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Transitional cell carcinoma

Transitional cell carcinoma, also known as urothelial carcinoma, is a malignancy that originates in the urothelial cells, which are specialized transitional epithelial cells lining the urinary tract; these cells are capable of stretching and changing shape without breaking apart to accommodate urine flow.^[1] It represents the predominant type of bladder cancer, accounting for nearly all cases in the United States, and can also develop in other parts of the urinary system.^[2] This cancer arises from DNA mutations in these cells, leading to uncontrolled growth and tumor formation.^[2] The primary site of transitional cell carcinoma is the bladder, where it typically begins on the inner lining, but it may also occur in the ureters, renal pelvis, urethra, or rarely in other organs lined by urothelial cells.^[3] In the bladder, the tumor can grow as a papillary structure protruding into the bladder cavity or as a flat lesion on the surface.^[3] Although less common outside the bladder, upper urinary tract involvement, such as in the renal pelvis or ureters, shares similar histological features and behaves aggressively if invasive.^[4] Globally, bladder cancer incidence is higher in industrialized regions, with transitional cell carcinoma comprising over 90% of cases in Western countries.^[3] Transitional cell carcinoma is classified into non-muscle-invasive and muscle-invasive types based on depth of penetration into the bladder wall.^[3] Non-muscle-invasive disease, which includes superficial tumors confined to the mucosa or lamina propria (stages Ta, Tis, or T1), accounts for the majority of initial diagnoses and has a high recurrence rate but lower mortality if managed promptly.^[3] In contrast, muscle-invasive carcinoma (stage T2 or higher) penetrates the muscularis propria and is associated with a greater risk of metastasis to lymph nodes, bones, lungs, or liver, necessitating more aggressive interventions like cystectomy or systemic therapy.^[3] Histologically, these tumors are graded from low to high based on cellular atypia and mitotic activity, influencing prognosis and treatment.^[2] Key risk factors for developing transitional cell carcinoma include tobacco smoking, which triples the lifetime risk due to carcinogenic compounds excreted in urine, as well as older age (most common over 55 years), male sex, and occupational exposure to certain chemicals like aromatic amines in dyes or rubber industries.^[2] Other contributors encompass chronic bladder irritation from infections or stones, prior radiation or chemotherapy for other cancers, and genetic predispositions such as Lynch syndrome.^[2] Early symptoms often mimic urinary tract infections, including hematuria, frequent urination, and pelvic pain, underscoring the importance of prompt diagnostic evaluation via cystoscopy and imaging.^[3] Despite advances in detection and treatment, the disease's propensity for recurrence demands lifelong surveillance for affected individuals.^[2]

Overview

Definition and Terminology

Transitional cell carcinoma, now more commonly referred to as urothelial carcinoma, is a malignant neoplasm originating from the transitional epithelium, also known as urothelium, that lines the inner surfaces of the urinary tract, including the renal pelvis, ureters, bladder, and proximal urethra.^[3]^[5] This epithelium is a specialized stratified tissue composed of multiple layers of cells that provide a protective barrier against the urinary environment while allowing for significant distension during urine storage.^[6] The superficial umbrella cells of the urothelium are particularly adapted to stretch and contract, enabling the bladder and other structures to accommodate varying volumes of urine without compromising integrity.^[7] The terminology has evolved over time, with "transitional cell carcinoma" historically used to describe these tumors based on their cellular origin, but the World Health Organization (WHO) classifications in 2004 and 2016 shifted to "urothelial carcinoma" to better reflect the epithelial lining's nomenclature across the urinary tract and to standardize pathological reporting.^[8]^[9] This change emphasized the tumor's derivation from urothelial cells rather than focusing solely on the transitional morphology observed in distended states.^[10] Urothelial carcinoma is distinguished from other malignancies arising in the urinary tract, such as squamous cell carcinoma or adenocarcinoma, by its retention of transitional epithelial characteristics without predominant squamous or glandular differentiation.^[11] While these variant histologies may occasionally coexist or arise from the same urothelial origin, pure forms of squamous or adenocarcinomas represent separate entities with distinct morphological and behavioral profiles.^[12]

Epidemiology

Transitional cell carcinoma (TCC), also known as urothelial carcinoma, accounts for the majority of bladder cancers and a significant portion of upper urinary tract malignancies worldwide. According to GLOBOCAN 2022 estimates from the International Agency for Research on Cancer, there were approximately 614,000 new cases of bladder cancer globally in 2022, with an age-standardized incidence rate (ASR) of 5.6 per 100,000 population; over 90% of these are TCC.^[13] The five-year prevalence is estimated at around 1.95 million cases, reflecting the disease's tendency for recurrence and long-term management needs.^[13] Mortality stands at about 221,000 deaths annually, with an ASR of 1.8 per 100,000.^[13] The disease predominantly affects older adults, with incidence rates rising sharply after age 50 and peaking between 65 and 70 years in most populations.^[14] In the United States, for example, the overall incidence rate from 2018 to 2022 was 18.0 per 100,000, but rates exceed 150 per 100,000 among those aged 75 and older.^[14] TCC shows a strong male predominance, with a male-to-female ratio of approximately 3-4:1 globally; in 2025 US estimates, about 65,000 new cases are projected in men compared to 20,000 in women.^[15] This disparity is attributed to higher exposure to risk factors among men, though incidence remains low in both sexes under age 40.^[15] Geographic variations are pronounced, with higher incidence in industrialized regions such as Southern Europe (ASR up to 19.3 per 100,000 in Spain) and North America, linked to environmental and occupational exposures.^[13] In contrast, rates are lower in Africa and parts of Asia (e.g., ASR of 5.0 per 100,000 in Burkina Faso).^[13]^[16] A notable exception is the Balkan region, where endemic nephropathy (BEN) in countries like Bosnia, Bulgaria, Croatia, Romania, and Serbia is associated with dramatically elevated rates of upper urinary tract TCC; historical data from 1969-1977 show incidence up to 57 times higher in BEN-endemic areas compared to non-endemic regions.^[17] Over time, trends reflect shifts in risk factor prevalence, particularly smoking, which is a major driver of TCC. In high-income countries like the United States, incidence rates have declined by about 1% annually since the early 2000s, coinciding with reduced smoking prevalence post-2000.^[15] Globally, while the absolute number of cases rose 7.1% from 2020 to 2022 due to population aging and growth, age-standardized rates have remained relatively stable or slightly decreased in Western regions, though increases are observed in transitioning economies.^[18]

Risk Factors and Etiology

Environmental and Lifestyle Factors

Cigarette smoking is the most significant modifiable risk factor for transitional cell carcinoma (TCC), accounting for approximately 50% of cases in men and 20-30% in women, with smokers facing at least a threefold increased risk compared to nonsmokers.^[19]^[20] The risk exhibits a dose-response relationship, escalating with the number of pack-years smoked, and persists even after cessation, though quitting reduces the hazard over time.^[21] Mechanistically, tobacco smoke contains carcinogenic aromatic amines, such as 4-aminobiphenyl and 2-naphthylamine, which are metabolized into reactive intermediates that form DNA adducts in the urothelium, promoting mutagenesis and tumor initiation.^[22]^[23] Occupational exposures to aromatic amines represent another key environmental risk, particularly in industries involving dye production, textiles, and chemicals, where workers historically faced elevated TCC incidence. Benzidine and aniline dyes, used in these sectors, are potent bladder carcinogens; cohort studies from the 1950s onward, such as one involving benzidine manufacturers, reported that over 50% of exposed workers developed TCC after an average of 13.6 years of exposure.^[24]^[25] These compounds undergo hepatic activation to form DNA-binding metabolites, similar to those from tobacco, leading to urothelial damage and oncogenesis.^[22] Dietary and chemical exposures, notably aristolochic acid from certain herbal remedies derived from Aristolochia plants, contribute to TCC development, especially in cases of Balkan endemic nephropathy (BEN), a chronic kidney disease endemic to regions of the Balkans. Consumption or environmental contamination with aristolochic acid induces characteristic A:T to T:A transversions in TP53, driving upper urinary tract TCC with multifocal, aggressive features.^[26]^[27] Additional lifestyle factors include inadequate fluid intake, which concentrates urinary carcinogens and prolongs urothelial contact time, thereby elevating TCC risk; the association between fluid intake and TCC risk remains inconsistent, with some meta-analyses indicating increased risk with high intake (>3000 ml/day) in Western populations, while others suggest a protective effect in certain groups such as Asians.^[28] In schistosomiasis-endemic areas like Egypt, chronic Schistosoma haematobium infection promotes bladder inflammation and metaplasia, increasing the risk of bladder cancer, particularly squamous cell carcinoma but also transitional cell carcinoma, through nitrosamine production and epithelial proliferation.^[29]^[30] These environmental factors can interact with genetic predispositions, such as variants in detoxification enzymes, to amplify risk.^[22]

Genetic and Molecular Factors

Transitional cell carcinoma, also known as urothelial carcinoma, is driven by a variety of somatic genetic alterations that contribute to its oncogenesis. Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are particularly prevalent in low-grade, non-muscle-invasive tumors, occurring in approximately 50-70% of such cases, and are associated with a more favorable prognosis compared to wild-type tumors.^[31] In contrast, mutations in the tumor protein p53 (TP53) gene are more common in high-grade and muscle-invasive disease, present in up to 50% of advanced cases, where they promote genomic instability and aggressive tumor behavior.^[32] Disruptions in the retinoblastoma 1 (RB1) pathway, often through biallelic inactivation, frequently co-occur with TP53 alterations in muscle-invasive bladder cancer, affecting around 20-30% of tumors and correlating with poor outcomes due to loss of cell cycle control.^[33] Hereditary factors also play a role in urothelial carcinoma susceptibility, most notably through Lynch syndrome, an autosomal dominant condition caused by germline mutations in DNA mismatch repair genes. Mutations in MSH2 or MLH1 significantly elevate the risk, with MSH2 carriers facing a 4- to 7-fold increased relative risk of urothelial carcinoma compared to the general population, particularly for upper tract tumors.^[34] This predisposition arises from defective mismatch repair leading to microsatellite instability, which accelerates somatic mutation accumulation in urothelial cells. While less common than somatic changes, these germline variants account for up to 10-15% of upper tract urothelial carcinomas and warrant genetic screening in select patients.^[35] The Cancer Genome Atlas (TCGA) project has delineated molecular subtypes of muscle-invasive urothelial carcinoma based on gene expression and genomic profiling, providing insights into tumor heterogeneity. These include the luminal-papillary subtype, enriched for FGFR3 mutations and papillary architecture, which comprises about 24% of cases and is linked to lower progression risk; the luminal subtype, resembling breast cancer luminal tumors; and the basal-squamous subtype, characterized by TP53 mutations and squamous differentiation, representing around 35% of cases with more aggressive features.^[36] Additional subtypes, such as luminal-infiltrated and neuronal, highlight immune and neuroendocrine influences, respectively. These classifications, derived from comprehensive analysis of over 400 tumors, inform prognostic stratification and the development of targeted therapies in the 2020s, such as FGFR inhibitors for luminal-papillary tumors.^[36] Epigenetic modifications, particularly DNA hypermethylation of promoter CpG islands, contribute to urothelial carcinoma by silencing tumor suppressor genes and promoting oncogenesis independently of genetic mutations. Hypermethylation is frequent in genes such as RASSF1A, which regulates cell cycle and apoptosis, and is detected in 50-80% of bladder tumors, correlating with higher grade and stage.^[37] Similarly, hypermethylation of APC and MGMT occurs in advanced disease, leading to reduced expression and enhanced tumor progression, with patterns detectable in urine sediments for non-invasive monitoring.^[38] These changes often interact with environmental exposures like smoking-induced DNA adducts but represent a distinct layer of dysregulation in tumor initiation and maintenance.^[39]

Clinical Presentation

Signs and Symptoms

The most common initial symptom of transitional cell carcinoma (TCC), also known as urothelial carcinoma, is hematuria, which occurs in 80-90% of cases and serves as the presenting complaint for the majority of patients.^[40] Hematuria can be gross, appearing as visible blood that turns urine bright red or cola-colored, or microscopic, detectable only through urinalysis, with gross hematuria being more alarming and prompting earlier medical attention in many instances.^[2] This symptom arises due to tumor disruption of the urothelial lining and is often painless and intermittent, though it may persist or recur.^[4] Patients with TCC involving the bladder frequently experience irritative voiding symptoms, such as urinary frequency, urgency, and dysuria (painful urination), affecting approximately 20% of those with non-muscle-invasive disease.^[41] These symptoms mimic urinary tract infections and can significantly impact quality of life, often worsening as the tumor irritates the bladder mucosa.^[42] In cases of upper urinary tract involvement, such as the renal pelvis or ureter, patients may report flank pain due to obstruction or distension, while bladder tumors can cause suprapubic pain from local invasion or clot retention.^[43] Site-specific variations in presentation are further detailed in the anatomic site discussion. Although hematuria is the most common sign, approximately 10-20% of cases may be asymptomatic and discovered incidentally during evaluation for other reasons.^[44] In advanced or metastatic TCC, systemic signs become prominent, including unexplained weight loss, fatigue, and anemia, reflecting the disease's cachectic effects and distant spread.^[4] These manifestations typically emerge later in the disease course and may accompany organ-specific complaints, such as bone pain from skeletal metastases.^[45] Early detection through recognition of urinary symptoms remains crucial, as advanced systemic involvement portends poorer prognosis.^[46]

Presentation by Anatomic Site

Transitional cell carcinoma, also known as urothelial carcinoma, most commonly arises in the bladder, where the predominant presenting symptom is painless gross hematuria, occurring in approximately 80-90% of cases.^[40] This hematuria may be intermittent and can lead to the urine appearing bright red or cola-colored without associated pain or urgency in early stages. In advanced bladder disease, patients may develop pelvic pain, lower back pain on one side, or lower abdominal discomfort due to local invasion or obstruction.^[47] In the upper urinary tract, including the renal pelvis and ureters, the clinical presentation differs somewhat from bladder involvement, with flank pain due to hydronephrosis or ureteral obstruction reported in about 20% of cases.^[48] Hematuria is still common, affecting 70-80% of patients, but it is often microscopic rather than gross and may be less prominent than in bladder cancer; instead, symptoms like colicky pain from blood clots or gradual distention of the collecting system are more characteristic.^[49] Advanced upper tract tumors can present with a palpable lumbar mass in roughly 10% of locally advanced cases or constitutional symptoms if obstruction leads to renal impairment.^[49] Urethral transitional cell carcinoma is rare, accounting for less than 1% of all urothelial malignancies, and isolated presentation is uncommon, often occurring in the context of multifocal disease. Symptoms typically include obstructive urinary issues such as difficulty urinating, weak stream, or urinary retention, alongside irritative voiding symptoms like frequency, urgency, and dysuria.^[50] Patients may also experience bloody urethral discharge, incontinence, or a palpable mass in advanced stages.^[51]^[49] The multifocal nature of transitional cell carcinoma is well-recognized, with approximately 17-20% of upper tract cases showing synchronous involvement of the bladder at diagnosis, highlighting the field cancerization effect along the urothelium.^[49] This concurrent presentation underscores the importance of thorough evaluation of the entire urinary tract in suspected cases.

Pathophysiology

Cellular Origin and Histology

Transitional cell carcinoma, also known as urothelial carcinoma, originates from the urothelium, a specialized transitional epithelium that lines the urinary tract, including the bladder, ureters, and renal pelvis. The urothelium is a multilayered structure composed of three primary cell types: basal cells adjacent to the basement membrane, intermediate cells forming the middle layers, and superficial umbrella cells that line the luminal surface and provide a barrier against urine. These cells exhibit unique properties, such as the umbrella cells' ability to stretch and maintain impermeability through tight junctions and asymmetric unit membrane plaques.^[52]^[53] Histologically, urothelial carcinomas are classified based on growth patterns and graded according to the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) systems from 2004, 2016, and 2022, which dichotomize tumors into low-grade and high-grade categories.^[54]^[55]^[56] Low-grade tumors typically show minimal cytologic atypia, orderly arrangement of cells, and resemble normal urothelium, while high-grade tumors exhibit marked pleomorphism, disorganized architecture, and increased mitotic activity, correlating with more aggressive behavior. Papillary lesions, the most common form, project into the lumen with fibrovascular cores lined by neoplastic urothelium, whereas flat lesions, such as carcinoma in situ, lack exophytic growth and appear as flat, atypical intraepithelial proliferations.^[54]^[56] Several histologic variants of urothelial carcinoma exist, accounting for less than 10% of cases and often displaying more aggressive clinical behavior than conventional types. The micropapillary variant features small clusters of tumor cells within lacunae-like spaces, mimicking lymphatic invasion, and is associated with higher rates of lymphovascular invasion and metastasis. The sarcomatoid variant shows spindle cell morphology resembling sarcoma, with epithelial and mesenchymal components, and tends to present at advanced stages with poor prognosis. These variants are graded as high-grade under WHO/ISUP criteria and may require adjusted therapeutic approaches due to their distinct biology.^[57]^[58] Immunohistochemistry plays a key role in confirming urothelial origin, particularly in challenging cases. Urothelial carcinomas typically express cytokeratin 7 (CK7) diffusely and GATA3, a transcription factor highly specific for urothelial differentiation, in over 90% of cases. These markers help distinguish urothelial carcinoma from other bladder malignancies, such as adenocarcinoma or squamous cell carcinoma, with GATA3 showing particular utility in metastatic settings. Additional markers like p63 and high-molecular-weight cytokeratins may support the diagnosis but are less specific.^[59]^[60]

Mechanisms of Growth and Metastasis

Transitional cell carcinoma, also known as urothelial carcinoma, displays two primary local growth patterns: superficial papillary tumors and invasive carcinoma in situ (CIS). Papillary carcinomas typically form exophytic, finger-like projections into the bladder lumen, confined to the urothelial layer without penetrating the basement membrane, which allows for a relatively indolent course in low-grade cases. In contrast, CIS manifests as a flat, non-papillary lesion that replaces the surface epithelium with high-grade dysplastic cells, exhibiting a pagetoid spread and a strong tendency to progress to invasive disease due to its inherent genetic instability. These patterns reflect differences in cellular behavior, with papillary growth often linked to FGFR3 mutations driving proliferation, while CIS is associated with TP53 alterations promoting apoptosis resistance.^[61] Invasion of the underlying stroma requires tumor cells to breach the basement membrane, a process mediated by matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9. These zinc-dependent endopeptidases degrade type IV collagen and other extracellular matrix components, facilitating epithelial-mesenchymal transition (EMT) where cells lose E-cadherin expression and gain migratory mesenchymal traits. Upregulation of MMPs in TCC correlates with muscle invasion and poorer prognosis, as observed in high-grade tumors where EMT is driven by transforming growth factor-β (TGF-β) signaling and loss of cell adhesion molecules.^[62]^[63] Metastasis in transitional cell carcinoma predominantly follows lymphatic routes, with initial spread to pelvic and iliac lymph nodes, followed by hematogenous dissemination to distant organs such as the liver, lungs, and bones. Lymphatic invasion occurs via tumor emboli entering regional vessels, while hematogenous spread involves penetration of venous structures, often leading to multi-organ involvement in advanced stages. Approximately 20% of patients with muscle-invasive disease present with regional lymph node metastases at diagnosis, underscoring the early metastatic potential of high-grade tumors.^[63]^[62] The multifocal occurrence of transitional cell carcinoma is attributed to field cancerization, a process involving widespread urothelial instability across the bladder mucosa due to chronic carcinogen exposure, such as from smoking or aromatic amines. This leads to shared genetic alterations, including loss of heterozygosity at 9p21 and 17p13 loci, in histologically normal tissue adjacent to tumors, promoting independent clonal expansions and synchronous or metachronous tumor development. Field effects manifest as elevated tumor mutational burden and chromatin remodeling defects (e.g., in KMT2D and ARID1A), contributing to recurrence rates exceeding 50% in affected patients.^[64]^[65]^[66]

Diagnosis

Clinical Evaluation and Imaging

The clinical evaluation of suspected transitional cell carcinoma (TCC), also known as urothelial carcinoma, begins with a detailed patient history and physical examination to identify risk factors and symptoms that prompt further investigation. The history typically focuses on the duration and nature of hematuria, which is the most common presenting symptom, occurring in over 80% of cases, as well as irritative voiding symptoms such as frequency or urgency that may suggest carcinoma in situ. Risk factors assessed include tobacco use, occupational exposures to carcinogens like aromatic amines, and prior radiation or cyclophosphamide therapy, which are strongly associated with disease development. Physical examination often yields limited findings, as non-muscle-invasive TCC is rarely palpable; however, a bimanual exam under anesthesia may detect a mass in cases of suspected muscle invasion during subsequent procedures.^[67]^[40]^[68] Urinalysis and cytology serve as initial non-invasive tests to detect abnormalities suggestive of TCC. Urinalysis identifies microscopic or gross hematuria, which warrants evaluation in patients over 35 years, though it lacks specificity due to benign causes like infection or stones. Urine cytology, involving microscopic examination of shed cells, has a sensitivity of approximately 70-85% for high-grade TCC, making it valuable for detecting aggressive lesions including carcinoma in situ, but its sensitivity drops to under 20% for low-grade tumors due to subtle cytologic changes. Specificity exceeds 90%, reducing false positives, and the test is particularly useful when combined with cystoscopy in high-risk patients. The Paris System for reporting urinary cytology standardizes interpretation to enhance diagnostic accuracy for high-grade disease.^[69]^[70]^[71] Imaging modalities play a crucial role in assessing the upper urinary tract and staging TCC while avoiding invasive procedures initially. Ultrasound is often used as an initial screening tool for hematuria, offering accessibility and no radiation, though it has limited sensitivity for small or upper tract lesions. Computed tomography (CT) urography, combining non-contrast, corticomedullary, and excretory phases, is the preferred modality for evaluating the upper tracts and detecting filling defects or hydronephrosis, with high sensitivity for tumors greater than 5 mm. Magnetic resonance imaging (MRI), particularly multiparametric sequences, excels in local bladder staging by differentiating muscle invasion (T2 or higher) from superficial disease, avoiding iodinated contrast risks. Positron emission tomography-computed tomography (PET-CT) using FDG is reserved for detecting distant metastases in muscle-invasive or high-risk cases, improving specificity over conventional CT alone. For upper tract TCC, CT urography remains the gold standard for initial diagnosis and staging.^[67]^[72]^[73] Cystoscopy is the cornerstone of direct visualization and diagnosis for bladder TCC, allowing identification of mucosal abnormalities. Standard white-light cystoscopy (WLC) involves endoscopic inspection of the urethra and bladder to locate tumors, with documentation of size, number, and location essential for risk stratification. Enhanced techniques, such as blue-light cystoscopy (BLC) using intravesical hexaminolevulinate, improve detection of non-muscle-invasive lesions, particularly flat carcinoma in situ, by causing neoplastic cells to fluoresce pink under blue light, increasing sensitivity by 20-40% over WLC and reducing recurrence rates. BLC is recommended when available, especially in high-risk patients, though it requires specialized equipment and patient preparation.^[67]^[69]^[74]

Biopsy, Pathology, and Staging

Diagnosis of transitional cell carcinoma, also known as urothelial carcinoma, requires tissue sampling through biopsy to confirm the presence of malignant cells and assess tumor characteristics. For tumors in the bladder, the standard procedure is transurethral resection of bladder tumor (TURBT), a minimally invasive endoscopic technique that allows for both diagnostic sampling and therapeutic removal of visible lesions.^[75] TURBT involves the use of a resectoscope inserted through the urethra to excise the tumor and surrounding tissue, providing material for histopathological evaluation while aiming to preserve bladder function.^[76] In cases of upper urinary tract involvement, such as the renal pelvis or ureter, ureteroscopy is the preferred biopsy method; this involves a flexible ureteroscope advanced through the bladder to visualize and biopsy suspicious areas, often combined with laser ablation for low-grade lesions.^[4] These techniques are guided by prior imaging to target lesions accurately, ensuring adequate tissue for pathological analysis.^[77] Pathological examination of biopsy specimens confirms the diagnosis of urothelial carcinoma, characterized by atypical transitional epithelial cells forming papillary or flat structures. Tumors are graded according to the World Health Organization/International Society of Urological Pathology (WHO/ISUP) system, which classifies them as low-grade (minimal cytologic atypia, orderly architecture) or high-grade (marked atypia, disorganized growth, associated with aggressive behavior).^[78] This binary grading replaces earlier three-tier systems and correlates with recurrence and progression risk, with high-grade tumors showing poorer outcomes.^[79] Histologic features such as invasion depth into the lamina propria or muscularis propria are critical for distinguishing non-invasive (Ta, Tis) from invasive disease.^[80] Staging follows the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM system (8th edition), which evaluates tumor extent (T), nodal involvement (N), and distant metastasis (M) to guide prognosis and treatment. For bladder urothelial carcinoma, non-muscle-invasive stages include Ta (papillary carcinoma confined to mucosa) and T1 (invasion into lamina propria but not muscularis propria), while muscle-invasive disease is T2 (inner half of muscularis) or T3 (perivesical fat invasion); T4 indicates extension to adjacent organs like the prostate or abdominal wall.^[81] The upper tract staging is analogous, with pTa/pT1 denoting non-invasive/lamina propria-limited tumors and pT2+ indicating muscularis or beyond invasion, though clinical understaging is common due to biopsy limitations.^[82] Pathologic staging (pTNM) from TURBT or nephroureterectomy provides the most accurate assessment, incorporating histologic confirmation of invasion depth.^[80] Key prognostic markers identified in pathological reports include lymphovascular invasion (LVI), the presence of tumor cells within lymphatic or vascular spaces, which independently predicts higher risks of metastasis and reduced survival in both muscle-invasive and upper tract disease.^[83] Positive surgical margins, indicating residual tumor at resection edges, also signify incomplete excision and correlate with local recurrence, particularly in non-muscle-invasive cases.^[84] These features are routinely documented to refine risk stratification beyond TNM staging. Molecular pathology has integrated immunohistochemistry (IHC) for programmed death-ligand 1 (PD-L1) expression, particularly in advanced or metastatic urothelial carcinoma, to assess eligibility for immunotherapy with PD-1/PD-L1 inhibitors like pembrolizumab or atezolizumab.^[85] PD-L1 positivity, evaluated via combined positive score (CPS) on tumor and immune cells, identifies patients likely to benefit from checkpoint blockade, with thresholds such as CPS ≥10 guiding first-line therapy in cisplatin-ineligible cases post-2018 approvals.^[86] This testing complements traditional pathology, enhancing personalized treatment decisions without altering core grading or staging.

Management and Treatment

Treatment for Non-Muscle-Invasive Disease

The primary treatment for non-muscle-invasive transitional cell carcinoma (NMIBC), also known as non-muscle-invasive urothelial carcinoma, is transurethral resection of bladder tumor (TURBT), a procedure that removes visible tumors through the urethra using a cystoscope equipped with a cutting loop.^[87] TURBT serves both diagnostic and therapeutic purposes, aiming for complete resection of all visible lesions while obtaining sufficient tissue, including detrusor muscle, for accurate staging.^[88] For high-grade Ta or T1 tumors, a repeat TURBT is recommended within 2-6 weeks if the initial specimen lacks muscularis propria or shows incomplete resection, reducing understaging risk by up to 20%.^[87] Enhanced techniques, such as blue light cystoscopy with hexaminolevulinate, improve tumor detection and reduce recurrence rates by 16-37% compared to white light alone. Immediately following TURBT, a single instillation of intravesical mitomycin C (40 mg in 40 mL saline for 1 hour) is standard for low- and intermediate-risk NMIBC to prevent early recurrence, provided no bladder perforation occurred during resection.^[87] This adjuvant chemotherapy reduces recurrence by approximately 39% at 2 years, based on meta-analyses of randomized trials, by targeting residual microscopic tumor cells. It is particularly beneficial for patients with multifocal or larger tumors (>1 cm), though not routinely used in high-risk cases due to limited impact on progression.^[88] For risk-stratified intravesical therapy, Bacillus Calmette-Guérin (BCG) immunotherapy is the cornerstone for high-risk NMIBC, including carcinoma in situ (CIS), high-grade Ta, or any T1 disease, administered as a 6-week induction course (one-third dose in 50 mL saline weekly) followed by maintenance instillations for up to 3 years.^[87] BCG reduces recurrence by 27-45% and progression by 27% compared to TURBT alone, with seminal trials demonstrating durable responses in 70% of responders at 5 years.^[89] In intermediate-risk cases, such as low-grade Ta tumors with multiple recurrences, intravesical chemotherapy agents like gemcitabine (2 g in 100 mL saline biweekly for 6 weeks) offer an alternative, achieving recurrence-free rates of 60-70% at 2 years with lower toxicity than BCG.^[88] Sequential gemcitabine and docetaxel combinations are increasingly used for BCG-naïve or low-intermediate risk, showing complete response rates of 80% in phase II studies. NMIBC has a high recurrence rate of 50-70% within 5 years, necessitating vigilant management through risk-adapted surveillance.^[87] Recurrent low-grade tumors are often managed with office-based fulguration under local anesthesia during cystoscopy, while high-grade recurrences prompt reinduction BCG or consideration of cystectomy.^[88] Surveillance protocols involve cystoscopy every 3-4 months for the first 2 years in high-risk patients, tapering to annually after 5 tumor-free years, combined with cytology to detect occult disease.^[87] Upper urinary tract imaging is advised every 1-2 years for intermediate- and high-risk cases to rule out synchronous or metachronous involvement.^[88] Recent advances include the 2022 FDA approval of nadofaragene firadenovec-vncg (Adstiladrin), an intravesical gene therapy for high-risk BCG-unresponsive NMIBC with CIS, delivering interferon alfa-2b via an adenoviral vector.^[90] Administered monthly for the first year and then quarterly, it achieves a 51% complete response rate at 3 months, with 46% durability at 12 months in the pivotal phase III trial, offering a bladder-preserving option for patients ineligible for cystectomy. Subsequent approvals include nogapendekin alfa inbakicept-pmln (Anktiva) with BCG in April 2024 for high-risk BCG-unresponsive NMIBC, showing a 71% complete response rate at 3 months and 51% at 12 months in the QUILT-3.032 trial;^[91] mitomycin intravesical solution (ZUSDURI) in June 2025 as a non-surgical option for recurrent low-grade intermediate-risk NMIBC, with 79% complete response at 3 months in the ENVISION trial;^[92] and gemcitabine intravesical system (INLEXZO) in September 2025 for BCG-unresponsive NMIBC with CIS, demonstrating efficacy in ongoing trials.^[93] These therapies address BCG shortages and unresponsiveness, affecting up to 40% of high-risk patients, and represent bladder-preserving advancements.

Treatment for Muscle-Invasive and Metastatic Disease

For muscle-invasive transitional cell carcinoma (TCC), also known as urothelial carcinoma, of the bladder, radical cystectomy with bilateral pelvic lymphadenectomy represents the standard surgical approach for surgically eligible patients with non-metastatic (M0) disease, involving removal of the bladder, prostate (in men), and surrounding lymph nodes to achieve local control.^[94] In cases of upper urinary tract involvement, radical nephroureterectomy with bladder cuff excision and regional lymphadenectomy is the preferred treatment for localized muscle-invasive TCC, addressing the kidney, ureter, and distal ureteral margin to prevent recurrence.^[95] Neoadjuvant chemotherapy, administered prior to surgery, is recommended for cisplatin-eligible patients with muscle-invasive bladder TCC to improve pathologic downstaging and overall survival, with regimens such as methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine plus cisplatin demonstrating a 5-10% absolute survival benefit based on meta-analyses of randomized trials.^[96] In March 2025, the FDA approved durvalumab (Imfinzi) in combination with gemcitabine and cisplatin as neoadjuvant therapy, based on the NIAGARA trial showing a 32% reduction in event-free survival events.^[97] Adjuvant chemotherapy may be considered postoperatively in patients with high-risk features like lymph node involvement or incomplete response to neoadjuvant therapy, using similar platinum-based regimens to reduce recurrence risk, though its benefit is less established than neoadjuvant approaches.^[98] In metastatic TCC, systemic therapies form the cornerstone of management. For cisplatin-eligible patients, the preferred first-line regimen is enfortumab vedotin plus pembrolizumab, approved by the FDA in December 2023, which demonstrated superior overall survival (31.5 vs. 16.1 months) compared to platinum chemotherapy in the EV-302 trial.^[99] For patients not eligible for platinum-containing chemotherapy or who have progressed after platinum therapy, immunotherapy options such as pembrolizumab, a PD-1 inhibitor, received FDA accelerated approval in 2017, showing improved response rates in clinical trials.^[100] Targeted therapies, including the FGFR inhibitor erdafitinib, were approved by the FDA in 2019 (with full approval in 2024) for advanced or metastatic disease harboring FGFR2 or FGFR3 alterations, offering objective response rates of approximately 40% in biomarker-selected patients from phase II studies.^[101] For select patients with muscle-invasive bladder TCC who are medically unfit for cystectomy or prefer bladder preservation, trimodality therapy—combining maximal transurethral resection of the bladder tumor with concurrent chemoradiation (typically cisplatin-based)—provides a curative alternative with comparable long-term survival to radical surgery in appropriately staged cases, achieving complete response rates of 70-80% in prospective series.^[102] This approach requires rigorous patient selection based on tumor characteristics and close surveillance to detect local failures early.^[103]

Prognosis and Follow-Up

Prognostic Factors

The prognosis of transitional cell carcinoma (TCC), also known as urothelial carcinoma, is primarily determined by tumor stage and grade at diagnosis. Tumor stage is the most influential factor, with 5-year relative survival rates exceeding 95% for non-muscle-invasive stages (Ta, Tis, T1)^[104], approximately 45% for muscle-invasive stage II (T2) disease^[105], and around 35-40% for regionally advanced stages (III, including T3, T4, or N1, N2)^[104]. For distant metastatic disease (IV, M1), 5-year survival rates are around 8%^[104]. Tumor grade also correlates strongly with outcomes, as high-grade tumors have a higher risk of progression to advanced stages and predict poorer survival independent of stage^[87]. Additional clinical factors significantly influence prognosis. Advanced age at diagnosis, typically peaking between 60-70 years, is linked to worse overall survival due to comorbidities and reduced treatment tolerance.^[5] Poor performance status (Eastern Cooperative Oncology Group score >0) is a strong adverse predictor in advanced disease, reducing median overall survival from 14 months in good-status patients to as low as 3-4 months in those with multiple risk factors.^[106] Lymph node involvement worsens prognosis markedly, with N1/N2 status halving 5-year survival compared to node-negative disease, while N3 involvement approaches 0% survival.^[5] Other factors include visceral metastases (particularly liver), low hemoglobin (<10 g/dL), and elevated neutrophil-to-lymphocyte ratio, all of which independently predict shorter survival in metastatic settings.^[106]^[107] Biological markers are emerging as key prognostic indicators, particularly in the context of immunotherapy. High tumor mutation burden (TMB), common in urothelial carcinoma (ranking third among solid tumors), is associated with improved prognosis and better response to immune checkpoint inhibitors, with studies showing enhanced overall survival in high-TMB subgroups (hazard ratio favoring benefit in meta-analyses).^[108]^[109] Programmed death-ligand 1 (PD-L1) expression similarly predicts favorable outcomes with immunotherapy, correlating with longer progression-free survival.^[107] Recent trials have highlighted the prognostic impact of neoadjuvant chemotherapy; for muscle-invasive bladder cancer, cisplatin-based regimens improve 5-year overall survival by approximately 5%.^[110] In metastatic disease, combinations such as enfortumab vedotin plus pembrolizumab have improved median overall survival to over 30 months as of 2025 follow-up data.^[111] These factors, integrated with TNM staging, enable risk stratification for personalized prognostic assessment.^[112]

Surveillance Strategies

Surveillance strategies for transitional cell carcinoma (TCC), also known as urothelial carcinoma, are primarily risk-stratified to detect recurrence or progression after treatment, with protocols tailored to non-muscle-invasive disease (NMIBC) given its high recurrence rates. The American Urological Association (AUA) and European Association of Urology (EAU) guidelines emphasize regular cystoscopy as the cornerstone of monitoring, supplemented by imaging, urine cytology, and select biomarkers, with adjustments based on low-, intermediate-, or high-risk categories determined by tumor grade, stage, and response to therapy such as bacillus Calmette-Guérin (BCG).^[87]^[88] Cystoscopy schedules vary by risk stratum to balance detection efficacy and patient burden. For low-risk NMIBC, the AUA recommends cystoscopy at 3-4 months post-treatment, followed by 6-9 months later and annually thereafter, with shared decision-making after 5 recurrence-free years (Moderate Recommendation; Evidence Level: Grade C). The EAU aligns closely, advising cystoscopy at 3 and 12 months, then annually for 5 years, considering discontinuation thereafter if no recurrence (Weak Recommendation). Intermediate-risk patients follow a more frequent AUA schedule: initial cystoscopy at 3-4 months, then every 3-6 months for 2 years, 6-12 months for years 3-4, and annually ongoing (Expert Opinion); EAU suggests every 6 months for 2 years post-initial 3-month check, then annually for up to 10 years (Weak). High-risk cases, including post-BCG therapy, warrant intensive monitoring: AUA guidelines specify cystoscopy every 3-4 months for 2 years, every 6 months for years 3-4, and annually lifelong (Expert Opinion), while EAU recommends every 3 months for 2 years, every 6 months until year 5, and annually thereafter (Weak). These protocols aim to detect up to 70-80% of recurrences via cystoscopy, though adherence reduces over time due to logistical challenges.^[87]^[113]^[87] Upper urinary tract imaging is recommended selectively to evaluate for synchronous or metachronous involvement, which occurs in 2-4% of NMIBC cases. The AUA advises considering CT urography every 1-2 years for intermediate- or high-risk patients, but not routinely for low-risk (Expert Opinion). EAU guidelines specify annual CT urography for high- or very high-risk NMIBC for the first 5 years, followed by every 2 years up to 10 years (Weak Recommendation), prioritizing those with prior upper tract tumors or risk factors like smoking. This modality provides high sensitivity (over 90%) for detecting upper tract TCC compared to ultrasound.^[87]^[113]^[113] Urine cytology remains a standard adjunct for high-grade disease surveillance due to its specificity exceeding 90% for high-grade urothelial carcinoma. AUA recommends it alongside cystoscopy for intermediate- and high-risk NMIBC (Expert Opinion), while EAU limits it to high- or very high-risk patients at cystoscopy intervals (Weak Recommendation); it is not advised for low-risk due to low sensitivity (under 50%) for low-grade tumors. Limitations include false negatives in low-grade lesions and interference from inflammation post-BCG.^[87]^[113]^[87] Novel urinary biomarkers enhance specificity but do not replace cystoscopy, per both AUA (Strong Recommendation; Evidence Level: Grade B) and EAU guidelines, which note insufficient high-level evidence for routine substitution. UroVysion fluorescence in situ hybridization (FISH) detects chromosomal abnormalities with 70-80% sensitivity for recurrence monitoring and is FDA-approved for surveillance in known TCC patients; AUA endorses it for assessing BCG response or clarifying equivocal cytology (Expert Opinion). Cxbladder tests, including Cxbladder Monitor (FDA-cleared in 2017 for NMIBC surveillance), offer multiplex gene expression analysis with 91-93% sensitivity and 96-97% negative predictive value for recurrence, outperforming cytology in meta-analyses, and are noted by EAU as promising for risk stratification (e.g., 95% sensitivity for high-grade). These are particularly useful in high-risk strata for lifelong monitoring or to reduce cystoscopies in stable low-risk cases after shared decision-making.^[87]^[113]^[87]

Special Considerations

Upper Urinary Tract Involvement

Upper urinary tract urothelial carcinoma (UTUC), also known as transitional cell carcinoma of the renal pelvis and ureters, accounts for approximately 5-10% of all urothelial malignancies.^[114]^[115] This incidence is notably higher among smokers, who face an elevated risk due to the carcinogenic effects of tobacco metabolites excreted into the upper urinary tract.^[116] Unlike bladder cancer, UTUC often presents at a more advanced stage, with about 60% of cases being invasive at diagnosis compared to 15-25% for bladder urothelial carcinoma.^[115] Diagnosis of UTUC poses significant challenges due to its rarity and the anatomical constraints of the upper tract, which limit access for evaluation and increase the risk of incomplete staging.^[114] Initial assessment typically involves cystoscopy combined with cross-sectional imaging such as CT urography to identify filling defects or hydronephrosis.^[114] For definitive diagnosis, ureteroscopy with biopsy and cytologic evaluation of washings is recommended, though it carries risks of tumor seeding and may show discordance between biopsy grade and final pathology in up to 50% of cases.^[114]^[115] When ureteroscopy is not feasible, retrograde pyeloureterography can provide diagnostic visualization of the collecting system.^[114] Treatment strategies for UTUC are tailored to tumor grade, stage, and patient factors, with radical nephroureterectomy (RNU) including bladder cuff excision serving as the standard for high-risk disease to address multifocality and prevent recurrence.^[114]^[115] This procedure, which can be performed via open, laparoscopic, or robotic approaches, removes the kidney, entire ureter, and a segment of the bladder to ensure complete excision.^[95] For low-grade, low-risk tumors in patients with contraindications to RNU, kidney-sparing endoscopic ablation using laser or electrocautery is an alternative, offering preservation of renal function but requiring vigilant surveillance due to recurrence risks.^[114] Adjuvant chemotherapy may follow RNU in select high-risk cases to improve disease-free survival.^[115] Prognosis for UTUC is generally worse than for bladder urothelial carcinoma, primarily due to delayed detection and higher rates of invasion at presentation, with 5-year overall survival rates of approximately 57%.^[117] Survival varies markedly by stage: noninvasive (Ta/Tis) tumors achieve near 100% 5-year survival, while muscle-invasive (T2-T3) cases drop to 40-80%, and advanced (T4) disease to below 20%.^[118] Factors such as tumor location, lymphovascular invasion, and smoking history further adversely influence outcomes, underscoring the need for early intervention.^[116]

Prostate and Urethral Involvement

Primary urothelial carcinoma of the urethra is exceedingly rare, comprising less than 1% of all genitourinary tract malignancies and approximately 0.02% of female cancers.^[119]^[120] It is more common in men (incidence of 4.3 per million) than in women (1.5 per million), with most cases presenting in those over 70 years of age.^[121] Common symptoms include urethral stricture leading to obstructive voiding, recurrent urinary tract infections, irritative symptoms, hematuria, and dyspareunia, with over 70% of affected women reporting such issues at diagnosis.^[122] Management typically involves multimodal therapy, including surgical resection such as partial or radical urethrectomy, often combined with chemotherapy and radiation for advanced stages; neoadjuvant chemotherapy has been shown to improve survival compared to surgery alone.^[122] Prostatic involvement by urothelial carcinoma most commonly arises secondarily from adjacent bladder tumors, occurring in approximately 31% of patients undergoing radical cystoprostatectomy for invasive disease.^[123] This involvement can manifest as prostatic urethral carcinoma in situ (28% of cases), ductal or acinar spread (25%), or stromal invasion (47%), with the latter representing direct penetration into the prostatic stroma by irregular nests of atypical cells.^[123]^[124] Ductal spread often occurs via pagetoid extension into prostatic ducts and acini, expanding preexisting structures before potential stromal invasion.^[125] Management of prostatic involvement generally requires en bloc prostatectomy during radical cystectomy to achieve complete resection, particularly when stromal invasion is present, as transurethral approaches alone are insufficient for deeper involvement.^[126] Post-treatment urethral surveillance is essential, involving regular cystoscopy and urine cytology to detect recurrence early, given the high risk associated with residual urothelial disease.^[127] Outcomes are influenced by the extent of involvement, with all forms linked to worse overall survival compared to uninvolved cases; however, prostatic stromal invasion confers the poorest prognosis, with a 5-year survival rate of only 12% versus 35-40% for non-stromal involvement.^[123] Stromal invasion also elevates the risk of urethral recurrence to 64% after cystectomy, necessitating caution with orthotopic neobladder reconstruction due to increased metastatic potential and local failure rates.^[128]

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Perform endoscopy under anaesthesia and bladder biopsies when office cystoscopy shows suspicious findings or if urinary cytology is positive.
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What follows is a brief review of the contemporary literature regarding the management of the prostate and urethra in men and women undergoing radical ...