Intratumoral Switch of Molecular Phenotype and Overall Survival in Muscle Invasive Bladder Cancer.

In recent years, immunohistochemical protein expression was studied as a surrogate to the molecular classification of bladder cancer, although no tissue biomarkers are available for clinical use to predict survival or the response to neoadjuvant chemotherapy (CT) in UC, as the literature produced conflicting results. This retrospective study included TURB specimens harboring foci of HG pT2 muscle-invasive bladder carcinoma (MIBC) from 251 patients who subsequently underwent radical cystectomy. We performed immunohistochemical analysis on tumor samples, for relevant gene-expression-based markers for basal type (CD44, CK5/6) and luminal type (CK20 and pPARγ). Piescore, investigated in both non-muscle-invasive (NMI) and muscle-invasive (MI) components of the tumor, divided basal and luminal UC-types when at least three of the four markers were consistent with a specific phenotype, mixed types if one/two luminal and basal markers were present simultaneously, and neu-like types when all four markers investigated were negative. Eighteen selected cases were also investigated with RT-PCR to validate, and to increase the specificity of, the immunohistochemical results. We observe an immunophenotypical difference in the NMI and MI components in 96/251 UC patients (38.25%): half of tumors (44/96 cases) have a transition to basal, 36.46% (35/96 cases) to neu-like, 12.5% (12/96 cases) to mixed, and 5.2% (5/96 cases) to luminal phenotypes. Mixed tumors in the NMI component are more likely to change phenotype than other groups, particularly compared with basal tumors, which demonstrate greater stability (only 8/96 cases, p < 0.00001). The transition of luminal tumors to basal display a better OS compared with the transition toward neu-like tumors (p = 0.027). Overall, the phenotypical switch does not affect lymphovascular invasion, pT, DFS, or OS compared with non-switched cases. In the MI component, the presence of CD44 expression, irrespective of score-related phenotype, shows a protective effect in papillary-type UC (OS p = 0.008, HR 0.453, PFS p = 0.07, HR 0.599), and in UC naïve for CT (p = 0.0479). Piescore immunophenotyping reveals an intratumoral phenotypical transition between the NMI and MI components of the same tumor. The molecular change is a common event in the mixed and luminal categories, but not in basal tumors, which show better phenotypical stability. This phenomenon could partially explain the sensitivity of a subset of luminal UC to chemotherapy: good responders could be "non-real" luminal UC, which acquire nasal markers, such as CD44.

Xpert Bladder Cancer Monitor May Avoid Cystoscopies in Patients Under "Active Surveillance" for Recurrent Bladder Cancer (BIAS Project): Longitudinal Cohort Study.

OBJECTIVES: To test the hypothesis that patients under active surveillance (AS) for Non-muscle Invasive Bladder Cancer (NMIBC) who were negative on longitudinal re-testing by the Xpert® Bladder Cancer Monitor (Xpert BC Monitor) assay may avoid unnecessary cystoscopies and urine cytology (UC). SUBJECTS/PATIENTS OR MATERIALS AND METHODS: This is a prospective cohort study of patients enrolled in the AS protocol for recurrent NMIBC (Bladder Cancer Italian Active Surveillance, BIAS project), whose urine samples were analyzed by Xpert BC Monitor upon entry in the study (T0). Patients who had a negative Xpert test and did not fail AS, underwent additional Xpert tests after 4 (T1), 8 (T2), and 12 (T3) months. The clinical utility of Xpert was assessed by determining the number of cystoscopies and UC that could be avoided within 1 year. RESULTS: Overall, 139 patients were tested with Xpert at T0. Median follow-up was 23 (IQR 17-27) months. Sixty-eight (48.9%) patients failed AS, 65 (46.7%) are currently on AS, and 6 (4.3%) were lost at follow-up. At T0 57 (41.0%) patients had a negative test and 36 (63.2%) are still in AS. In patients with 2 consecutives negative Xpert tests, we could have avoided 73.9% of unnecessary cystoscopies, missing 26.4% failure, up to avoid all cystoscopies with 4 negative tests missing only 12% of failure. All the patients with negative Xpert had negative UC. Failure-free-survival at median follow-up (23 month) stratified for having 0, 1, or ≥2 negative tests was 67.0, 55.1. and 84.1, respectively. CONCLUSION: Our findings suggest that Xpert BC Monitor assay, when it is longitudinally repeated, could significantly reduce the number of unnecessary cystoscopies and UC during their follow-up.

Case Report: Unclassified Renal Cell Carcinoma With Medullary Phenotype and SMARCB1/INI1 Deficiency, Broadening the Spectrum of Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a rare entity with poor prognosis bearing inactivating genomic alterations in SMARCB1/INI1 resulting in the loss of expression of INI1 and occurring in young patients with sickle cell trait or sickle cell disease. Recently, rare examples with histological characteristics of RMC have been described in older patients without hemoglobinopathies and provisionally termed "Renal cell carcinoma unclassified with medullary phenotype" (RCCU-MP). Fluorescence in situ Hybridization (FISH) can detect alterations in SMARCB1/INI1 consisting mostly in inactivating translocation of one allele and deletion of the second. To date, only seven further cases of RCCU-MP have been described in the literature. Here we report the second Italian case of RCCU-MP, a 62-year-old man presenting with persistent dull back pain and incidentally discovering a 13 cm mass in the right kidney. The nomenclature of this entity is still debated and might be updated as a variant of medullary carcinoma in the upcoming WHO classification. In the meantime, we encourage awareness of these extraordinarily rare neoplasms with poor outcomes.

Case report: Primary Ewing sarcoma of the ureter, an exceptional finding of unique manifestation of disease.

Ewing sarcoma (ES) is the second most common malignant bone tumor in children and has also been described in adults with highly aggressive behavior. ES belongs to the small round blue cell tumor family and presents the distinctive translocation of FET-ETS family genes (85% with EWSR1), generating gene fusions. Extraskeletal ES mainly occurs in soft tissues; the urogenital tract is rarely affected, and ureteral localization is an exceptional event with only 4 cases described in the literature. Here we report the first Italian case of primary ES of the ureter, a 24-year-old young man with lower back pain and a narrowed left ureteral lumen on CT scan. ES of the urogenital tract is an almost unique condition with a nonspecific clinical presentation and a challenging diagnosis for pathologists. We encourage awareness of these exceptional events in the differential diagnosis of ureteral lesions in young patients.

Diagnostic Accuracy of Microultrasound in Patients with a Suspicion of Prostate Cancer at Magnetic Resonance Imaging: A Single-institutional Prospective Study.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI) represents the gold standard for the diagnosis of clinically significant prostate cancer (csPCa). The search for alternative diagnostic techniques is still ongoing. OBJECTIVE: To determine the accuracy of microultrasound (microUS) for the diagnosis of csPCa within prospectively collected cohort of patients with a suspicion of prostate cancer (PCa) according to MRI. DESIGN, SETTING, AND PARTICIPANTS: A total of 320 consecutive patients with at least one Prostate Imaging Reporting and Data System (PIRADS) ≥3 lesion according to MRI were prospectively enrolled. INTERVENTION: All patients received microUS before prostate biopsy using the ExactVu system; the Prostate Risk Identification using microUS (PRI-MUS) protocol was used to identify targets. The urologists were blinded to MRI results until after the microUS targeting was completed. All patients received both targeted (based on either microUS or MRI findings) and randomized biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The sensitivity and specificity of microUS to determine the presence of csPCa (defined as at least one core with a Gleason score ≥7 PCa) were determined. Multivariable logistic regression analysis was fitted to determine the predictors of csPCa. RESULTS AND LIMITATIONS: Clinically significant PCa was diagnosed in 116 (36.3%) patients. The sensitivity and negative predictive value of microUS for csPCa diagnosis were 89.7% and 81.5%, while specificity and positive predictive value were 26.0% and 40.8%, respectively. A combination of microUS-targeted and randomized biopsies would allow diagnosing the same proportion of csPCa as that diagnosed by an approach combining MRI-targeted and randomized biopsies (n = 113; 97.4%), with only three (2.6%) csPCa cases diagnosed by a microUS-targeted and three (2.6%) by an MRI-targeted approach. In a logistic regression model, an increasing PRI-MUS score was an independent predictor of csPCa (p ≤ 0.005). The main limitation of the current study is represented by the fact that all patients had suspicious MRI. CONCLUSIONS: Microultrasound is a promising imaging modality for targeted prostate biopsies. Our results suggest that a microUS-based biopsy strategy may be capable of diagnosing the great majority of cancers, while missing only few patients with csPCa. PATIENT SUMMARY: According to our results, microultrasound (microUS) may represent an effective diagnostic alternative to magnetic resonance imaging for the diagnosis of clinically significant prostate cancer, providing high sensitivity and a high negative predictive value. Further randomized studies are needed to confirm the potential role of microUS in the diagnostic pathway of patients with a suspicion of prostate cancer.

Assessing the Feasibility and Accuracy of High-resolution Microultrasound Imaging for Bladder Cancer Detection and Staging.

BACKGROUND: Magnetic resonance imaging (MRI) has been proposed as a staging tool for bladder cancer (BC), but its use has been limited by its high costs and limited availability. Microultrasound (mUS) is a novel technology capable of providing high-resolution images of the prostate. OBJECTIVE: To test the feasibility of high-resolution mUS in patients diagnosed with BC and its ability to differentiate between non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). DESIGN, SETTING, AND PARTICIPANTS: This is an observational prospective study performed in 23 patients with a diagnosis of primary BC scheduled for an endoscopic treatment. SURGICAL PROCEDURE: Micro-US was performed before transurethral resection of bladder tumor using the ExactVu system with an EV29L 29-MHz side-fire transducer (Exact Imaging, Markham, Canada). MEASUREMENTS: The endpoints were to test the feasibility, describe the normal bladder wall anatomy, identify the lesions, and compare the mUS findings with the histopathological results. RESULTS AND LIMITATIONS: Micro-US was accurate in differentiating the three layers of the bladder wall in all cases. Bladder cancers were clearly identified as heterogeneous structures protruding from the normal bladder wall. In 14 cases the lesions appeared confined to the lamina propria, and in all cases NMIBC was confirmed by the final pathological report. In the other patients, the lesions seemed to extend into the muscular layer, but MIBC was confirmed in five out of seven cases (71.4%) from the pathologist. The small sample size was the main limitation of the current study. CONCLUSIONS: Our findings showed that mUS is able to differentiate the bladder wall layers and identify the bladder cancer stage. Further studies with a larger population and imaging correlation with MRI are warranted before its introduction in clinical practice. PATIENT SUMMARY: In this report, a new imaging technique was tested for the characterization of bladder cancer. Microultrasound appears to be feasible and capable of discriminating between superficial and invasive tumors.

Clinical performance of Xpert Bladder Cancer (BC) Monitor, a mRNA-based urine test, in active surveillance (AS) patients with recurrent non-muscle-invasive bladder cancer (NMIBC): results from the Bladder Cancer Italian Active Surveillance (BIAS) project.

PURPOSE: To investigate the clinical performance of a new mRNA-based urine test, aiming to avoid unnecessary follow-up cystoscopy in patients under active surveillance (AS) for recurrent NMIBC. METHODS: This is a prospective cohort study enrolling patients with history of low-grade (LG) NMIBC, who developed a recurrence during the follow-up and underwent AS. Their urinary samples were analyzed by Xpert BC Monitor (Cepheid, Sunnyvale, CA, USA). The primary endpoint was to investigate if Xpert BC Monitor could avoid unnecessary cystoscopy during the follow-up period. Its sensitivity, specificity, PPVs and NPVs were calculated. A cutoff of 0.4 "linear discriminant analysis" (LDA) was optimized for the AS setting. RESULTS: The cohort consisted of 106 patients with a mean age of 72 ± 9.52 and a median follow-up from AS start of 8.8 (range 0-56.5) months. No statistically significant difference was found for the mean age, smoker status, lesion size, and number of lesions with a cutoff of 0.4. Of 106 patients, 22 (20.8%) were deemed to require treatment because of cystoscopic changes in size and/or number of lesions during the follow-up period. Using a cutoff value of < 0.4, 34 (33.7%) cystoscopies could be avoided due to low LDA value, missing 2/22 (9%) failures, none with high-grade (HG) NMIBC. Further research on larger population remains mandatory before its clinical use. CONCLUSION: Xpert BC Monitor seems to be a reliable assay, which might avoid unnecessary cystoscopies without missing HG NMIBC when its cutoff is optimized for the AS setting.

Pathological Outcomes for Patients Who Failed To Remain Under Active Surveillance for Low-risk Non-muscle-invasive Bladder Cancer: Update and Results from the Bladder Cancer Italian Active Surveillance Project.

BACKGROUND: It has been shown that active surveillance (AS) is feasible and effective in a subset of patients with recurrent low-grade (LG) non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To update a previous preliminary series and investigate pathological outcomes for patients who failed to remain on AS. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational cohort study started in February 2008, and currently still active, at a tertiary university hospital, including patients with pathologically confirmed NMIBC who experienced recurrence during follow-up. INTERVENTION: AS monitoring consisted of cytology and in-office flexible cystoscopy every 3 mo for the first year, and every 6 mo thereafter. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was pathological results for patients who failed to remain on AS. The secondary outcome was an update of clinical results from our previous series. Data were complemented by descriptive statistical analysis and univariable and multivariable proportional hazards Cox regression. RESULTS AND LIMITATIONS: Overall, 167 patients were included. Of 181 AS events, 61 (33.7%) were deemed to require treatment because of positive cytology (n=10), gross haematuria (n=11), and increases in the tumour number (n=15), or size (n=17), or both (n=8). The median time on AS was 12 mo (interquartile range 4-26). Pathological specimens from AS failures did not show any malignancy in 20 cases. Histopathology identified urothelial hyperplasia and oedema, submucosal vascular ectasia, mucosal erosion, polypoid cystitis, von Brunn nest hyperplasia, and squamous metaplasia. The time from first transurethral resection to AS start was inversely associated with recurrence-free survival (hazard ratio 0.97, 95% confidence interval 0.96-1.00; p=0.024). The study lacks statistical subanalyses focusing on patients with failure and negative neoplastic pathological outcomes. CONCLUSIONS: AS might be a reasonable strategy in patients presenting with small LG pTa/pT1a recurrent bladder tumours. Approximately 30% of patients deemed to have AS failure did not harbour any neoplastic lesion, strengthening the role of AS. PATIENT SUMMARY: Patients with small low-grade pTa/pT1a recurrent papillary bladder tumours could benefit from an active surveillance protocol with no significant risk of pathological progression to muscle-invasive cancer.

Disseminated Cerebrospinal Embryonal Tumor in the Adult.

Introduction. According to the 2016 World Health Organization classification of Tumors of the Central Nervous System, the term Primitive Neuroectodermal Tumor has been replaced by the term Embryonal Tumor (ET). We present a case of disseminated cerebrospinal ET presenting in an adult patient. Illustrative Case. A 49-year-old male presenting with low back pain, dysuria, and hypoesthesia of the lower extremities referred to our emergency department. Brain and whole spine contrast-enhanced MRI documented a diffusively disseminated heterogeneous neoplasm with intradural extra- and intramedullary involvement of the cervicothoracic tract and cauda equina. A primary biopsy of the lumbosacral localization was performed through L5 bilateral laminectomy. Histologic diagnosis was Embryonal Tumor Not Otherwise Specified. The patient underwent chemotherapy with postoperative adjuvant alternating Vincristine-Doxorubicin-Ifosfamide (VAI) and Ifosfamide-Etoposide (IE). Discussion. Spinal ETs are exceedingly rare especially when presenting in the adult patient. Neurosurgical and oncologic management is still unclear. When feasible, surgical removal should always be performed to obtain a histologic diagnosis. Postoperative adjuvant therapy might entail both chemo- and radiotherapy; however a consensus on this matter is still lacking.