an activating mutation in PIK3CA, and 17% showed activating mutation in GNAS or MRE11. Additionally, 33% of cases showed a truncating mutation in CDKN1B. All LNVUC in our study that harbored the FGFR-3 mutation showed additional activating or truncating mutations in other genes. Overall, 6/32 (18.75%) cases of random metastatic invasive UC showed missense mutations of the FGFR-3 gene. The LNVUC variant showed the higher incidence of FGFR-3 mutations compared to other types of mutations. Additionally, all LNVUC cases show additional activating or truncating mutations in other genes, thus being amenable to novel targeted therapy.

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Nested variant of urothelial carcinoma (NV-UC) is an extremely rare cancer with a nonspecific presentation. It is usually identified at a late stage, which makes the treatment challenging. Herein we report the case of a 52-year-old woman with an advanced NV-UC treated by anterior exenteration after a poor response to neoadjuvant chemotherapy. One year after completion of adjuvant radiotherapy, the patient remains disease-free.

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INTRODUCTION: The nested variant of urothelial carcinoma is rare and shows poor prognosis. We report a case of complete response to pembrolizumab in recurrent nested variant. CASE PRESENTATION: A 50-year-old man visited another hospital with hematuria and weight loss. Clinical stage T4aN0M0 bladder cancer and acute renal failure were diagnosed. He was referred to our hospital and underwent radical cystectomy. Histological examination showed pathological stage T4aN2 nested variant of urothelial carcinoma. He received 3 cycles of gemcitabine and carboplatin adjuvant chemotherapy. However, para-aortic lymph node metastasis appeared 7 months after cystectomy. He received pembrolizumab as systemic chemotherapy. After 10 cycles, the lesion remained undetectable and we evaluated the response as complete. He has received 18 cycles in total and no recurrences or metastases have been observed. CONCLUSION: Pembrolizumab may offer effective treatment for nested variant of urothelial carcinoma.

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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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There is no ideal marker or established immunohistochemistry panel to confirm urothelial differentiation. Immunohistochemistry must be always indicated in concrete differential diagnostic consideration. In this review article, immunohistochemistry will be discussed in the three different settings - distinction of benign and malignant changes of urothelium, the most frequent pitfalls and non-urothelial neoplasms of urinary tract.

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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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We report on four patients with the nested variant of urothelial carcinoma (NVUC) of the urinary bladder and focus on their magnetic resonance imaging (MRI) findings. MRI showed that all lesions had irregular wall thickening with little protrusion into the bladder lumen. All had extravesical invasion, and two had invaded other organs (uterus and seminal vesicle). On T2-weighted images, all tumors mainly showed relatively strong hypointensity similar to that of the muscularis propria, and in three cases there was also a thin hyperintense layer on the tumor surface, suggesting edematous mucosa. Diffusion-weighted images demonstrated different degrees of hyperintensity, which was faint in one case. Dynamic contrast-enhanced MRI was performed in two cases and both showed gradual contrast enhancement. It has been suggested that NVUC may produce unique MRI findings reflecting its pathological features. It would be useful for those who interpret bladder MRI to recognize this rare urothelial carcinoma variant.

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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.

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AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

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Large nested urothelial carcinoma (LNUC) is a recently recognized variant of urothelial carcinoma (UC), which is characterized with inverted growth pattern and bland cytology. Diagnosis can be extremely challenging, especially in transurethral resection (TUR) materials. Haematoxylin-eosin stained slides of TUR materials with UC, submitted to our department between 2008 and 2017 were re-examined. Twenty-two LNUC cases were found. LNUC frequency was 0.7%. Mean age was 69.9, 82% were male. Mean tumor diameter was 4.9 cm. Non-invasive UC was present in all cases; low-grade in 6, high-grade in 1, low and high-grade in 15. Five and 16 cases were pT1 and pT2, respectively, no invasion was detected in one case. In addition to medium-large nests, small nests and conventional UC areas was present in 2 and 3 cases, respectively. Stroma-tumor interface was irregular in 19 cases and 3 cases had invasive nests with rounded contours. Fibrous stromal reaction and/or stromal lymphoid infiltration were present in 21 cases. Budding, described as small nests in stromal interface of medium-large nests was found in 16 cases. Follow-up was available for 18 cases with an average of 59 months. Four cases had metastasis, 1 patient died of disease. LNUC causes diagnostic difficulty, especially in TUR materials. Large size of tumor, irregularity of nests, presence of stromal reaction and budding can be clues for correct diagnosis.

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Objective To analyze the clinical features of nested variant of bladder urothelial carcinoma.Methods The clinical data of 13 patients with nested variant of bladder urothelial carcinoma treated in our hospital from July 2014 to April 2018 were retrospectively analyzed.There were 10 males and 3 females and the mean age was 64.6(37-81) years.All 13 cases had symptom of hematuria,3 cases with anemia,1 cases with urinary frequency,urgency and dysuria,1 case with all the above symptoms.Six cases underwent transurethral resection of the bladder tumor (TURBT),7 cases underwent radical cystectomy.Results All 13 cases had nested structures in pathology.Six cases did immunohistochemistry but none of them were specific.Twelve cases were high-grade invasive urothelial carcinoma,of which 2 cases were associated with carcinoma in situ,and 1 case was low-grade invasive.Two patients' pathological stages were ≤T1,4 patients in T2 phase,and 7 patients in T3-4 phase.Four patients who underwent TURBT received intravesical instillation chemotherapy,and 3 patients who underwent radical cystectomy and 1 patient with TURBT received intravenous chemotherapy.One patient with TURBT received both intravesical chemotherapy and intravenous chemotherapy.The remaining 4 patients who underwent radical cystectomy did not receive special treatment.The progression-free survival time of 13 patients was 2-39 months,of which 2 patients relapsed,1 patient metastasized,1 patient with tumor progression,and 2 patients with non-tumor specific death.Conclusions The clinical features of nested variant of urothelial carcinoma special.However,the pathology of nested variant of bladder urothelial carcinoma has a unique nested structure.At present,TURBT and radical cystectomy are still the main treatment modalities for nested variant of bladder urothelial carcinoma,and the prognosis of which is poor.

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OBJECTIVES: The nested variant of bladder transitional cell carcinoma is extremely rare and has a different biological behavior to other bladder tumors. The aim of this study is to analize if their behavior is as aggressive as has been described in the literature. MATERIAL AND METHOD: Review of 12 diagnosed cases with nested variant of bladder transitional cell carcinoma and analysis of demographic characteristics, clinical presentation, tumor characteristics, treatment options, analysis of recurrence and cancer-specific survival between January 1997 and December 2010 in our hospital. RESULTS: 50% of the cases had a pathologic stage ≥T2, with grade of differentiation G2 (50%) or G3 (50%). After the pathological result of the TUR (transurethral resection) Bladder, 5 cases underwent radical cystoprostatectomy, 3 a second TUR bladder and 4 cases with treatment chemotherapy and/or radiotherapy (RT). Five out of 12 cases (41.7%) died due to bladder cancer and 3 died (25%) of other causes (urinary sepsis, respiratory failure, renal failure). With a median follow up of 40 months, the overall survival was 50% and cancer-specific survival of 65.6%. CONCLUSIONS: The nested variant of bladder transitional cell carcinoma is a disease with an advanced-stage presentation, with high recurrence and mortality rates despite the use of different treatments. So far there is not a clinical practice guideline for this variety of urothelial tumor.

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The nested variant of urothelial carcinoma is a rare but very important histological entity due to its deceptively bland-looking appearance and aggressive behavior. We present a case of a 30-year-old man who was found to have a solitary polypoid growth in the bladder. It was resected and found to be a fibroepithelial polyp; a rare entity in itself, harboring the above tumor. The lesion also showed a second population of scattered bizarre stromal cells. To our knowledge, this is the first instance of a nested variant of urothelial carcinoma arising in a fibroepithelial polyp. The presence of atypical stromal cells has also not been described previously.

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Invasive urothelial carcinoma has a potential to show divergent differentiation. Several uncommon morphological variants have been described in the recent past. One such rare type is the nested variant of urothelial carcinoma. Most of the published reports depict occurrence of this variant in the urinary bladder. We report an unusual presentation of this uncommon entity in the renal pelvis of a 54-year-old lady who presented with widespread skeletal metastases without any urinary symptoms.

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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.