Molecular evidence supporting the precursor nature of atypical adenomatous hyperplasia of the prostate.

Atypical adenomatous hyperplasia (AAH) of the prostate is characterized by lobular proliferation of closely packed small acini. It is hypothesized that AAH is a precursor lesion for low-grade prostate cancer arising from the transition zone. Telomere dysfunction is common during malignant transformation of epithelia. In this study, we investigate telomere shortening in AAH (n = 93), high-grade prostatic intraepithelial neoplasia (HGPIN) ( n = 68), and prostatic adenocarcinoma (PCA) ( n = 70) using quantitative fluorescence in situ hybridization. Twenty percent (19 of 93) of AAH specimens, 68% (46 of 68) of HGPIN, and 83% (58 of 70) of PCA showed significant telomere shortening. Thirty-two percent of AAH lesions had α-methylacyl-CoA racemase (AMACR) expression, a sensitive and specific marker for HGPIN and PCA. AMACR expression in AAH was seen more frequently in AAH foci with telomere shortening or coexisting PCA. Our findings indicate that a subset of AAH lesions have telomere shortening and AMACR expression, suggesting that these foci may be precursors for PCA.

TERT promoter mutation status in sarcomatoid urothelial carcinomas of the upper urinary tract.

AIM: To determine TERT promoter mutation status as well as the expression of PAX8, GATA3, p63, p40, p53 and uroplakin III in 17 patients with the upper urinary tract sarcomatoid urothelial carcinoma. METHODS & RESULTS:  TERT C228T mutations were found in six of 17 cases (35%). p53 was expressed in 77% of these tumors. PAX8, GATA3, p40 and uroplakin III are less frequently expressed. Lymph node metastases were present in ten cases (59%). Eight patients (47%), including all three patients with TERT mutation, died of cancer within 2 years after surgery. CONCLUSION: Sarcomatoid carcinoma of the upper urinary tract is an aggressive tumor and the presence of TERT mutation may portend poor prognosis.

Telomerase reverse transcriptase (TERT) promoter mutation analysis of benign, malignant and reactive urothelial lesions reveals a subpopulation of inverted papilloma with immortalizing genetic change.

AIMS: To understand more clearly the genetic ontogeny of inverted papilloma of urinary bladder, we analysed telomerase reverse transcriptase (TERT) promoter mutation status in a group of 26 inverted papillomas in comparison with the mutation status of urothelial carcinoma with inverted growth (26 cases), conventional urothelial carcinoma (36 Ta non-invasive urothelial carcinoma, 35 T2 invasive urothelial carcinoma) and cystitis glandularis (25 cases). METHODS AND RESULTS: TERT promoter mutations in inverted papilloma, urothelial carcinoma with inverted growth, urothelial carcinoma and cystitis glandularis were found in 15% (four of 26), 58% (15 of 26), 63% (45 of 71) and 0% (none of 25), respectively. C228T mutations were the predominant mutations (97%) found in bladder tumours, while C250T aberrations occurred in approximately 3% of bladder tumours. In the inverted papilloma group, TERT mutation occurred predominantly in female patients (P = 0.006). Among urothelial carcinomas, TERT promoter mutation status did not correlate with gender, histological grade or pathological stage. CONCLUSIONS: TERT promoter mutations were found in 15% of inverted papillomas. Our data suggest that there is a subpopulation of inverted papilloma that shares a carcinogenetic pathway with urothelial carcinoma with inverted growth and conventional urothelial carcinomas. Caution is warranted in exploring TERT promoter mutation status as a screening or adjunct diagnostic test for bladder cancer.

Incidental prostate cancer in Asian men: high prevalence of incidental prostatic adenocarcinoma in Chinese patients undergoing radical cystoprostatectomy for treatment of bladder cancer and selection of candidates for prostate-sparing cystectomy.

BACKGROUND: Previous studies report a low prevalence of incidental prostate cancer in Chinese patients (3-7%). We evaluated incidental prostatic adenocarcinoma (PCa) and urothelial carcinoma (UCa) involvement of the prostate in cystoprostatectomy specimens. METHODS: We analyzed 340 cystoprostatectomy specimens from patients who underwent radical cystoprostatectomy for the treatment of bladder cancer in China from 2004 to 2014. None of the patients had known prostate cancer prior to cystoprostatectomy. RESULTS: Overall, 180 (53%) patients had either PCa or UCa in the prostate. We found that 95 (28%) had PCa and 115 (34%) had UCa involvement of prostate. The rate of incidental prostate cancer was 21% and 31%, respectively, from two study periods (2004-2008 and 2009-2014). Among the 95 patients with PCa, 19 (20%) had Gleason score of ≥7, nine (10%) had PCa tumor volume >0.5 cc, and eight (8.4%) had extracapsular extension. Of the 115 with prostatic UCa, 61 had prostatic urethra and/or periurethral prostatic duct involvement only, while 54 had prostatic stromal invasion. Age (odds ratio [OR] = 1.04, P = 0.001), increasing stage of bladder tumor (OR = 1.28, P = 0.005), multifocal tumors of bladder (OR = 3.22, P < 0.001), carcinoma in situ (CIS) in the bladder (OR = 5.52, P < 0.001), and bladder neck involvement (OR = 6.12, P < 0.001) were strongly associated with prostatic UCa. CONCLUSIONS: The rate of incidental PCa in cystoprostatectomy specimens in China has increased over the last decade. Patients with advanced age, elevated serum PSA level, advanced bladder tumor stage, multifocal bladder tumors, CIS in the bladder, and tumor location at the bladder neck should be excluded as candidates for prostate-sparing cystectomy.

Molecular subtyping of metastatic renal cell carcinoma: implications for targeted therapy.

BACKGROUND: Renal cell carcinoma (RCC) is known for its ability to metastasize synchronously or metachronously to various anatomic sites. Distinguishing histologic subtypes of metastatic RCC has become increasingly important, as prognosis and therapy can differ dramatically between subtypes. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping metastatic RCC in light of these potential therapeutic implications. RESULTS: Specimens from 103 cases of metastatic RCC were retrieved, including 32 cases originally diagnosed as metastatic clear cell renal cell carcinoma (CCRCC), 8 as metastatic papillary renal cell carcinoma (PRCC), and 63 metastatic RCC without a specific subtype. Immunohistochemistry was performed with antibodies against cytokeratin 7 (CK7) and alpha-methylacyl-CoA racemase (AMACR). Dual color interphase fluorescence in situ hybridization was utilized to assess for deletion of chromosome 3p and trisomy of chromosomes 7 and 17 in all tumors. Chromosome 3p deletion was detected in 41% of all metastatic RCC specimens, and trisomy of chromosomes 7 and/or 17 was detected in 16%. Of metastatic CCRCC, chromosome 3p deletion was detected in 63%. Of metastatic PRCC, 75% showed trisomy of chromosomes 7 and/or 17. Of the tumors not previously classified, 6% were positive for CK7, and 64% were positive for AMACR; 35% showed chromosome 3p deletion, and 16% showed trisomy of chromosomes 7 and/or 17. Combined analysis of immunohistochemistry and cytogenetics enabled reclassification of 52% of these metastatic tumors not previously classified. CONCLUSION: Our findings support the utility of immunohistochemistry and cytogenetics for subtyping metastatic RCC.

EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder.

The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.

Molecular pathology of lung cancer: key to personalized medicine.

The majority of lung adenocarcinoma patients with epidermal growth factor receptor- (EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

Ultrasound gel causes fine needle aspiration artifact? A clear choice.

OBJECTIVES: Ultrasound-guided fine needle aspiration (FNA) is a commonly employed tool in cytopathologic practice. Artifacts resulting in misinterpretation of specimens have been noted with various ultrasound gel media. Our purpose was to perform a prospective human cadaveric study of this phenomenon to identify a low-cost solution that eliminates the artifact. STUDY DESIGN: Three separate ultrasound-guided FNAs were performed on the thyroid and parotid glands in situ of a fresh human cadaver using three different types of ultrasound gel media. Slides were prepared in standard fashion (Quik-Diff and Papanicolaou stains). Two cytopathologists subsequently analyzed the slides for the presence of any artifact interfering with their ability to visualize and interpret the cellular aspirate material. RESULTS: Two of the three gel media revealed significant artifacts mimicking apoptosis, necrosis or colloid, making it difficult to visualize the cellular components and differentiate the artifact from the thyroid colloid. One gel medium did not show any significant artifact, and there was no discernable difference in its quality with regard to the ultrasound image during FNA procedures. CONCLUSIONS: Ultrasound gels can be associated with a significant artifact in FNA specimens. To eliminate this artifact, which may alter the adequacy, diagnosis or cytologic appearance, we confirm a specific gel type that is useful for ultrasound-guided FNAs.

Safety and feasibility of carotid revascularization in patients with cerebral embolic strokes associated with carotid webs and histopathology revisited.

INTRODUCTION: Carotid web is increasingly recognized as the cause of ischemic embolic strokes in younger patients. The best way to treat carotid web is debatable and carotid artery stenting (CAS) has been reported as a treatment for the carotid web in only a few case series. In this study we evaluate the safety and feasibility of CAS in symptomatic carotid webs and examined the histopathology of a carotid web. MATERIALS AND METHODS: At our institution between 2017 and 2019, 10 consecutive patients with symptomatic carotid webs were treated. We retrospectively analyzed the data for patient demographics, clinical presentation, imaging, treatment methodology and follow up. RESULTS: All the patients had presented with ipsilateral embolic stroke. The mean age at presentation was 50 years (range 37-71) with seven female and three male patients. All patients underwent CAS except one patient who underwent carotid endarterectomy (CEA). In one stented patient, there was significant hypotension in the post-procedural period lasting a week. The patients were followed for a mean of 5.5 months (range one day-12 months). No recurrent stroke or transient ischemic attack (TIA) occurred. Surgical pathological studies confirmed fibromuscular dysplasia in one specimen. CONCLUSION: In our experience CAS for carotid web is feasible and safe in patients presenting with ischemic embolic strokes.

Fluorescence In Situ Hybridization (FISH) Detection of Chromosomal 12p Anomalies in Testicular Germ Cell Tumors.

Gains of genetic material or internal rearrangements of chromosome 12p, including 12p overrepresentation or isochromosome 12p [i(12p)], are observed in virtually all germ cell tumors (GCT), in all histologic subtypes, and from various body locations. The chromosomal region involved in these alterations contains the growth and survival promoting oncogene KRAS (12p12.1). Gains or rearrangements of 12p characterize GCT from in situ to chemoresistant stages. Fluorescence in situ hybridization (FISH) detection of chromosome 12p anomalies is a sensitive and specific test for the diagnosis of germ cell tumors. Here we provide a detailed protocol for FISH detection of isochromosome 12p and chromosome 12p overrepresentation. The method is helpful for diagnosis of germ cell origin, and for selection of patients who may benefit from cisplatin-based chemotherapy.

Molecular Characterization of Testicular Germ Cell Tumors Using Tissue Microdissection.

Testicular germ cell tumors are among the most common malignancies seen in children and young adults. Genomic studies have identified characteristic molecular profiles in testicular cancer, which are associated with histologic subtypes and may predict clinical behavior including treatment responses. Emerging molecular technologies analyzing tumor genomics, transcriptomics, and proteomics may now guide precision management of testicular tumors. Laser-assisted microdissection methods such as laser capture microdissection efficiently isolate selected tumor cells from routine pathology specimens, avoiding contamination from nontarget cell populations. Laser capture microdissection in combination with next generation sequencing makes precise high throughput genetic evaluation effective and efficient. The use of laser capture microdissection (LCM) for molecular testing may translate into great benefits for the clinical management of patients with testicular cancers. This review discusses application protocols for laser-assisted microdissection to investigate testicular germ cell tumors.

Staging and reporting of urothelial carcinoma of the urinary bladder.

Significant progress has been made in the standardization of bladder neoplasm classification and reporting. Accurate staging using the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) TNM system is essential for patient management, and has been reinforced by clinical evidence in recent years. It is now recognized that 'superficial' bladder carcinomas are a heterogenous group of tumors with diverse biological and clinical manifestations. The term 'superficial,' therefore, is no longer used for bladder tumor nomenclature. Recognition of diagnostic pitfalls associated with lamina propria invasion is critical for the evaluation of bladder tumor specimens. Neither the 1973 nor the 2004 WHO grading system appears to be useful for predicting the clinical outcome of invasive urothelial carcinoma. This review will discuss recent progress and controversial issues on the staging and substaging of bladder carcinomas. Essential elements for handling and reporting of bladder tumor specimens will also be discussed.

Urothelial carcinoma following augmentation cystoplasty: an aggressive variant with distinct clinicopathological characteristics and molecular genetic alterations.

AIMS: Patients who have undergone intestinal augmentation cystoplasty are at risk for developing latent vesicle malignancy. The aim was to evaluate the histological and immunohistochemical characteristics and molecular genetic alterations in these neoplasms. METHODS AND RESULTS: Four patients developing urothelial neoplasms after augmentation cystoplasty were included in the current study. The mean age of the patients, including two men and two women, was 37 years. The latency from bladder augmentation to developing malignancy ranged from 17 to 21 years (mean 19 years). All patients died of cancer shortly after diagnosis (mean 5 months). In the morphological evaluation, all tumours were high-grade (grade 3) invasive urothelial carcinoma comprising various architectural patterns with brisk mitoses and tumour necrosis. Three harboured glandular differentiation and the remaining one showed squamous differentiation. All cases revealed abnormal decreasing beta-catenin expression. Two tumours showed nuclear expression of CDX2. On UroVysion fluorescence in situ hybridization (FISH) analysis, all tumours displayed characteristic chromosomal abnormalities. Point mutations of both FGFR3 and p53 genes were identified in one case. CONCLUSIONS: Urothelial carcinomas developed after augmentation cystoplasty are extremely aggressive and exhibit distinct morphological, immunohistochemical and genetic characteristics. UroVysion FISH analysis may offer a surveillance strategy in patients who undergo augmentation cystoplasty.

Molecular determinants of tumor recurrence in the urinary bladder.

Tumor recurrence is a major clinical concern for patients with urothelial carcinoma of the urinary bladder. Traditional morphological analysis is of limited utility for identifying cases in which recurrence will occur. However, molecular and genetic analyses offer new perspectives on the prediction of bladder tumor recurrence. Recent studies have suggested that urothelial carcinogenesis occurs as a 'field effect' that can involve any number of sites in the bladder mucosa. Accumulating evidence supports the notion that resident urothelial stem cells in the affected field are transformed into cancer stem cells by acquiring genetic alterations that lead to tumor formation through clonal expansion. Both initial and recurrent tumors are derived from cancer stem cells in the affected field via two distinct molecular pathways. These provide a genetic framework for understanding urothelial carcinogenesis, tumor recurrence and progression: the FGFR3-associated pathway and the TP53-associated pathway. These two pathways are characterized by different genomic, epigenetic and gene-expression alterations. Their outcomes correlate with the markedly different clinical and pathologic features of both relatively indolent low-grade cancers and the aggressive high-grade cancers. As such, these molecular findings are potentially useful for counseling patients and for assessing risk of recurrence or biological aggressiveness of the patient's tumor. The molecular changes may additionally prove useful for developing preventive and therapeutic strategies for urothelial bladder cancer. A unifying model of urothelial carcinogenesis, tumor recurrence and progression is proposed in this review.

Reshapable hydrogel tissue expander for ridge augmentation: Results of a series of successive insertions at the same intraoral site.

BACKGROUND: Oral mucosa expansion before ridge augmentation is a procedure to reduce soft tissue exposure and to improve bone graft density and volume after augmentation. This study explored a novel, shapeable hydrogel tissue expander (HTE) in intraoral sites that had undergone previous expansion and surgery. METHODS: Nine beagle dogs had all premolar teeth extracted and adjacent alveolar bone reduced. After at least 3 months healing hydrogels were placed at 4 sites in each dog: maxilla and mandible, right and left. After 6 weeks of expansion, the hydrogels were removed and measured for volume expansion and physical condition. Punch biopsies were taken of the expanded oral mucosa. After 3 months, a second hydrogel insertion was performed at each of the same sites. After this second expansion cycle, volume and hydrogel condition were recorded. Three dogs received ultrasound imaging of the hydrogels during the second expansion. Necropsy specimens were taken of both expanded and non-expanded oral mucosa. RESULTS: Within 2 weeks after HTE insertion in both first and second insertions, blood flow returned to the pre-insertion level. The first and second insertions resulted in linear oral mucosa gain of 8.13 mm, and 6.44 mm, respectively. First and second insertion hydrogels erupted from 4% of the first expansion sites, and 3% of the second expansion sites. There was no directional migration of the expanding hydrogel at any site. Histology found little inflammatory reaction to any hydrogel implant. CONCLUSION: Oral mucosa can be consistently and successfully expanded before bone graft for ridge augmentation even at sites with a history of prior surgeries.

Giant Cell Polymyositis and Myocarditis in a Patient With Thymoma and Myasthenia Gravis: A Postviral Autoimmune Process?

Thymomas are associated with autoantibody formation. The most common are anti-acetylcholine receptor antibodies, which correspond to myasthenia gravis (MG). Other autoantibodies, such as antistriational antibodies, can occur, but their relation to clinical syndromes is frequently uncertain. The etiology of antistriational antibodies is also poorly understood. In this case, a 61-year-old man with a history of thymoma was admitted with respiratory failure. The patient was positive for anti-acetylcholine receptor antibodies and antistriational antibodies. He developed cardiogenic shock and died within 2 days despite aggressive therapy. Laboratory studies revealed elevated cardiac enzymes and marked IgG elevation against Coxsackie A virus serotypes 9 and 24. Subclinical IgG elevations against additional Coxsackie A and Coxsackie B virus serotypes were also noted. Autopsy revealed lymphohistiocytic infiltrates with multinucleated giant cells in the myocardium and skeletal muscles, including the diaphragm. Giant cell polymyositis and myocarditis is a rare, lethal complication in patients with thymoma and MG. The pathogenesis is uncertain. An autoimmune process, possibly elicited by antistriational antibodies, has been suggested. The coexistence of antistriational antibodies and Coxsackie viral serologies has not been reported. This case may suggest that giant cell polymyositis and myocarditis in patients with thymoma and MG is a postviral autoimmune process.

Baseline Biomechanical Properties of Epithelia prior to Tissue Expansion in Dogs.

BACKGROUND: Soft-tissue deficiencies pose a challenge in a variety of disease processes when the end result is exposure of underlying tissue. Although multiple surgical techniques exist, the transposition of tissue from one location to another can cause donor-site morbidity, long incisions prone to dehiscence, and poor patient outcomes as a result. Use of tissue expansion prior to grafting procedures has been shown to have success in increasing available soft tissue to aid in repairing wounds. However, the current tissue expanders have biomechanical limits to the extent and rate of expansion that usually exceeds the tissue capacity, leading to incisional dehiscence or expander extrusion. Understanding the baseline biomechanical properties of the tissue to be expanded would provide useful information regarding surgical protocol employed for a given anatomical location. Therefore, the aim of this study was to test and compare the baseline (preexpansion) biomechanical properties of different common expansion sites in dogs. METHODS: Four samples measuring approximately 20 × 15 × 1 mm were harvested from 8 dogs. The samples were collected from the hard palate, alveolar mucosa, scalp, and chest of the animal and analyzed for stress, strain, maximum tangential stiffness, maximum tangential modulus, and tensile strength using a Texture Technologies TA.XT texture analyzer with corresponding biomechanical measurement software. Samples were compared as to their baseline biomechanical properties prior to any soft-tissue expansion. Histological sections of the samples were analyzed using hematoxylin eosin in an attempt to correlate the histological description to the biomechanical properties seen during testing. Summary statistics (mean, standard deviation, standard error, range) are reported for stress, strain, maximum tangential stiffness, maximum tangential modulus, and tensile strength and for the histological parameters by intraoral site. Analysis of variance was used to compare the biomechanical and histological parameters among the 4 locations while accounting for multiple measurements from each dog. RESULTS: The scalp had significantly higher maximum stress (σmax) than chest, mucosa, and palate (P < 0.0001), with no differences among the other 3 locations (P > 0.63). Scalp site also had significantly higher maximum tangential modulus (ε) than chest, mucosa, and palate (P < 0.006), with no differences among the other 3 locations (P > 0.17). The locations did not have significantly different maximum tangential stiffness (k; P = 0.72). Histologically, 2 separate patterns of collagen disruption were evident. CONCLUSION: Although different results were obtained than theorized, this study showed that the scalp had the greatest resiliency to expand prior to tearing, and the highest tangential modulus, with all sites having statistically similar modulus of elasticity. Based on this study, the scalp could be expanded more aggressively compared with the other sites.

Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced-stage colorectal cancer.

Current prognostic indicators are ineffective for identifying advanced-stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases. Up-regulation of p53 was associated with smaller tumor size (P=.001) and higher Ki-67 labeling index (LI) (P=.031). The tumor Ki-67 LI was high (≥20%) in 197 (78%) of the patients. High Ki-67 LI was associated with higher TNM stage (P=.031), positive p53 expression (P=.031), and negative PD-L1 expression (P=.003). The 5-year relapse-free survivals (RFS) were 53% and 89%, respectively, for the p53-positive and Ki-67 LI-high patients and the p53-negative and Ki-67 LI-low patients (P<.001). In univariate analysis, negative p53 (P=.001), low Ki-67 LI (P=.006), low PD-L1 expression (P=.044), low TNM stage (P<.001), rectosigmoid location (P=.026), and small size (P=.013) were significantly related to RFS. In multivariate Cox regression analysis, positive p53 expression (hazard ratio [HR]: 2.48; 95% confidence interval: 1.34-4.59, P=.004), high Ki-67 LI (HR, 2.62; 95% CI, 1.12-6.14, P=.027) and high TNM stage (HR, 2.598; 95% CI, 1.55-4.37, P<.001,) were independent predictors of unfavorable prognosis. In summary, PD-L1, Ki-67, and p53 staining individually had significant prognostic value for patients with stage II and III CRC. Moreover, combining p53 H-score ≥35 and Ki-67 LI ≥20% identifies patients with poor clinical outcome.

Small-cell Carcinomas of the Urinary Bladder and Prostate: TERT Promoter Mutation Status Differentiates Sites of Malignancy and Provides Evidence of Common Clonality Between Small-cell Carcinoma of the Urinary Bladder and Urothelial Carcinoma.

BACKGROUND: Small-cell carcinoma (SCC) of the urinary bladder frequently appears alongside urothelial carcinoma, suggesting common clonality. TERT promoter mutations have been recently implicated in urothelial carcinogenesis. OBJECTIVE: To investigate the degree to which TERT promoter mutations are involved in SCC of the urinary bladder, the linked tumorigenesis between urothelial carcinoma and SCC of the urinary bladder, and the molecular distinctions between SCC of the urinary bladder and of the prostate. DESIGN, SETTING, AND PARTICIPANTS: We investigated TERT promoter mutations in 53 cases of SCC of the urinary bladder and in 26 cases of SCC of the prostate using laboratory-based studies of tissue samples and clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the frequency of TERT promoter mutations in SCCs of the urinary bladder and prostate, and concordance of the mutation status between concurrent urinary bladder SCC and urothelial carcinoma. RESULTS AND LIMITATIONS: TERT promoter mutations were detected in 29/53 (55%) cases of urinary bladder and 0/26 (0%) cases of prostate SCC. Of 25 cases with concurrent urinary bladder SCC and non-small-cell components, all cases harbored identical TERT promoter mutation status in both phenotypes. CONCLUSIONS: TERT promoter mutations are found in more than half of urinary bladder SCCs. Mutation status is also identical in urothelial carcinoma and SCC components of concomitant malignancies, providing evidence of a common clonality. TERT promoter mutation status can differentiate SCC of the urinary bladder from prostate SCC, suggesting potential diagnostic use. PATIENT SUMMARY: Small-cell carcinoma of the urinary bladder shares a common clonal origin with conventional urothelial carcinoma and may arise from a heterogeneous subclone. TERT promoter mutations may have utility as a differential biomarker for determining the primary site of a genitourinary small-cell carcinoma.