Signaltransduktion im Urothelkarzinom

Targeted therapies have helped to improve the quality of life and prolong the survival of many cancer patients. This progress is based on the growing understanding of cellular signal transduction pathways and regulatory systems in human cancers. In urothelial carcinoma, a number of specific alterations have been identified. These include mutations in FGFR3, HRAS, and PIK3CA leading to overactivity of MAPK and Akt signaling pathways especially in papillary tumors. In comparison, the RB1 and p53 regulatory systems that act more directly on cell cycle control are more commonly compromised in invasive carcinomas. Nevertheless, targeted therapies have shown little efficacy in the treatment of urothelial carcinoma so far, owing presumably to our incomplete knowledge of molecular changes affecting signal transduction pathways in this cancer type. Target genes of cancer pathways are regulated by epigenetic mechanisms, which determine their inducibility. Elucidating these control mechanisms could therefore prove important for developing targeted therapies for urothelial carcinoma.     

Prognostische und prädiktive molekulare Marker urologischer Tumoren

Molecular prognostic factors and genetic alterations as predictive markers for cancer-specific targeted therapies are used today in the clinic for many malignancies. In recent years, many molecular markers for urogenital cancers have also been identified. However, these markers are not clinically used yet. In prostate cancer, novel next-generation sequencing methods revealed a detailed picture of the molecular changes. There is growing evidence that a combination of classical histopathological and validated molecular markers could lead to a more precise estimation of prognosis, thus, resulting in an increasing number of patients with active surveillance as a possible treatment option. In patients with urothelial carcinoma, histopathological factors but also the proliferation of the tumor, mutations in oncogenes leading to an increasing proliferation rate and changes in genes responsible for invasion and metastasis are important. In addition, gene expression profiles which could distinguish aggressive tumors with high risk of metastasis from nonmetastasizing tumors have been recently identified. In the future, this could potentially allow better selection of patients needing systemic perioperative treatment. In renal cell carcinoma, many molecular markers that are associated with metastasis and survival have been identified. Some of these markers were also validated as independent prognostic markers. Selection of patients with primarily organ-confined tumors and increased risk of metastasis for adjuvant systemic therapy could be clinically relevant in the future.     

Morphologic and Molecular Characteristics of Bladder Cancer

Bladder cancer is the fourth most common cancer in men, and is associated with significant morbidity and mortality. Pathologic evaluation of urothelial cancers relies predominantly on histomorphologic features but can be aided in a small subset of cases by immunohistochemical analyses. Distinction of papillary versus flat lesions, low-grade versus high-grade cytology, and histologic variants and the presence or absence of invasive tumor is important for proper clinical management. Advances in the molecular alterations associated with the various subtypes of urothelial carcinoma have been made but such studies are ongoing.     

Mutational landscape of non-muscle-invasive bladder cancer

Non-muscle-invasive bladder cancer (NMIBC) includes stage Ta and stage T1 tumors and carcinoma in situ (CIS). Grading of Ta tumors subdivides these lesions into papillary urothelial neoplasms of low malignant potential and low- and high-grade noninvasive papillary urothelial carcinoma. CIS is by definition high-grade and the majority of stage T1 tumors are of high-grade. This pathologic heterogeneity is associated with divergent clinical outcome, with significantly worse prognosis for patients with T1 tumors or CIS. A wealth of molecular information has accumulated on NMIBC including mutational data that ranges from the whole chromosome level to next generation sequence data at nucleotide level. This has not only identified key genes that are mutated in NMIBC, but also provides insight into the processes that shape their mutational landscape. Although molecular analyses cannot yet provide definitive personal prognostic information, many differences between these entities promise improved disease management in the future. Most information is available for Ta and T1 samples and this is the focus of this review.     

Significance of denuded urothelium in papillary urothelial lesions

Flat urothelial carcinoma in situ (CIS) is often characterized by prominent dyscohesion with some cases having only a few clinging CIS cells remaining on biopsy. The finding of extensive denudation on urothelial biopsies is associated with a risk of CIS on either prior or subsequent biopsies. The significance of denudation in papillary urothelial lesions has not been formally studied. We identified from our surgical pathology files 31 specimens (from 28 patients) of papillary urothelial lesions with extensive denudation. In cases in which denudation was associated with low-grade urothelial neoplasms, follow-up of subsequent cytologic and histologic specimens was obtained. Of the 28 patients, 25 (89%) were men and 3 (11%) were women with an age range of 40 to 88 years old (mean age 62). Of 31 biopsies, 15 were from anatomically confined areas (ie, renal pelvis, ureter, and urethra). In 22/28 (79%) patients, prominent denudation was associated with high-grade papillary carcinomas, 4/28 (14%) low-grade papillary carcinomas, and 2/28 (7%) papillary urothelial neoplasms of low-grade malignant potential. The average extent of urothelial denudation was 82% with 61% of cases having > or =90% denudation. Prominent cautery artifact was present in 17/31 (55%) cases. In 13/28 patients with high-grade lesions, there was a concurrent biopsy of a second urothelial lesion that was either high-grade papillary urothelial carcinoma or invasive urothelial carcinoma. Five of the 6 patients in which the prominent denudation was associated with a low-grade papillary urothelial lesion have not progressed to a high-grade lesion. One patient with a denuded papillary urothelial neoplasm of low malignant neoplasm was subsequently diagnosed with a noninvasive low-grade papillary urothelial carcinoma in the bladder and a high-grade infiltrating urothelial carcinoma of the ureter. We conclude that (1) the majority of papillary urothelial lesions associated with prominent urothelial denudation are high grade; (2) a significant percentage of papillary urothelial lesions with denudation occur with either prominent cautery artifact or in anatomically confined areas, suggesting both iatrogenic and mechanical contributing factors, respectively; (3) a minority of cases with prominent urothelial denudation occur in association with low-grade papillary urothelial lesions and are not associated with progression to higher grade lesions on follow-up studies; and (4) prominent urothelial denudation in papillary lesions should prompt careful examination of these specimens for rare clinging high-grade carcinoma cells, although in a minority of cases the underlying lesion will be low grade.     

Molecular and immunopathology studies of oncogenes and tumor-suppressor genes in bladder cancer

Summary Target genes implicated in cellular transformation and tumor progression have been divided into two categories: proto-oncogenes (that when activated become dominant events characterized by gain of function) and tumor-suppressor genes (recessive events characterized by the loss of function). Alterations in proto-oncogenes and tumor-suppressor genes seem equally prevalent among human cancers. Multiple mutations appear to be required to conform the malignant phenotype. It is therefore conceivable that cancer be viewed fundamentally as a genetic disease entailing inherited (also calledgerm-line) and/or acquired (also termedsomatic) mutations of genes in these two categories. Molecular studies of bladder neoplasms have identified a series of nonrandom genetic alterations affecting a particular set of oncogenes and tumor-suppressor genes. Because the modality of therapy for patients with bladder neoplasms primarily depends onmorphological evaluation and clinical staging, the diagnosis carries significant consequences. However, it is well known that morphologically similar tumors presenting in any assigned stage may behave in radically different fashions, which seriously hampers the physician's ability accurately to predict clinical behavior in a given case. Recent studies have shown that inactivation of certain tumor-suppressor genes, such as RB andTP53, occur in bladder tumors that have a more aggressive clinical outcome and poor prognosis. In the present paper we review the molecular abnormalities associated with these dominant and recessive genes in bladder cancer and discuss the potential clinical use of their detection. The implementation of objective predictive assays to identify these alterations in clinical material will enhance our ability to assess tumor biological activities and to design effective treatment regimens. The need now is to translate this newly developed scientific knowledge into diagnostic and therapeutic strategies, which in turn will enhance the quality of life and prolong the survival of patients with bladder cancer.     

Toward urinary cell-free DNA-based treatment of urothelial carcinoma: a narrative review

Liquid biopsy technique targeting urinary cell-free DNA (cfDNA) is getting a lot of attention to overcome limitations of the present treatment strategy for urothelial carcinoma, including urothelial bladder carcinoma (UBC) and upper tract urothelial carcinoma (UTUC). Analysis of tumor-derived DNA in urine focusing either on genomic or epigenomic alterations, holds great potential as a noninvasive method for the detection of urothelial carcinoma with high accuracy. It is also predictive of prognosis and response to drugs, and reveals the underlying characteristics of different stages of urothelial carcinoma. Although cfDNA methylation analyses based on a combination of several methylation profiles have demonstrated high sensitivity for UBC diagnosis, there have been few reports involving epigenomic studies of urinary cfDNA. In mutational analyses, frequent gene mutations (TERT promoter, TP53, FGFR3, PIK3CA, RAS, etc.) have been detected in urine supernatant by using remarkable technological innovations such as next-generation sequencing and droplet digital PCR. These methods allow highly sensitive detection of rare mutation alleles while minimizing artifacts. In this review, we summarize the current insights into the clinical applications of urinary cfDNA from patients with urothelial carcinoma. Although it is necessary to conduct prospective multi-institutional clinical trials, noninvasive urine biopsy is expected to play an important role in the realization of precision medicine in patients with urothelial carcinoma in the near future.     

Differences in genomic profile of high-grade urothelial carcinoma according to tumor location

ObjectivesTo establish targeted therapies based on the molecular landscape in upper urinary tract urothelial carcinoma (UTUC), we tried to investigate the molecular characteristics of UTUC compared with those of bladder urothelial carcinoma (BLUC) by next-generation sequencing (NGS).Materials and methodsWe selected 71 high-grade infiltrating urothelial carcinoma tissue specimens from 33 UTUC and 38 BLUC patients. NGS analysis was performed with the Illumina TruShigt Oncology-500 panel.ResultsBoth UTUC and BLUC showed similar clinicopathologic characteristics, as well as morphologic similarities. The median tumor mutation burden (TMB) of all cases was 7.8 mutations/Mb. The majority of alterations were missense mutations. TP53 (40/71, 56.3%), KDM6A (30/71, 42.3%), and TERT promoter mutations (23/71, 32.4%) were observed regardless of tumor location. Compared with UTUC, BLUC showed frequent mutations in several genes: ARID1A (P = 0.001), ASXL1 (P = 0.017), ERBB3 (P = 0.005), PRKDC (P = 0.004) and RB1 (P = 0.041). On the contrary, copy number loss of FGFR3 was observed more in UTUC than BLUC (P = 0.018). Also, 6 cases showed oncogenic fusions: 3 cases with FGFR2 fusion in UTUC and 3 cases with FGFR3-TACC3 fusion in BLUC.ConclusionDespite the small cohort size, we identified genetic differences between UTUC and BLUC in Korean patients by NGS. An understanding of the comprehensive molecular characteristics of UTUC and BLUC may be helpful in detecting candidates for targeted therapy.     

Detection of residual tumor cells in bladder biopsy specimens: pitfalls in the interpretation of cytokeratin stains

Some patients who have had prior bladder biopsies or transurethral resections undergo a repeat resection within several months for various reasons. The detection of a few residual tumor cells in bladder specimens with prior biopsy site changes can be challenging based on histology alone. Immunohistochemistry for cytokeratins may be used as an adjunct in this situation. We have noted several cases in which keratin stains were performed and positive cells were noted, raising the issue as to whether the cytokeratin positive cells were residual tumor cells or stromal cells. Immunohistochemistry for a panel of antibodies [AE1/AE3, CAM 5.2, high molecular weight cytokeratin, smooth muscle actin (SMA), desmin, and anaplastic lymphoma kinase (ALK)] was performed on 29 cases of bladder biopsies with prior biopsy site changes. Of 29 patients, 25 had a prior history of bladder tumor: 17 had invasive high-grade urothelial carcinoma (T1, 5 cases; T2, 11 cases; T3,1 case); 7 had noninvasive high-grade papillary urothelial carcinoma; 1 had noninvasive low-grade papillary urothelial carcinoma). One of the patients with noninvasive high-grade papillary urothelial carcinoma and one of the patents with invasive high-grade urothelial carcinoma had associated carcinoma in-situ. Four patients had prior benign bladder diagnoses: cystitis cystica et glandularis; polypoid cystitis; follicular cystitis; and neurogenic bladder with benign prostate hyperplasia. Of the 29 cases, 6 (21%) had cells with staining for at least 2 of the cytokeratin markers. Cytokeratin (CK) AE1/ AE3 was positive for cells in 8/29 cases (28%). In 6 of these cases, cells displayed a spindle cell and 2 cases a more epithelioid morphology. CAM 5.2 was positive in cells in 5/29 cases (17%); 3 of the cases had spindle cell and 2 cases epithelioid morphology. High molecular weight cytokeratin was expressed in cells in 2/29 cases (7%) with 1 case having spindle cell and 1 epithelioid morphology. SMA was positive in cells with a spindle cell morphology and negative in the more epitheloid cytokeratin positive cells. Desmin was positive in 3/6 keratin positive spindle cells and negative in keratin positive epithelioid cells. ALK was negative in all the cases. Three cases with spindle cell morphology and positivity for at least 1 of the keratins and SMA stains were interpreted as aberrant keratin expression in myofibroblastic cells based on the staining and the morphology of the spindle cells. Another 3 cases with concurrent staining for at least 1 of the keratins, SMA and desmin were consistent with smooth muscle cells on the basis of their cellular morphology. Another 2 cases had cells, which expressed at least 2 CK markers but did not express SMA, desmin, or ALK and a more epithelioid morphology. These cells were interpreted as residual tumors cells. When interpreting CK stains for the detection of residual tumor cells, one should pay attention to the nature of the cells and not assume all CK staining cells are residual tumor cells.     

The genetics of glioma: molecular classification

Gliomas result from specific genetic alterations--such as activation of specific oncogenes and/or inactivation of specific tumor suppressor genes. These alterations affect specific pathways involved in either signal transduction or cell cycle control, leading to phenotypic changes such as uncontrolled proliferation, inhibition of apoptosis, genetic instability, invasive properties. Tumoral progression includes multiple molecular pathways of clinical relevance: early alterations (p53 mutations for astrocytomas, 1p and 19q loss for oligodendrogliomas) and late alterations (EGF-R amplification, PTEN and P16/CDKN2A inactivation). Genetic profile is not only of diagnostic--but also prognostic relevance, as shown by 1p associated to 19q loss in oligodendrogliomas which is predictive of better prognosis and higher response rate.     

Genotype-Phenotype Correlations in Breast Cancer

Only a few breast cancer histologic subtypes harbor distinct genetic alterations that are associated with a specific morphology (genotype-phenotype correlation). Secretory carcinomas and adenoid cystic carcinomas are each characterized by recurrent translocations, and invasive lobular carcinomas frequently have CDH1 mutations. Solid papillary carcinoma with reverse polarity is a rare breast cancer subtype with a distinctive morphology and recently identified IDH2 mutations. We review the clinical and pathologic features and underlying genetic alterations of those breast cancer subtypes with established genotype-phenotype correlations and discuss the phenotypes associated with germline mutations in genes associated with hereditary breast cancer.     

Nephron-sparing surgery with autotransplantation for high-grade upper urinary tract urothelial carcinoma in a patient with solitary kidney

Instead of nephroureterectomy with bladder cuff excision, nephron-sparing surgery can be considered in selected patients with non-muscle invasive upper urinary tract urothelial carcinoma. The role of kidney-sparing surgery has been established for the management of low-grade urothelial carcinoma. We report a solitary kidney patient with high-grade renal pelvis urothelial carcinoma treated with nephron-sparing surgery by ex vivo tumor excision and autotransplantation. The results of the surgery were excellent.     

Bladder cancer. I. Molecular and genetic basis of carcinogenesis.

The transformation of a normal into a malignant cell is a multistep mechanism, which involves various alterations on the molecular and genetic level. These molecular alterations occur spontaneously or are induced by carcinogens (e.g. naphthylamine--a component of cigarette smoke and one of the most important carcinogens leading to bladder tumor carcinogenesis). This report summarizes some of the most important molecular and genetic alterations in bladder cancer. As in most other malignancies the generation of bladder cancer is caused by the accumulation of various molecular changes. The expression of oncogenes (ras, erbB-2 and EGF receptor), tumor-suppressor genes (Rb, p53), cell-cycle genes (p15, p16) and DNA-repair genes is altered mostly by mutation or chromosomal aberration. Loss of heterozygosity of chromosome 9p and 9q has been shown to be a crucial event in the transition of normal urothelium to papillary transitional cell carcinoma while p53 is primarily involved in the development of carcinoma in situ.     

Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation

The infrequent association of serous borderline tumors (SBTs) with invasive serous carcinoma has led to the view that SBTs are unrelated to invasive serous carcinoma. Nonetheless, mortality associated with SBTs is generally attributed to malignant transformation, and traditionally these tumors have been designated as "carcinomas of low malignant potential." Previous immunohistochemical studies evaluating p53 expression and molecular genetic studies evaluating mutational status have reported that p53 overexpression and mutations are infrequent in SBTs and occur in as many as 50% to 80% of invasive serous carcinomas. The different methodologies for determining p53 status and the failure to correlate the findings with tumor grade make these studies difficult to interpret. The current study was undertaken to overcome these deficiencies and to reconcile the relationship of SBTs to invasive serous carcinoma by performing a morphologic, immunohistochemical, and molecular genetic analysis comparing SBTs with low- and high-grade serous carcinoma. The molecular genetic analysis used a highly stringent, carefully designed nucleotide-sequencing method. A total of 96 sporadic serous tumors including 25 SBTs (11 atypical proliferative serous tumors and 14 intraepithelial low-grade serous carcinomas [noninvasive micropapillary serous carcinomas, MPSCs]), 12 low-grade serous carcinomas (invasive MPSCs), and 59 high-grade serous carcinomas were analyzed for their p53 mutational status of exons 5 to 9. Functional mutations, defined as mutations resulting in the alteration of the structure of the encoded protein, were detected in 30 of 59 (50.8%) high-grade serous carcinomas and 1 (8.3%) of 12 low-grade invasive serous carcinomas compared with 2 (8%) of 25 SBTs, both of these in intraepithelial low-grade serous carcinomas (noninvasive MPSCs). The similar frequency of p53 mutations in SBTs and low-grade invasive serous carcinomas in contrast to the significantly higher frequency of p53 mutations in high-grade serous carcinomas (P < 0.0005) suggests a common lineage for SBTs and low-grade invasive serous carcinomas and supports the view that SBTs are unrelated to the usual type of invasive serous carcinoma, which is a high-grade neoplasm. Mutational status was also correlated with p53 immunoreactivity. Although p53 immunoreactivity is generally higher in those specimens containing mutant p53, immunostaining is neither sufficiently specific nor sensitive enough to predict p53 mutations. The molecular genetic findings confirm our hypothesis of dual pathways of serous carcinogenesis based on previous analyses of KRAS and BRAF mutations on the same set of cases in which KRAS and BRAF mutations were found in 60% of SBTs and low-grade serous carcinoma but not in high-grade serous carcinomas. Based on these studies, we have proposed a model of serous carcinogenesis in which SBTs are the precursors of low-grade serous carcinomas whereas the usual type of invasive serous carcinoma is a high-grade neoplasm that develops "de novo" from in situ alterations in epithelial inclusion cysts.     

Molecular Pathology of the Genitourinary Tract: Prostate and Bladder

The knowledge of cellular mechanisms in tumors of the prostate and bladder has grown exponentially. Molecular technologies have led to the discovery of TMPRSS2 in prostate cancer and the molecular pathways distinguishing low- and high-grade urothelial neoplasms. UroVysion with fluorescence in situ hybridization is already commonplace as an adjunct to cytologic diagnosis of urothelial neoplasms. This trend portends the future in which classification and diagnosis of tumors of the prostate and bladder through morphologic analysis will be supplemented by molecular information correlating with prognosis and targeted therapy. This article outlines tumor molecular pathology of the prostate and bladder encompassing current genomic, epigenomic, and proteonomic findings.     

Advances in Molecular Biological and Translational Studies in World Health Organization Grades 2 and 3 Meningiomas: A Literature Review

The treatment of World Health Organization (WHO) grades 2 and 3 meningiomas remains difficult and controversial. The pathogenesis of high-grade meningiomas was expected to be elucidated to improve treatment strategies. The molecular biology of meningiomas has been clarified in recent years. High-grade meningiomas have been linked to NF2 mutations and 22q deletion. CDKN2A/B homozygous deletion and TERT promoter mutations are independent prognostic factors for WHO grade 3 meningiomas. In addition to 22q loss, 1p, 14p, and 9q loss have been linked to high-grade meningiomas. Meningiomas enriched in copy number alterations may be biologically invasive. Furthermore, several new comprehensive classifications of meningiomas have been proposed based on these molecular biological features, including DNA methylation status. The new classifications may have implications for treatment strategies for refractory aggressive meningiomas because they provide a more accurate prognosis compared to the conventional WHO classification. Although several systemic therapies, including molecular targeted therapies, may be effective in treating refractory aggressive meningiomas, these drugs are being tested. Systemic drug therapy for meningioma is expected to be developed in the future. Thus, this review aims to discuss the distinct genomic alterations observed in WHO grade 2 and 3 meningiomas, as well as their diagnostic and therapeutic implications and systemic drug therapies for high-grade meningiomas.     

Spectrum of genomic alterations in FGFR3: current appraisal of the potential role of FGFR3 in advanced urothelial carcinoma

Molecular analysis has identified subsets of urothelial carcinoma (UC) expressing distinct genetic signatures. Genomic alterations in the oncogenic fibroblast growth factor receptor 3 (FGFR3) pathway are among the most well described in UC and have led to extensive and ongoing investigation of FGFR3‐targeted therapies in this disease, although no new drugs have yet been approved. Given the unmet need for effective treatments in advanced and metastatic UC, a better understanding of the known molecular alterations of FGFR3 and of the previous and ongoing clinical investigations of this promising target in UC deserves attention. The objective of the present review is to describe the landscape of alterations and biology of FGFR3 in UC, comprehensively summarize the current state of UC clinical trials of FGFR3 inhibitors, and discuss future therapeutic applications. Using the Pubmed and Clinicaltrials.gov databases, articles describing the spectrum and biological activity of FGFR3 genomic alterations and trials of FGFR3 inhibitors in UC were identified. Search terms included ‘FGFR3 genomic alterations’ and ‘urothelial cancer’ or ‘bladder cancer’. Genomic alterations, including translocations and activating mutations, are increasingly described in advanced and metastatic UC. The majority of clinical trials have been performed in unselected populations; however, recent studies have reported encouraging preliminary data. We argue that routine use of molecular genomic tumour analysis in UC may inform selection of patients for appropriate trials and we further investigate the potential of FGFR3 as a meaningful clinical target for this difficult disease.     

Prognostic significance in substaging ofT1 urinary bladder urothelial carcinoma on transurethral resection

T1 papillary urothelial carcinomas of the urinary bladder run a variable clinical course, and an effective substaging system has not been defined yet. This study was conducted to devise an easy-to-use substaging method and to validate its prognostic value in T1 cancer on transurethral resection specimens. A total of 103 cases of T1 low-grade papillary urothelial carcinoma and 406 cases of T1 high-grade papillary urothelial carcinoma from a series of 1515 non-muscle-invasive bladder tumors treated by transurethral resection were studied. Substaging was performed using 0.5, 1.0, and 1.5 mm as thresholds to distinguish extensive from focal invasion. Correlations to recurrence, progression, cancer-specific mortality, and all-cause mortality were explored and compared with Ta tumors. All lamina propria invasions in low-grade papillary urothelial carcinomas were confined to 1.0 mm. The proportions of T1 high-grade papillary urothelial carcinoma invading beyond 0.5, 1.0 (T1>1 mm), and 1.5 mm were 53%, 32%, and 27%, respectively. No prognostic differences were found between Ta and T1 low-grade papillary urothelial carcinomas. T1>1 mm high-grade papillary urothelial carcinomas were associated with significantly greater risks for recurrence, progression, cancer-specific mortality, and all-cause mortality compared with T1≤1 mm and Ta tumors. Comparable statistical results could be obtained using 0.5 and 1.5 mm as cutoff points, but we recommend using 1.0 mm for practical consideration. Taking all non-muscle-invasive urothelial neoplasms of the bladder into consideration, 5 prognostically distinct categories can be established: (1) papillary urothelial neoplasms of low malignant potential; (2) low-grade papillary urothelial carcinoma Ta/1; (3) high-grade papillary urothelial carcinoma Ta; (4) high-grade papillary urothelial carcinoma T1≤1 mm; and (5) high-grade papillary urothelial carcinoma T1>1 mm. Our study demonstrates that the substaging of T1 bladder cancer is feasible, based on the evaluation of transurethral resection specimens, and can provide more precise prognostic information to identify a subset of patients with a more unfavorable prognosis.     

Fibroblast growth factor receptor-3 in urothelial tumorigenesis

Fibroblast growth factor receptor-3 (FGFR3) is a receptor tyrosine kinase implicated in the tumorigenesis of multiple malignancies, including bladder and other urothelial cancers, multiple myeloma, and cervical cancer. In urothelial carcinoma (UC), constitutive receptor activation occurs most commonly through substitution of a wild-type residue with cysteine in the extracellular domain of FGFR3, thereby resulting in dimerization (through disulfide bridge formation) and subsequent stimulation of tyrosine kinase activity. Activating mutations of FGFR3 have been observed in up to 70% of non-muscle-invasive bladder tumors, while overexpression of a wild-type receptor, found in approximately 40% of tumors, has been correlated with more invasive disease. The identification of FGFR3 mutations in UC has sparked substantial interest in the therapeutic exploitation of these aberrations, and in vitro studies have provided evidence that such alterations may represent driver oncogenic lesions. In this review, we discuss the biologic and prognostic impact of FGFR3 mutations in UC as well as FGFR3 as a potential target for novel therapeutics.