Bladder cancer has moved up from the 10th to the 9th most diagnosed cancer worldwide, with both incidence and mortality rates increasing. The new data estimated that 614,298 people were diagnosed with bladder cancer in 2022 around the world, marking a 7.1% increase from the data reported in 2020. The new 5-year prevalence also shows that 1,950,315 people (all genders) are living with bladder cancer within five years of a past diagnosis. Focusing on gender-specific data, it estimates 523,674 new bladder cancer cases in men, representing 5.4% of all new cancer cases in men globally, making it the 6th most common cancer among men. [1]
In Saudi Arabia, among 1,791 genitourinary (GU) tumor cases were identified. Bladder cancer was the most prevalent (42%), followed by prostate cancer (21%) and renal cell carcinoma (21%). [2]. 82.7% of bladder cancer cases are found to be in men, while 17.3% are in women. Transitional cell carcinoma was the most common histological type, followed by adenocarcinoma and squamous cell carcinoma. Of the transitional cell carcinoma cases, the most common type is superficial, followed by muscle-invasive. [3] In a comprehensive analysis from the Najran region, a significant male predominance, with a high rate of advanced-stage presentation, and substantial survival disparities were observed. [4]
The most common types of bladder cancer are urothelial bladder cancer, comprising 90% of bladder cancer, and other non-urothelial bladder cancer, such as Squamous cell bladder cancer, Adenocarcinoma bladder cancer and other rare cancer. [5]
Smoking is the most important risk factor for bladder cancer, increasing the incidence and mortality-related bladder cancer. [6] Not only traditional cigarette smoking but also electronic cigarettes have been linked to the increased incidence and progression of bladder cancer. [7] Since tobacco contains many known carcinogenic compounds, including aromatic amines and N-nitroso compounds, which are excreted in the urine and therefore come into close contact with the bladder lining, resulting in DNA adducts that can induce different mutations [8].
High fluid intake reduces the risk of bladder cancer by diluting the urinary concentrations of lifestyle- or environment-related metabolites or by decreasing the duration of exposure of the bladder epithelium to such compounds owing to more frequent voiding. Conversely, high fluid intake might increase the risk if the fluids contain carcinogens such as arsenic, simply because of a higher cumulative dose of carcinogens [9].
On the other hand, green tea and its polyphenols may lower the risk of bladder cancer due to their strong antioxidant and anticarcinogenic effects. [10,11] Additionally, fruits and vegetables may reduce bladder cancer risk due to their antioxidant properties. [12] Following the Mediterranean diet, which features a high intake of fruits, vegetables, legumes, and cereals; moderate to high consumption of fish; low to moderate intake of milk and dairy products; and limited intake of meat and meat products, reduces the risk of developing bladder cancer [13].
Diabetes and obesity negatively influence bladder cancer prognosis and outcomes, in addition to increased risk of mortality. [14]
Six categories of carcinogenic exposures in the workplace have been reported in the IARC monographs as risk factors for bladder cancer: ortho-toluidine; arsenic and inorganic arsenic compounds; X-ray radiation and γ-radiation; 2-naphthylamine; 4-aminobiphenyl; and benzidine [15]. Exposures to benzene in the petroleum stream, toluene, and xylene among shoe machine operators, tenders, automobile mechanics, and other textile machine operators may be linked to an increased risk of bladder cancer [16,17].
Numerous genetic factors significantly influence the risk of developing bladder cancer. Notably, mutations in several key chromosomal genes, including FGFR3, RB1, HRAS, TP53, and TSC1, can elevate this risk. Alterations in the genes located on human chromosome 9 are often linked to tumor formation in bladder cancer, while mutations on chromosome 22 may also contribute to the disease. Research indicates that approximately 70% of bladder cancers harbor a specific mutation in the telomerase reverse transcriptase (TERT) gene, underscoring its role in bladder cancer. Additionally, HRAS, being a proto-oncogene, has the potential to lead to cancer development in various organs, including the bladder. [18]
Chronic bladder irritation includes chronic or recurrent urinary tract infection, chronic indwelling urinary catheter, bladder calculi, foreign bodies, intravesical Bacillus Calmette-Guerin (BCG), and prolonged exposure to cyclophosphamide, all of which are associated with increased bladder cancer risk. [19] Human papillomavirus (HPV) may play a role in bladder carcinogenesis and contribute to a worse prognosis for patients with bladder cancer, especially men [20].
Participants with a first-degree relative who has bladder cancer had nearly twice the risk of developing the disease. The risk was also higher when participants reported a first-degree relative with a history of female genital cancer, melanoma, or tobacco-related cancers. [21]
Squamous cell carcinoma (SCC) and adenocarcinoma of the bladder typically present with nonspecific lower urinary tract symptoms that overlap with other bladder cancer subtypes. Current evidence does not support symptom-based differentiation between these histologies. Definitive diagnosis relies on cystoscopic evaluation and histopathological confirmation, rather than clinical presentation alone.
Regardless of tumor histology (urothelial carcinoma, SCC, or adenocarcinoma), patients most frequently present with:
Hematuria (microscopic or gross), the most common presenting symptom [22, 23].
Irritative voiding symptoms, including urinary frequency, urgency, dysuria, nocturia, and burning on micturition [22, 23].
Pelvic, suprapubic, or lower abdominal pain [22, 24].
Obstructive urinary symptoms, such as weak urinary stream, difficulty voiding, urinary retention, and, in advanced cases, hydronephrosis [22, 23].
Systemic manifestations of advanced disease, including weight loss, bone pain, abdominal pain, or symptoms related to metastatic spread [25].
While not diagnostic, SCC of the bladder is more frequently associated with:
A background of chronic bladder irritation, including long-term catheterization, spinal cord injury, bladder stones, recurrent urinary tract infections, or schistosomiasis [22, 23, 26].
High rates of hematuria, with a substantial proportion of patients also reporting irritative urinary symptoms [22–24].
Concomitant chronic cystitis or active urinary tract infection at the time of diagnosis [23, 26].
Similarly nonspecific, adenocarcinoma of the bladder is often described with:
Hematuria accompanied by irritative symptoms, such as urinary frequency, dysuria, and suprapubic discomfort [27, 28].
In select cases—particularly mucinous variants or tumors involving the bladder neck or outlet—voiding difficulty or bladder outlet obstruction, which may occur with minimal or absent hematuria [27].
Squamous cell carcinoma (SCC) and adenocarcinoma of the bladder are both diagnosed through histopathological evaluation of tissue specimens obtained via cystoscopy or surgical resection. No imaging modalities or urine-based tests can independently distinguish these histologic subtypes. Differentiation relies on morphologic assessment, supported by clinical context and selected immunohistochemical (IHC) markers.
The initial diagnostic approach is similar for both entities and includes:
Cystoscopy with biopsy or transurethral resection of bladder tumor (TURBT) following evaluation of hematuria; histology remains the diagnostic gold standard for all bladder cancers [26].
Cross-sectional imaging (CT or MRI)—including structured systems such as VI-RADS—used for staging and assessment of local or distant spread rather than histologic classification [29, 30].
Additional evaluation in suspected adenocarcinoma, aimed at excluding secondary involvement from colorectal, prostatic, gynecologic, or urachal primaries through targeted imaging and clinical work-up [28, 31].
Definitive differentiation is based on characteristic microscopic findings:
Squamous cell carcinoma is defined by a pure squamous phenotype, including keratin pearl formation, intercellular bridges, and keratin debris, with no urothelial component [23, 26, 31].
Adenocarcinoma is characterized by true glandular differentiation, often with mucin production, and may exhibit enteric, mucinous, signet-ring, or mixed growth patterns [28, 31, 32].
Tumors containing any urothelial component are classified as urothelial carcinoma with squamous or glandular differentiation, rather than pure SCC or adenocarcinoma [28, 31].
The diagnosis of primary bladder adenocarcinoma is reserved for tumors with pure non-urothelial glandular morphology [28, 31].
Immunohistochemistry serves as a supportive tool, not a standalone diagnostic method:
In SCC, markers such as p40, p63, and CK5/6 confirm squamous differentiation but do not reliably distinguish pure SCC from urothelial carcinoma with squamous differentiation [23, 28, 31]..
In adenocarcinoma, marker panels (e.g., CK7, CK20, CDX2, SATB2, β-catenin) assist in differentiating primary bladder adenocarcinoma from metastatic colorectal or Müllerian tumors [31-33]
Molecular and genomic profiling has demonstrated distinct mutational and immune-oncology signatures across bladder cancer subtypes; however, these approaches are not routinely required for basic histologic classification in current practice[31–33].
Current treatments for bladder SCC mainly involve surgery, as systemic options are limited. For localized, non-metastatic disease, radical cystectomy with pelvic lymph node dissection is the standard, providing better survival than radiotherapy or chemotherapy. Radiotherapy, alone or combined, is reserved for unfit patients but yields worse outcomes. The carcinoma often resists chemotherapy, with no clear survival benefit from neoadjuvant or adjuvant therapies over surgery. In advanced cases, prognosis is poor, and treatment is usually palliative, often following urothelial carcinoma protocols. Emerging data suggest some activity of immune checkpoint inhibitors, especially before surgery, but evidence is limited. Early surgery and participation in clinical trials are strongly advised.
Radical cystectomy with pelvic lymph node dissection is widely regarded as the reference standard for the management of localized SCC and is associated with the most favorable survival outcomes compared with non-surgical approaches[36].
Evidence from large population-based analyses, systematic reviews, and institutional series consistently demonstrates that radical cystectomy, performed with or without perioperative chemotherapy, confers superior overall and cancer-specific survival compared with chemotherapy alone, radiotherapy alone, or combined chemoradiation in patients with nonmetastatic disease[37].
Long-term outcomes following surgery highlight the prognostic importance of tumor stage and nodal involvement, with durable disease-free survival reported in appropriately selected patients[37–39].
The benefit of peri-operative chemotherapy in node-negative localized SCC remains unproven, and available data suggest limited chemosensitivity in pure squamous histology, supporting a surgery-first approach in resectable disease[40].
Bladder-preserving strategies, including chemoradiation, have been explored in small retrospective series but are generally reserved for patients who are medically unfit for radical surgery or who decline cystectomy, given the weaker and less consistent supporting evidence[41].
Partial cystectomy is considered only in highly selected cases with favorable anatomy and requires stringent long-term surveillance[41].
Overall, current evidence supports early radical cystectomy with lymphadenectomy as the guideline-concordant primary treatment for non-metastatic bladder SCC, with non-surgical alternatives limited to selected clinical scenarios[42].
For patients with localized or locally advanced SCC of the bladder, surgery, particularly radical cystectomy with pelvic lymph node dissection, represents the cornerstone of curative treatment, while other therapeutic modalities generally serve adjunctive or alternative roles[37, 43].
Large population-based analyses from SEER and the National Cancer Database consistently demonstrate that radical surgery is associated with superior overall and cancer-specific survival compared with radiotherapy alone, observation, or other non-surgical approaches in non-metastatic disease[44].
Survival benefits with surgery are observed in both localized and regional (locally advanced) stages, although the magnitude of benefit decreases in the presence of distant metastases, where surgery is largely palliative[44, 45].
Bladder-preserving approaches, including partial cystectomy or TURBT-based strategies, have been reported only in highly selected cases and are supported primarily by limited retrospective data[46].
Long-term outcomes from population studies indicate that these approaches generally provide inferior cancer-specific survival compared with radical cystectomy and require intensive lifelong surveillance[36].
The addition of perioperative systemic therapy has not shown a clear survival benefit in node-negative localized SCC and is therefore not routinely recommended; however, in patients with very high-risk features—such as node-positive, T4b, or metastatic disease—combined surgical and systemic approaches may reduce cancer-specific mortality[37, 40, 47].
In bilharzial-associated SCC, selected series suggest a potential role for perioperative radiotherapy to improve local control, though the quality of evidence remains limited.
Overall, early radical cystectomy remains the most effective curative strategy for localized and locally advanced bladder SCC, with non-surgical options reserved for carefully selected or surgically unfit patients[26, 36].
For bladder SCC, radical cystectomy should almost always include bilateral PLND, as omission clearly worsens survival. Pelvic lymph node dissection (PLND) clearly improves survival in bladder SCC when performed with cystectomy, but current data support a “standard” rather than an extended template. In a SEER analysis of variant histology, PLND versus no PLND significantly improved overall survival in SCC (HR ~0.65), with median OS nearly doubled (≈71 vs 37 months)[48].
A large NCDB study of variant bladder cancers confirmed that lymph node dissection is independently associated with better OS in the squamous subtype (HR 0.50), one of the strongest benefits among variants[49].
Despite this, SCC has high pNx rates (~68%), indicating PLND is underused in this histology[49].
Evidence on extent comes from mixed histology (mostly urothelial) MIBC, but no data suggest SCC behaves differently:
Two RCTs and multiple meta-analyses show no improvement in overall or disease-free survival with extended PLND to the aortic bifurcation compared with standard PLND up to the common iliac bifurcation [50, 51].
Extended PLND increases major complications, lymphoceles, and 90-day mortality [50].
SEER analysis in variant histology found greater PLND extent did not reduce cancer-specific mortality in VHBC (including SCC), although it improved staging yield [52].
For variant histologies, PLND remains prognostic even when chemotherapy or neoadjuvant therapy is used, but the added survival benefit from more extensive dissection diminishes after neoadjuvant chemotherapy[53].
Immunotherapy outcomes (pembrolizumab) do not appear improved by more extensive node harvest, and >14 nodes after NAC may even correlate with worse progression-free survival in mixed histology cohorts[54].
Definitive radiotherapy is feasible for non‑surgical bladder SCC, but expected cure rates are low; concurrent chemoradiation is preferable to RT alone when possible. Non-bilharzial SCC of the bladder is aggressive and usually treated with radical cystectomy. For patients who cannot undergo surgery, evidence for definitive radiotherapy (RT) is limited and mostly retrospective, but offers a potentially curative alternative to best supportive care.
In the largest NCDB analysis of localized cT2–3N0 pure SCC, RT alone and chemoradiation (CRT) had substantially worse overall survival (OS) than cystectomy (HR for death vs RC: RT 4.78; CRT 1.61) [37]. A SEER study of 5653 SCC cases found median survival 12 months with RT, 9 months with chemotherapy, vs markedly better with surgery; adding RT to surgery did not improve OS, likely reflecting selection bias [44]. Historical RT alone series in SCC report ~16% 3 year disease free survival with 60–65 Gy, indicating poor local control [55].
NCDB CRT analysis (79 SCC, cT2–T4N0M0) using concurrent Chemoradiation (CRT) found median OS ~15 months for SCC vs ~29–30 months for urothelial carcinoma; SCC histology independently predicted worse OS [55]. Case-based and small series suggest some long-term survivors using 5 FU/mitomycin or cisplatin-based CRT, extrapolating from anal SCC and urothelial CRT trials [36, 55].
Guidelines for MIBC support definitive RT or CRT in cystectomy-unfit patients, acknowledging lower-level evidence, and this is often extrapolated to SCC [56]. Narrative and systematic reviews emphasize that RT with concomitant chemotherapy is a reasonable alternative for unresectable tumors or in patients seeking bladder preservation, but data specific to SCC are sparse and of low level [36]. In broader MIBC cohorts unfit for surgery or cisplatin, RT (often without chemo) substantially improves OS vs supportive care, supporting its use as active treatment in frail patients [57].
Definitive radiotherapy is feasible for non-surgical bladder SCC, but expected cure rates are low; concurrent chemoradiation is preferable to RT alone when possible. Non-bilharzial SCC of the bladder is aggressive and usually treated with radical cystectomy. For patients who cannot undergo surgery, evidence for definitive radiotherapy (RT) is limited and mostly retrospective, but offers a potentially curative alternative to best supportive care.
In the largest NCDB analysis of localized cT2–3N0 pure SCC, RT alone and chemoradiation (CRT) had substantially worse overall survival (OS) than cystectomy (HR for death vs RC: RT 4.78; CRT 1.61)
[37]. A SEER study of 5653 SCC cases found median survival 12 months with RT, 9 months with chemotherapy, versus markedly better outcomes with surgery; adding RT to surgery did not improve OS, likely reflecting selection bias
[44]. Historical RT-alone series in SCC report ~16% 3-year disease-free survival with 60–65 Gy, indicating poor local control
[55].
NCDB CRT analysis (79 SCC, cT2–T4N0M0) using concurrent chemoradiation found median OS ~15 months for SCC versus ~29–30 months for urothelial carcinoma; SCC histology independently predicted worse OS
[55]. Case-based and small series suggest some long-term survivors using 5-FU/mitomycin or cisplatin-based CRT, extrapolating from anal SCC and urothelial CRT trials
[36, 55].
Guidelines for MIBC support definitive RT or CRT in cystectomy-unfit patients, acknowledging lower-level evidence, and this is often extrapolated to SCC
[56]. Narrative and systematic reviews emphasize that RT with concomitant chemotherapy is a reasonable alternative for unresectable tumors or in patients seeking bladder preservation, but data specific to SCC are sparse and of low level
[36]. In broader MIBC cohorts unfit for surgery or cisplatin, RT (often without chemotherapy) substantially improves OS versus supportive care, supporting its use as active treatment in frail patients
[57].
In bladder SCC patients not suitable for cystectomy, a bladder-preserving approach with TURBT followed by chemoradiotherapy is preferred. Curative radiotherapy often involves doses ≥60 Gy with radiosensitizers such as 5-fluorouracil, mitomycin C, cisplatin, or weekly gemcitabine. While this may control disease in some patients, cure rates are lower than with cystectomy
[36].
For those unable to receive chemotherapy, definitive radiotherapy alone at radical doses may improve survival compared with no treatment, but outcomes remain limited and often palliative
[44]. Due to high local recurrence risk, close surveillance with cystoscopy and imaging is essential, and salvage cystectomy should be considered if patient fitness improves
[36, 55].
Adjuvant radiotherapy (ART) after radical cystectomy is being revisited because loco-regional recurrence rates for ≥pT3 disease remain high, and salvage is difficult. Modern intensity-modulated techniques have reduced historical toxicity, enabling safer postoperative treatment. High-risk features associated with loco-regional failure include pT3–4, pN+, positive margins, and limited lymph-node dissection (<10 nodes) [58] [59].
Phase II–III and retrospective studies consistently show substantial reductions in pelvic relapse with ART or chemoradiotherapy compared with observation or chemotherapy alone, especially in ≥pT3/4 or margin-positive disease [60] [61].
With IMRT/VMAT, severe GI toxicity is markedly lower than in historical 2D RT: grade ≥3 GI events ~3–6%, though grade 2 GI symptoms are common. Phase II trials show acceptable urinary toxicity even in neobladder patients [62].
Reviews and guidelines suggest that ART is reasonable for selected high-risk MIBC, especially with positive margins, pT3–4, pN+, or suboptimal node dissection, and where access to salvage or immunotherapy is limited [63]. Large databases show no consistent OS benefit overall, but a possible benefit in marginally-positive patients [64] [65]. International consensus CTV guidelines now recommend including the cystectomy bed and common iliac nodes for high-risk cases [66].
Most work on neoadjuvant radiotherapy (RT) in bladder cancer is in mixed or predominantly urothelial histology. For pure bladder squamous cell carcinoma (SCC), evidence is largely indirect, coming from older series or reviews that pool histologies. A systematic review of bladder SCC notes that preoperative RT + radical cystectomy (RC) appears to improve survival compared with RC alone, but the data are from small, older series and are insufficient for firm recommendations. The same review highlights SCC’s high local-recurrence risk and suggests neoadjuvant or adjuvant RT (± systemic therapy) may reduce recurrence, but emphasizes the lack of randomized SCC-only trials [36].
Contemporary reviews of perioperative RT in muscle-invasive bladder cancer argue that preoperative RT is attractive in very high-risk, locally advanced disease to sterilize microscopic extension and improve pathologic response, but call the evidence “preliminary” and non-definitive [67]. Current neoadjuvant RT trials (often with immunotherapy such as nivolumab or durvalumab) are in urothelial carcinoma, not SCC; they explore feasibility and pathological complete response but do not yet guide SCC practice [68].
For operable, locally advanced SCC, RC remains standard; neoadjuvant RT can be considered only in selected very high-risk cases, extrapolating from mixed-histology data and acknowledging the lack of SCC-specific proof [36] [38]. For patients unfit for RC, management usually shifts to definitive chemoradiation, not “neoadjuvant” RT, again extrapolated from urothelial MIBC paradigms rather than SCC trials [69].
For bladder squamous cell carcinoma, radical cystectomy remains standard; chemoradiation is mainly a bladder-sparing or non-surgical option and appears less effective for survival but can offer local control when surgery is not feasible.
A large NCDB study of 828 patients with localized muscle-invasive pure SCC (cT2–3N0M0) compared RC ± perioperative chemotherapy, chemotherapy alone, radiation alone, and definitive chemoradiation. RC (with or without chemo) had the best survival; chemoradiation carried a higher death risk (HR 1.61 vs RC alone) but was better than radiation alone or chemotherapy alone [37]. A systematic review of non-bilharzial SCC concluded RC is the gold standard; radiotherapy alone gives poor outcomes, while multimodality approaches (pre-op RT + RC, or RC + systemic therapy) may help, but evidence is low-level and heterogeneous [36].
Variant histology (including SCC) shows worse survival after bladder-preserving RT than pure urothelial carcinoma, highlighting more aggressive biology and the need for intensification or surgery when possible [55].
Indications of chemoradiation in Bladder SCC:
Regimens generally mirror urothelial protocols: conventional or hypofractionated pelvic RT (≈55–64 Gy) with concurrent cisplatin, gemcitabine, or 5-FU/mitomycin C as radiosensitizer [56]. Given chemotherapy resistance concerns in SCC, systemic control may still be suboptimal, and close surveillance or consideration of combined RC, where feasible, is important [36] [55].
Chemotherapy has limited proven benefit in pure bladder SCC and is not currently a standard curative modality outside of surgery-based approaches. Large NCDB analysis of 828 localized, muscle-invasive pure SCC (cT2–3N0M0) found radical cystectomy (RC) with or without “perioperative” chemotherapy had the best survival, while chemotherapy alone, radiation alone, and chemoradiation were all significantly worse (HR for death vs RC alone: chemo alone 2.43, chemoradiation 1.61). Addition of neoadjuvant or adjuvant chemotherapy to RC did not improve overall survival compared with RC alone (HR 1.33 for neoadjuvant + RC; 1.11 for adjuvant + RC, both NS) [37]. A systematic review of non-bilharzial SCC concluded there is little evidence that chemotherapy improves survival over RC and that SCC appears relatively chemotherapy-resistant [36].
Variant-histology NAC data show SCC is the least responsive: lower clinical-to-pathologic downstaging and significantly worse cancer-specific survival after NAC+RC vs pure urothelial carcinoma [41]. NCDB and institutional series of invasive SCC found no survival advantage to neoadjuvant chemotherapy before RC; downstaging may increase but OS is unchanged [70]. Cisplatin-based regimens (MVAC, GC) yield poor pCR and high recurrence in SCC compared with urothelial carcinoma [36] [70].
Prospective non-urothelial trial (including 8 SCC) showed ifosfamide–paclitaxel–cisplatin had activity (median survival 8.9 months; 2 complete remissions among SCC) but numbers are very small [36]. Recent institutional data in metastatic SCC using gemcitabine/platinum or taxane/platinum show modest responses with short median PFS (~3–5 months) and universal progression [71].
Platinum regimens (mainly cisplatin-based) are standard for urothelial MIBC, but bladder SCC/marked squamous differentiation responds less well and derives smaller survival benefit. Direct data for pure bladder SCC are extremely limited; most studies pool urothelial carcinoma with squamous differentiation (UCSD) or other variants. In a small neoadjuvant series, UCSD showed no pathologic complete responses to cisplatin-based NAC vs 34.5% in pure UC, with much poorer DFS and OS, indicating relative cisplatin resistance [71]. A large Japanese NAC cohort found squamous differentiation carried a worse prognosis, though some such tumors still benefited from cisplatin-based NAC, underscoring biological heterogeneity [72]. In metastatic disease treated with gemcitabine–platinum, patients with variant histology (most commonly squamous differentiation) had similar response rates but shorter PFS and OS vs pure UC [73].
For bladder SCC, neither neoadjuvant nor adjuvant chemotherapy has proven a survival advantage over surgery alone; evidence does not clearly favor one sequence over the other. NCDB study of 828 localized pure SCC (T2–3N0M0) found radical cystectomy (RC) alone, RC+neoadjuvant (NAC), and RC+adjuvant (AC) chemotherapy had similar overall survival; perioperative chemotherapy (NAC or AC) did not improve outcomes versus RC alone [37]. Another NCDB analysis in 671 SCC patients showed no survival benefit for NAC+RC vs RC alone (HR 1.17; OS curves overlapping) [47]. Multi-institutional variant-histology series (283 SCC) reported worse cancer-specific survival and less downstaging after NAC than in pure urothelial carcinoma, supporting relative chemoresistance [41]. A systematic review of NAC in variant histologies concluded SCC is less sensitive to NAC; three NCDB-based SCC studies all showed no significant OS gain with NAC+RC vs RC alone [70].
SCC-focused datasets rarely distinguish NAC from AC in detail; the large comparative-effectiveness SCC study reports RC+NAC and RC+AC both comparable to RC alone, without a clear difference between NAC and AC [37]. Variant-histology reviews describe possible but unproven benefit of perioperative chemotherapy in SCC; no data demonstrate AC superior to NAC in SCC [70].
NCDB cohort (671 pure SCC) found no overall survival advantage from neoadjuvant chemotherapy (NAC) before cystectomy (HR 1.17; p=0.46) [47]. A larger SEER/RC series of 1018 SCC patients showed no cancer-specific or overall survival benefit from perioperative chemotherapy in node-negative (T2–4aN0M0) disease; benefit appeared only in T4b/N+/M+ subsets [40]. Comparative-effectiveness analysis of 828 pure SCC reported RC alone, RC+NAC, and RC+adjuvant chemotherapy had similar OS, while chemo-only or chemoradiation were inferior to RC-based approaches [37].
Multi-institutional variant-histology series showed SCC had the lowest effect of NAC, with markedly worse cancer-specific survival and significantly less clinical-to-pathologic downstaging than urothelial carcinoma (UC) [41]. In another cohort, urothelial tumors with squamous differentiation had 0% pathologic complete response to cisplatin-based NAC vs 34.5% in pure UC, and much worse DFS/OS [74]. A Western pure SCC series reported no objective responses in 4 patients given NAC and limited benefit from adjuvant chemotherapy [75].
Most SCC data are retrospective registry or small single-center series, often mixing pure and mixed SCC, lacking regimen detail, and with selection bias [36] [41]. A systematic review concluded there is little evidence supporting chemotherapy in non-bilharzial SCC, and its efficacy relative to cystectomy is unknown [36].
Immune checkpoint inhibitors are promising for bladder squamous cell carcinoma, but evidence is indirect and based mainly on biomarker and small-cohort data. Pure and mixed squamous bladder cancers frequently express PD-L1 at levels comparable to conventional urothelial carcinoma, and up to ~20% of pure SCC would meet FDA CPS≥10 eligibility for pembrolizumab first-line use [76]. Quantitative immune profiling shows many squamous tumors are “hot”, with high CD8⁺/perforin⁺ T-cell and macrophage infiltration, especially when PD-L1 is high, suggesting potential sensitivity to ICIs[77].
Neoadjuvant pembrolizumab trials in MIBC that included variant histologies reported modest activity in SCC variants, with response rates similar across non-urothelial types but based on very small numbers. Retrospective series of advanced non-urothelial BC (including SCC and UC with squamous differentiation) show overall response rates ~22–26% to PD-1/PD-L1 inhibitors, comparable across variants, but numbers for pure SCC are limited and heterogeneous [78]. A case of UC with squamous differentiation treated with nivolumab showed an excellent metastatic response, supporting activity in squamous-containing tumors[76].
Across metastatic bladder cancer, PD-1/PD-L1 inhibitors achieve response in ~20–30% and improve survival after platinum, with avelumab maintenance now standard in responders [79] [80]. High TMB and inflamed microenvironment—features seen in many bladder cancers—correlate with ICI response in large meta-analyses [81].
Bladder SCC (pure and with squamous differentiation) frequently expresses PD-L1 and often shows an inflamed tumor microenvironment, providing a strong biologic rationale for PD-1/PD-L1 blockade. Direct outcome data on ICI response in this histology are limited to small series and extrapolation from broader urothelial cohorts.
In non-schistosomal bladder SCC/UC with squamous differentiation, PD-L1 positivity on tumor and/or immune cells ranges from ~5–60% depending on antibody and scoring system, with no major difference between pure SCC and mixed UC/SCC. Using FDA-style CPS scoring, up to ~20% of pure SCC would meet CPS ≥10 eligibility for first-line pembrolizumab, similar to conventional urothelial carcinoma[76].
A focused review of schistosomal and non-schistosomal SCC reports PD-L1 positivity in ~65% of primary pure SCC in one cohort, frequently associated with basal/squamous-like molecular subtype and CDKN2A alterations[82].
Quantitative profiling of 68 pure SCC and 46 mixed tumors shows many are “hot” tumors: high intratumoral CD8⁺/perforin⁺ T cells and CD68⁺/CD163⁺ macrophages; perforin⁺ CD8⁺ density predicts better overall survival. High PD-L1 (CPS ≥10) strongly associates with higher CD3⁺, CD8⁺, and CD163⁺ densities and proliferative (Ki-67-high) tumor cells, defining a subgroup that “might pose a promising subgroup for clinically successful ICI therapy”[77].
Real-world immunotherapy in non-urothelial bladder cancer: activity is present but generally lower than in urothelial carcinoma, with limited data. The most direct real-world series is PEMBROBLAD, a 24-center retrospective cohort of 139 patients with advanced bladder cancer carrying histological variants (UC-V) or pure non-urothelial cancers (NUC) treated with checkpoint inhibitors after platinum failure[83].
Most patients received pembrolizumab; serious treatment-related AEs occurred in 9.3%, with 5% discontinuation, similar to pivotal mUC trials[83].
A systematic review of neoadjuvant/adjuvant ICI in MIBC notes preliminary activity of pembrolizumab in non-urothelial variants, including squamous and lymphoepithelioma-like, and summarizes two retrospective series in advanced non-urothelial BC reporting ORR 22–26% to PD-1/PD-L1 inhibitors across mixed variants[78].
A broader narrative review dedicated to non-urothelial and variant bladder cancers concludes that accumulating case series and small cohorts “suggest that immune checkpoint inhibition might have a role,” but emphasizes the lack of robust, prospective histology-specific data and the need for dedicated trials[84].
Most interventional work in bladder SCC occurs either via the dedicated AURORA (atezolizumab) trial or by including SCC within broader “non-urothelial/variant” or all-comers bladder cancer immunotherapy trials. First prospective ICI trial dedicated to advanced urinary tract SCC (UTSCC); allows mixed histology if no urothelial component. Primary endpoint ORR (Simon 2-stage). Translational work includes PD-L1 and immune biomarkers
[85]. Stage-1 analysis showed ORR 15.8% (3/19) and trial was closed for insufficient activity as monotherapy[86].
A recent narrative review on non-urothelial bladder cancers summarizes that SCC and other variants are commonly excluded from phase III urothelial trials, but some perioperative and metastatic ICI trials now allow limited numbers of non-urothelial/variant histologies (squamous, adenocarcinoma, small cell)[87]. A systematic analysis of 2899 global bladder cancer trials shows that PD-1/PD-L1 immunotherapy dominates the modern trial landscape, but histology-specific breakdown (e.g., pure SCC) is rarely specified; non-urothelial tumors are a small fraction of enrolled patients[88].
A systematic review of SCC of the bladder up to 2016 found no immunotherapy trials specifically in SCC, and recommended explicitly including SCC in future ICI protocols, given PD-1/PD-L1 success in urothelial cancer and other squamous tumors
[36]. More recent SCC-focused reviews reiterate that most ongoing ICI work still extrapolates from urothelial carcinoma, and that prospective SCC-only trials remain largely absent aside from AURORA[26, 89, 90].
Large neoadjuvant and perioperative ICI trials (e.g., durvalumab+cisplatin/gemcitabine in NIAGARA; various nivolumab, pembrolizumab, atezolizumab neoadjuvant trials) form the bulk of current immunotherapy development in muscle-invasive bladder cancer, but either exclude non-urothelial histologies or include only very small variant cohorts without SCC-specific reporting[91, 92].
For muscle‑invasive bladder squamous cell carcinoma (SCC), radical cystectomy is the mainstay; evidence for chemo‑ or immunotherapy is limited and extrapolated from urothelial cancer.
Multiple reviews identify radical cystectomy (RC) with pelvic lymph node dissection as the “gold-standard” for bladder SCC, including muscle-invasive disease[36, 93].
A 2020 NCDB study of 828 patients with clinical T2–3N0M0 pure SCC compared RC ± perioperative chemotherapy with chemotherapy alone, radiation alone, or chemoradiation. RC (with or without chemotherapy) had significantly better overall survival; chemo alone HR 2.43, RT alone HR 4.78, chemoradiation HR 1.61 vs RC[37].
Case-based data suggest partial cystectomy can control carefully selected, solitary muscle-invasive SCC with negative margins, but requires lifelong cystoscopic follow-up due to high late-recurrence risk[93].
The large SCC systematic review found little evidence that cisplatin-based chemotherapy improves outcomes in non-bilharzial SCC, and its benefit relative to RC is unknown. Preoperative radiotherapy plus RC may improve survival versus RC alone in historical series, whereas definitive RT alone is associated with poor outcomes in SCC[36].
Contemporary MIBC guidelines and perioperative reviews that shape current practice are almost entirely based on urothelial carcinoma; they acknowledge that variant histologies (including SCC) often respond less well and are under-represented in trials[94, 95].
The SCC systematic review states that immunotherapy for bladder SCC “has yet to be investigated” in dedicated trials[36].
Current ICI use is extrapolated from urothelial carcinoma reviews and guidelines, not SCC-specific data[96].
For metastatic bladder SCC, treatment is palliative and largely extrapolated from metastatic urothelial cancer; cisplatin‑based chemotherapy remains standard, with immunotherapy used empirically in selected patients.
A recent focused review on metastatic SCC of the bladder highlights very poor outcomes and limited responsiveness to systemic therapy and radiotherapy [90].
Retrospective and small prospective data show that cisplatin-based combinations (MVAC, CMB, gemcitabine/cisplatin) and 5-FU/mitomycin C with radiotherapy can produce partial responses, but response rates are lower than in conventional urothelial carcinoma, and long-term survivors are rare [36, 90].
One prospective non-urothelial study (including 8 pure SCC) found that ifosfamide–paclitaxel–cisplatin was active, with a median OS of 8.9 months and 2 complete remissions among SCC cases [36].
For metastatic/locally advanced SCC, radiotherapy alone is generally palliative, but combinations such as 5-FU/mitomycin C + RT or cisplatin-RT yielded occasional durable responses in small series [90].
In oligometastatic bladder cancer more broadly, multidisciplinary groups support metastasis-directed radiotherapy plus systemic therapy for carefully selected patients, though not SCC-specific [97].
The systematic SCC review states that immunotherapy “has yet to be investigated” specifically for bladder SCC; any ICI use is extrapolated from urothelial data [36].
Meta-analyses and reviews in advanced bladder cancer show overall-survival benefit and better tolerability of ICIs vs chemotherapy in unselected advanced bladder carcinoma, supporting their use after or instead of chemotherapy in appropriate patients [98].
(if fit): cisplatin‑based combination (e.g., GC or MVAC), acknowledging modest and uncertain benefit in SCC.
carboplatin‑gemcitabine or PD‑1/PD‑L1 inhibitor (especially PD‑L1–positive), with palliative intent.
PD‑1/PD‑L1 inhibitor; consider avelumab‑style maintenance if disease control on platinum, though SCC evidence is absent.
Management should be individualized in a multidisciplinary setting, with clinical‑trial enrollment strongly encouraged whenever available.
Bilharzial and non‑bilharzial bladder SCC share a surgical standard (radical cystectomy), but differ in epidemiology, biology, and the extent of radiotherapy integration into treatment.
Bilharzial SCC (B-SCC) arises in Schistosoma haematobium–endemic regions, often in the 5th decade, predominantly male, usually well- to moderately differentiated but muscle-invasive at diagnosis[26, 36].
Non-bilharzial SCC (NB-SCC) is rare in Western and many Asian settings (<5% of bladder cancers), presents later (6th–7th decade), and is more often poorly differentiated, bulky T3 tumors linked to chronic irritation (catheters, stones, infections)[26, 36, 99].
Both subtypes have low distant metastasis rates, with death mainly from uncontrolled pelvic disease rather than systemic spread[99, 100].
a.Local Therapy (Non-metastatic)
Across both B-SCC and NB-SCC, radical cystectomy (RC + pelvic lymphadenectomy) is the accepted “gold standard” for resectable, non-metastatic disease, offering substantially better survival than TURBT, radiotherapy (RT) alone, or chemotherapy alone
[36, 99]. NB-SCC series and registry analyses confirm surgery-based approaches provide the longest overall survival, with RT-only strategies associated with poor outcomes[36, 44, 99, 100].
b.Role of Radiotherapy and Chemoradiation
In bilharzial SCC, preoperative radiotherapy followed by radical cystectomy may enhance long-term survival, and this approach has been routinely used in some endemic areas. In contrast, evidence for non-bilharzial SCC is limited and mainly based on extrapolation[36, 99, 101].
Definitive radiotherapy or chemoradiation typically targets patients who are not suitable for surgery, providing occasional local control but is generally associated with a poor prognosis[99, 100].
In bilharzial SCC, adjuvant radiotherapy is more frequently employed to lower pelvic recurrence, whereas in non-bilharzial cases, it might be considered for patients with high-risk features, though a clear survival benefit remains unproven[36, 99, 101].
c.Systemic Therapy & Immunotherapy
For both B-SCC and NB-SCC, evidence for chemotherapy is weak; cisplatin-based regimens show limited and inconsistent benefit, mainly in small NB-SCC series or mixed SCC cohorts[36, 99, 100].
A systematic SCC review notes that immunotherapy has not been specifically studied in either B-SCC or NB-SCC; any use is extrapolated from urothelial carcinoma[36].
In bilharzial-endemic settings, patients are younger but often present with extensive local disease; RC is frequently combined with neoadjuvant or adjuvant RT in high-volume centers, informed by historical B-SCC data[36, 102].
In non-bilharzial disease, guidelines and series emphasize RC alone as standard, with RT or chemoradiation reserved for non-surgical candidates or within multimodal protocols whose benefit is unproven[36, 99, 100].
Elderly or frail patients with bladder SCC face major therapeutic challenges because standard curative options (radical cystectomy and cisplatin‑based therapy) are often poorly tolerated; care must be individualized using frailty‑based, not age‑based, decisions.
Under-representation and undertreatment: Older bladder cancer patients (median diagnosis ~73 years) are frequently excluded from trials and receive less curative treatment, leading to worse disease-specific outcomes than younger patients [103–106].
High comorbidity and frailty: Multimorbidity, reduced organ function, and geriatric syndromes increase surgical and chemotherapy toxicity risk, especially in those >70–80 years [103–106].
Aggressive SCC biology with limited systemic options: SCC is more chemoresistant than urothelial carcinoma, with poor response to neoadjuvant chemotherapy and no proven survival benefit from NAC before cystectomy [89, 90].
Metastatic SCC responds poorly to chemotherapy and radiotherapy, with median survivals often around 1 year or less [90].
Radical cystectomy: Perioperative mortality and complications rise sharply with age, yet selected fit elderly can achieve meaningful survival; age alone should not be an exclusion, but frailty strongly predicts complications and death[103, 106].
Urinary diversion: Non-continent diversion (e.g., ileal conduit) reduces operative time and complications and is usually preferred in frail elderly; orthotopic neobladder is reserved for highly selected, robust patients[103].
Radiotherapy/chemoradiation: Many older/frail patients are unfit for full-course chemoradiation; ultra-hypofractionated or short palliative RT regimens can control hematuria and pain with acceptable toxicity[103, 105, 107, 108].
Systemic therapy & immunotherapy: Cisplatin eligibility is often limited by renal and performance status; carboplatin-based or non-platinum regimens are less effective. Checkpoint inhibitors show similar efficacy and tolerability in older vs younger metastatic bladder cancer patients and may be preferable in cisplatin-unfit patients, though SCC-specific data are sparse[90, 103, 107].
Use comprehensive geriatric assessment/frailty tools (e.g., G8, GA) to guide treatment intensity, not chronological age. Discuss goals of care and quality of life early; integrate palliative care from diagnosis of metastatic SCC or when curative therapy is not feasible[103, 105, 107, 108].
For advanced bladder SCC, palliation focuses on local symptom control (especially bleeding and pain) with radiotherapy and careful use of systemic therapy, alongside early, specialist palliative care.
Advanced SCC behaves similarly to other aggressive bladder cancers, with death often from uncontrolled pelvic disease rather than distant spread [36, 90].
Palliative bladder RT provides high short-term relief of haematuria (~70–75%), pain, and irritative urinary symptoms, with schedules ranging from single 8 Gy to 21 Gy/3 fx or 30–36 Gy in 5–6 fx [109].
Meta-analysis shows higher RT dose does not improve the initial haematuria/frequency response, though it may prolong haematuria control at the cost of more toxicity [110].
Narrative and recent reviews emphasize hypofractionated RT (e.g., 21 Gy/3 fx, weekly 6 × 6 Gy) as a practical standard for frail, symptomatic patients [109].
Single 8 Gy or short hypofractionated course gives rapid, often durable control [109].
21 Gy/3 fx or 30–36 Gy in 5–10 fx improves pain, dysuria, frequency [109].
RT effective for bone pain, spinal cord compression, brain mets as in other cancers [109].
Metastatic bladder SCC responds poorly to standard chemotherapy and RT; survival after metastasis is often only a few months in small series [36, 90].
For metastatic bladder cancer overall, palliative platinum-based chemotherapy (gemcitabine–cisplatin or –carboplatin) improves median OS to ~9–14 months versus <1 year without treatment, but with substantial toxicity [111, 112].
Real-world data show sequential chemotherapy then immunotherapy yields mOS ~19 months, and immunotherapy alone is comparable to chemotherapy as first- or second-line palliative therapy [112].
Checkpoint inhibitors (e.g., pembrolizumab, atezolizumab, avelumab) are standard palliative options in metastatic bladder cancer and may be particularly valuable for cisplatinineligible patients, though SCC-specific benefit remains unproven [36]. Emerging data and case reports support combining RT with immune checkpoint inhibitors for symptomatic control and possiblesystemic benefit (abscopal-like effects) [113, 114].
Only ~4% of US patients with advanced bladder cancer receive specialist palliative care, despite clear benefits [115, 116].
In advanced/metastatic bladder cancer, early palliative care alongside oncologic treatment improves quality of life, reduces fatigue and psychological distress, and increases family satisfaction over 6 months [117].
General oncology literature confirms that structured symptom assessment and palliative care optimize control of pain, breathlessness, nausea/vomiting, and fatigue and can improve treatment adherence and sometimes survival [118, 119].
Symptom control and patient‑centred, early palliative care are central to preserving quality of life in bladder SCC, which shares most QoL issues with other bladder cancer subtypes.
Large QoL cohorts in bladder cancer (all histologies) show that Global HRQoL is substantially worse than in the general population and other pelvic cancers, driven more by age/comorbidities than stage or treatment type [120]. Most patients report problems in ≥1 domain (pain, mobility, self-care, usual activities, anxiety/depression) [120].
During systemic therapy, the most problematic symptoms correlating with worse QoL are anxiety, sadness, fatigue, poor concentration, and feeling discouraged, more than urinary symptoms alone [120].
Common treatment-related symptoms include frequent urination, pain, fatigue, dry mouth, limb swelling, and hospitalizations; over half of patients fail to complete planned chemo/immunotherapy, underscoring the need for better supportive care [121].
Physical: Urinary/bowel symptoms, pain, fatigue, sexual dysfunction[120–122].
Psychological: Anxiety, depression, fear of death/recurrence, body-image concerns[121, 123, 124].
Social/practical: Financial toxicity, reduced social life, dependence on caregivers[120, 123].
Information/support: High rates of unmet needs for symptom management, treatment information, and emotional support[125].
Current major bladder cancer guidelines (EAU, NCCN, SITC) recognize pure squamous cell carcinoma (SCC) of the bladder as high-risk and biologically distinct, but evidence is weak and most recommendations are extrapolated from urothelial carcinoma. There are no level I, SCC-specific trials, and several reviews explicitly state that formal, high-evidence guidelines for SCC are lacking[26, 36, 89].
| Guideline/source | Key statements relevant to SCC | Reference | |||
|---|---|---|---|---|---|
|
EAU bladder cancer guidelines |
Classify any variant histology, including SCC, as high‑risk bladder cancer; recommend upfront radical cystectomy (RC) + lymph‑node dissection for non‑metastatic SCC; no neoadjuvant chemo for pure SCC |
[26, 90] |
Recent SCC reviews |
Conclude there is insufficient evidence to give definitive treatment algorithms; RC is de facto standard, multimodal approaches and immunotherapy still investigational. |
[26, 36, 89, 90] |
|
NCCN bladder cancer guidelines |
Provide specific sections for nonurothelial histologies but base systemic therapy on urothelial data; for non‑muscle‑invasive T1 SCC, data favor early RC over BCG. |
[90, 129] |
|||
|
EAU bladder cancer guidelines |
Classify any variant histology, including SCC, as high‑risk bladder cancer; recommend upfront radical cystectomy (RC) + lymph‑node dissection for non‑metastatic SCC; no neoadjuvant chemo for pure SCC |
[26, 90] |
Recent SCC reviews |
Conclude there is insufficient evidence to give definitive treatment algorithms; RC is de facto standard, multimodal approaches and immunotherapy still investigational. |
[26, 36, 89, 90] |
Multiple population-based and institutional series show radical cystectomy provides the best survival for non-metastatic SCC compared with radiotherapy, chemoradiation, or observation [44].
EAUaligned reviews and NCCNbased discussions therefore recommend:
Upfront radical cystectomy with pelvic lymph-node dissection for non-metastatic pure SCC (including many pT1 cases), rather than bladder-preservation or BCG [26, 90].
For T1 SCC and schistosomal-associated SCC, early RC improves cancer-specific survival compared with conservative strategies [90].
Large registry and NCDB analyses show no overall-survival benefit from neoadjuvant chemotherapy in localized, muscle-invasive SCC [37, 90].
Adding perioperative chemotherapy (neo- or adjuvant) to RC does not clearly improve survival versus RC alone, though numbers are small and retrospective [37, 90].
Radiotherapy alone, or chemoradiation without surgery, is consistently associated with worse survival than RC in non-metastatic SCC [37, 43, 44].
For schistosomal SCC, some regional practice and older data support neoadjuvant RT before cystectomy, but guidelines note insufficient high-quality evidence to recommend routine adjuvant RT or chemotherapy [26, 36].
EAU guidance and contemporary reviews:
For metastatic SCC, there is no standard systemic regimen; outcomes with chemo or RT are poor, and treatment should be individualized [90].
Systemic therapy generally follows urothelial cancer paradigms (platinum-based chemotherapy, then immune checkpoint inhibitors), but SCC-specific efficacy is unproven, and evidence is limited to small series and case reports [89, 90].
The role of radical cystectomy for bladder adenocarcinomas has been found to be the cornerstone of reducing the overall mortality[130].
External beam radiotherapy (EBRT) alone is not the preferred treatment option for bladder cancer patients, as it is considered inferior to radical cystectomy. However, the addition of chemotherapy enhances outcomes, and chemoradiation can be used as a radical treatment alternative for patients with adenocarcinoma who are either unfit or unwilling to undergo cystectomy[130].
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Bladder cancer has moved up from the 10th to the 9th most diagnosed cancer worldwide, with both incidence and mortality rates increasing. The new data estimated that 614,298 people were diagnosed with bladder cancer in 2022 around the world, marking a 7.1% increase from the data reported in 2020. The new 5-year prevalence also shows that 1,950,315 people (all genders) are living with bladder cancer within five years of a past diagnosis. Focusing on gender-specific data, it estimates 523,674 new bladder cancer cases in men, representing 5.4% of all new cancer cases in men globally, making it the 6th most common cancer among men. [1]
In Saudi Arabia, among 1,791 genitourinary (GU) tumor cases were identified. Bladder cancer was the most prevalent (42%), followed by prostate cancer (21%) and renal cell carcinoma (21%). [2]. 82.7% of bladder cancer cases are found to be in men, while 17.3% are in women. Transitional cell carcinoma was the most common histological type, followed by adenocarcinoma and squamous cell carcinoma. Of the transitional cell carcinoma cases, the most common type is superficial, followed by muscle-invasive. [3] In a comprehensive analysis from the Najran region, a significant male predominance, with a high rate of advanced-stage presentation, and substantial survival disparities were observed. [4]
The most common types of bladder cancer are urothelial bladder cancer, comprising 90% of bladder cancer, and other non-urothelial bladder cancer, such as Squamous cell bladder cancer, Adenocarcinoma bladder cancer and other rare cancer. [5]
Smoking is the most important risk factor for bladder cancer, increasing the incidence and mortality-related bladder cancer. [6] Not only traditional cigarette smoking but also electronic cigarettes have been linked to the increased incidence and progression of bladder cancer. [7] Since tobacco contains many known carcinogenic compounds, including aromatic amines and N-nitroso compounds, which are excreted in the urine and therefore come into close contact with the bladder lining, resulting in DNA adducts that can induce different mutations [8].
High fluid intake reduces the risk of bladder cancer by diluting the urinary concentrations of lifestyle- or environment-related metabolites or by decreasing the duration of exposure of the bladder epithelium to such compounds owing to more frequent voiding. Conversely, high fluid intake might increase the risk if the fluids contain carcinogens such as arsenic, simply because of a higher cumulative dose of carcinogens [9].
On the other hand, green tea and its polyphenols may lower the risk of bladder cancer due to their strong antioxidant and anticarcinogenic effects. [10,11] Additionally, fruits and vegetables may reduce bladder cancer risk due to their antioxidant properties. [12] Following the Mediterranean diet, which features a high intake of fruits, vegetables, legumes, and cereals; moderate to high consumption of fish; low to moderate intake of milk and dairy products; and limited intake of meat and meat products, reduces the risk of developing bladder cancer [13].
Diabetes and obesity negatively influence bladder cancer prognosis and outcomes, in addition to increased risk of mortality. [14]
Six categories of carcinogenic exposures in the workplace have been reported in the IARC monographs as risk factors for bladder cancer: ortho-toluidine; arsenic and inorganic arsenic compounds; X-ray radiation and γ-radiation; 2-naphthylamine; 4-aminobiphenyl; and benzidine [15]. Exposures to benzene in the petroleum stream, toluene, and xylene among shoe machine operators, tenders, automobile mechanics, and other textile machine operators may be linked to an increased risk of bladder cancer [16,17].
Numerous genetic factors significantly influence the risk of developing bladder cancer. Notably, mutations in several key chromosomal genes, including FGFR3, RB1, HRAS, TP53, and TSC1, can elevate this risk. Alterations in the genes located on human chromosome 9 are often linked to tumor formation in bladder cancer, while mutations on chromosome 22 may also contribute to the disease. Research indicates that approximately 70% of bladder cancers harbor a specific mutation in the telomerase reverse transcriptase (TERT) gene, underscoring its role in bladder cancer. Additionally, HRAS, being a proto-oncogene, has the potential to lead to cancer development in various organs, including the bladder. [18]
Chronic bladder irritation includes chronic or recurrent urinary tract infection, chronic indwelling urinary catheter, bladder calculi, foreign bodies, intravesical Bacillus Calmette-Guerin (BCG), and prolonged exposure to cyclophosphamide, all of which are associated with increased bladder cancer risk. [19] Human papillomavirus (HPV) may play a role in bladder carcinogenesis and contribute to a worse prognosis for patients with bladder cancer, especially men [20].
Participants with a first-degree relative who has bladder cancer had nearly twice the risk of developing the disease. The risk was also higher when participants reported a first-degree relative with a history of female genital cancer, melanoma, or tobacco-related cancers. [21]
Squamous cell carcinoma (SCC) and adenocarcinoma of the bladder typically present with nonspecific lower urinary tract symptoms that overlap with other bladder cancer subtypes. Current evidence does not support symptom-based differentiation between these histologies. Definitive diagnosis relies on cystoscopic evaluation and histopathological confirmation, rather than clinical presentation alone.
Regardless of tumor histology (urothelial carcinoma, SCC, or adenocarcinoma), patients most frequently present with:
Hematuria (microscopic or gross), the most common presenting symptom [22, 23].
Irritative voiding symptoms, including urinary frequency, urgency, dysuria, nocturia, and burning on micturition [22, 23].
Pelvic, suprapubic, or lower abdominal pain [22, 24].
Obstructive urinary symptoms, such as weak urinary stream, difficulty voiding, urinary retention, and, in advanced cases, hydronephrosis [22, 23].
Systemic manifestations of advanced disease, including weight loss, bone pain, abdominal pain, or symptoms related to metastatic spread [25].
While not diagnostic, SCC of the bladder is more frequently associated with:
A background of chronic bladder irritation, including long-term catheterization, spinal cord injury, bladder stones, recurrent urinary tract infections, or schistosomiasis [22, 23, 26].
High rates of hematuria, with a substantial proportion of patients also reporting irritative urinary symptoms [22–24].
Concomitant chronic cystitis or active urinary tract infection at the time of diagnosis [23, 26].
Similarly nonspecific, adenocarcinoma of the bladder is often described with:
Hematuria accompanied by irritative symptoms, such as urinary frequency, dysuria, and suprapubic discomfort [27, 28].
In select cases—particularly mucinous variants or tumors involving the bladder neck or outlet—voiding difficulty or bladder outlet obstruction, which may occur with minimal or absent hematuria [27].
Squamous cell carcinoma (SCC) and adenocarcinoma of the bladder are both diagnosed through histopathological evaluation of tissue specimens obtained via cystoscopy or surgical resection. No imaging modalities or urine-based tests can independently distinguish these histologic subtypes. Differentiation relies on morphologic assessment, supported by clinical context and selected immunohistochemical (IHC) markers.
The initial diagnostic approach is similar for both entities and includes:
Cystoscopy with biopsy or transurethral resection of bladder tumor (TURBT) following evaluation of hematuria; histology remains the diagnostic gold standard for all bladder cancers [26].
Cross-sectional imaging (CT or MRI)—including structured systems such as VI-RADS—used for staging and assessment of local or distant spread rather than histologic classification [29, 30].
Additional evaluation in suspected adenocarcinoma, aimed at excluding secondary involvement from colorectal, prostatic, gynecologic, or urachal primaries through targeted imaging and clinical work-up [28, 31].
Definitive differentiation is based on characteristic microscopic findings:
Squamous cell carcinoma is defined by a pure squamous phenotype, including keratin pearl formation, intercellular bridges, and keratin debris, with no urothelial component [23, 26, 31].
Adenocarcinoma is characterized by true glandular differentiation, often with mucin production, and may exhibit enteric, mucinous, signet-ring, or mixed growth patterns [28, 31, 32].
Tumors containing any urothelial component are classified as urothelial carcinoma with squamous or glandular differentiation, rather than pure SCC or adenocarcinoma [28, 31].
The diagnosis of primary bladder adenocarcinoma is reserved for tumors with pure non-urothelial glandular morphology [28, 31].
Immunohistochemistry serves as a supportive tool, not a standalone diagnostic method:
In SCC, markers such as p40, p63, and CK5/6 confirm squamous differentiation but do not reliably distinguish pure SCC from urothelial carcinoma with squamous differentiation [23, 28, 31]..
In adenocarcinoma, marker panels (e.g., CK7, CK20, CDX2, SATB2, β-catenin) assist in differentiating primary bladder adenocarcinoma from metastatic colorectal or Müllerian tumors [31-33]
Molecular and genomic profiling has demonstrated distinct mutational and immune-oncology signatures across bladder cancer subtypes; however, these approaches are not routinely required for basic histologic classification in current practice[31–33].
Current treatments for bladder SCC mainly involve surgery, as systemic options are limited. For localized, non-metastatic disease, radical cystectomy with pelvic lymph node dissection is the standard, providing better survival than radiotherapy or chemotherapy. Radiotherapy, alone or combined, is reserved for unfit patients but yields worse outcomes. The carcinoma often resists chemotherapy, with no clear survival benefit from neoadjuvant or adjuvant therapies over surgery. In advanced cases, prognosis is poor, and treatment is usually palliative, often following urothelial carcinoma protocols. Emerging data suggest some activity of immune checkpoint inhibitors, especially before surgery, but evidence is limited. Early surgery and participation in clinical trials are strongly advised.
Radical cystectomy with pelvic lymph node dissection is widely regarded as the reference standard for the management of localized SCC and is associated with the most favorable survival outcomes compared with non-surgical approaches[36].
Evidence from large population-based analyses, systematic reviews, and institutional series consistently demonstrates that radical cystectomy, performed with or without perioperative chemotherapy, confers superior overall and cancer-specific survival compared with chemotherapy alone, radiotherapy alone, or combined chemoradiation in patients with nonmetastatic disease[37].
Long-term outcomes following surgery highlight the prognostic importance of tumor stage and nodal involvement, with durable disease-free survival reported in appropriately selected patients[37–39].
The benefit of peri-operative chemotherapy in node-negative localized SCC remains unproven, and available data suggest limited chemosensitivity in pure squamous histology, supporting a surgery-first approach in resectable disease[40].
Bladder-preserving strategies, including chemoradiation, have been explored in small retrospective series but are generally reserved for patients who are medically unfit for radical surgery or who decline cystectomy, given the weaker and less consistent supporting evidence[41].
Partial cystectomy is considered only in highly selected cases with favorable anatomy and requires stringent long-term surveillance[41].
Overall, current evidence supports early radical cystectomy with lymphadenectomy as the guideline-concordant primary treatment for non-metastatic bladder SCC, with non-surgical alternatives limited to selected clinical scenarios[42].
For patients with localized or locally advanced SCC of the bladder, surgery, particularly radical cystectomy with pelvic lymph node dissection, represents the cornerstone of curative treatment, while other therapeutic modalities generally serve adjunctive or alternative roles[37, 43].
Large population-based analyses from SEER and the National Cancer Database consistently demonstrate that radical surgery is associated with superior overall and cancer-specific survival compared with radiotherapy alone, observation, or other non-surgical approaches in non-metastatic disease[44].
Survival benefits with surgery are observed in both localized and regional (locally advanced) stages, although the magnitude of benefit decreases in the presence of distant metastases, where surgery is largely palliative[44, 45].
Bladder-preserving approaches, including partial cystectomy or TURBT-based strategies, have been reported only in highly selected cases and are supported primarily by limited retrospective data[46].
Long-term outcomes from population studies indicate that these approaches generally provide inferior cancer-specific survival compared with radical cystectomy and require intensive lifelong surveillance[36].
The addition of perioperative systemic therapy has not shown a clear survival benefit in node-negative localized SCC and is therefore not routinely recommended; however, in patients with very high-risk features—such as node-positive, T4b, or metastatic disease—combined surgical and systemic approaches may reduce cancer-specific mortality[37, 40, 47].
In bilharzial-associated SCC, selected series suggest a potential role for perioperative radiotherapy to improve local control, though the quality of evidence remains limited.
Overall, early radical cystectomy remains the most effective curative strategy for localized and locally advanced bladder SCC, with non-surgical options reserved for carefully selected or surgically unfit patients[26, 36].
For bladder SCC, radical cystectomy should almost always include bilateral PLND, as omission clearly worsens survival. Pelvic lymph node dissection (PLND) clearly improves survival in bladder SCC when performed with cystectomy, but current data support a “standard” rather than an extended template. In a SEER analysis of variant histology, PLND versus no PLND significantly improved overall survival in SCC (HR ~0.65), with median OS nearly doubled (≈71 vs 37 months)[48].
A large NCDB study of variant bladder cancers confirmed that lymph node dissection is independently associated with better OS in the squamous subtype (HR 0.50), one of the strongest benefits among variants[49].
Despite this, SCC has high pNx rates (~68%), indicating PLND is underused in this histology[49].
Evidence on extent comes from mixed histology (mostly urothelial) MIBC, but no data suggest SCC behaves differently:
Two RCTs and multiple meta-analyses show no improvement in overall or disease-free survival with extended PLND to the aortic bifurcation compared with standard PLND up to the common iliac bifurcation [50, 51].
Extended PLND increases major complications, lymphoceles, and 90-day mortality [50].
SEER analysis in variant histology found greater PLND extent did not reduce cancer-specific mortality in VHBC (including SCC), although it improved staging yield [52].
For variant histologies, PLND remains prognostic even when chemotherapy or neoadjuvant therapy is used, but the added survival benefit from more extensive dissection diminishes after neoadjuvant chemotherapy[53].
Immunotherapy outcomes (pembrolizumab) do not appear improved by more extensive node harvest, and >14 nodes after NAC may even correlate with worse progression-free survival in mixed histology cohorts[54].
Definitive radiotherapy is feasible for non‑surgical bladder SCC, but expected cure rates are low; concurrent chemoradiation is preferable to RT alone when possible. Non-bilharzial SCC of the bladder is aggressive and usually treated with radical cystectomy. For patients who cannot undergo surgery, evidence for definitive radiotherapy (RT) is limited and mostly retrospective, but offers a potentially curative alternative to best supportive care.
In the largest NCDB analysis of localized cT2–3N0 pure SCC, RT alone and chemoradiation (CRT) had substantially worse overall survival (OS) than cystectomy (HR for death vs RC: RT 4.78; CRT 1.61) [37]. A SEER study of 5653 SCC cases found median survival 12 months with RT, 9 months with chemotherapy, vs markedly better with surgery; adding RT to surgery did not improve OS, likely reflecting selection bias [44]. Historical RT alone series in SCC report ~16% 3 year disease free survival with 60–65 Gy, indicating poor local control [55].
NCDB CRT analysis (79 SCC, cT2–T4N0M0) using concurrent Chemoradiation (CRT) found median OS ~15 months for SCC vs ~29–30 months for urothelial carcinoma; SCC histology independently predicted worse OS [55]. Case-based and small series suggest some long-term survivors using 5 FU/mitomycin or cisplatin-based CRT, extrapolating from anal SCC and urothelial CRT trials [36, 55].
Guidelines for MIBC support definitive RT or CRT in cystectomy-unfit patients, acknowledging lower-level evidence, and this is often extrapolated to SCC [56]. Narrative and systematic reviews emphasize that RT with concomitant chemotherapy is a reasonable alternative for unresectable tumors or in patients seeking bladder preservation, but data specific to SCC are sparse and of low level [36]. In broader MIBC cohorts unfit for surgery or cisplatin, RT (often without chemo) substantially improves OS vs supportive care, supporting its use as active treatment in frail patients [57].
Definitive radiotherapy is feasible for non-surgical bladder SCC, but expected cure rates are low; concurrent chemoradiation is preferable to RT alone when possible. Non-bilharzial SCC of the bladder is aggressive and usually treated with radical cystectomy. For patients who cannot undergo surgery, evidence for definitive radiotherapy (RT) is limited and mostly retrospective, but offers a potentially curative alternative to best supportive care.
In the largest NCDB analysis of localized cT2–3N0 pure SCC, RT alone and chemoradiation (CRT) had substantially worse overall survival (OS) than cystectomy (HR for death vs RC: RT 4.78; CRT 1.61)
[37]. A SEER study of 5653 SCC cases found median survival 12 months with RT, 9 months with chemotherapy, versus markedly better outcomes with surgery; adding RT to surgery did not improve OS, likely reflecting selection bias
[44]. Historical RT-alone series in SCC report ~16% 3-year disease-free survival with 60–65 Gy, indicating poor local control
[55].
NCDB CRT analysis (79 SCC, cT2–T4N0M0) using concurrent chemoradiation found median OS ~15 months for SCC versus ~29–30 months for urothelial carcinoma; SCC histology independently predicted worse OS
[55]. Case-based and small series suggest some long-term survivors using 5-FU/mitomycin or cisplatin-based CRT, extrapolating from anal SCC and urothelial CRT trials
[36, 55].
Guidelines for MIBC support definitive RT or CRT in cystectomy-unfit patients, acknowledging lower-level evidence, and this is often extrapolated to SCC
[56]. Narrative and systematic reviews emphasize that RT with concomitant chemotherapy is a reasonable alternative for unresectable tumors or in patients seeking bladder preservation, but data specific to SCC are sparse and of low level
[36]. In broader MIBC cohorts unfit for surgery or cisplatin, RT (often without chemotherapy) substantially improves OS versus supportive care, supporting its use as active treatment in frail patients
[57].
In bladder SCC patients not suitable for cystectomy, a bladder-preserving approach with TURBT followed by chemoradiotherapy is preferred. Curative radiotherapy often involves doses ≥60 Gy with radiosensitizers such as 5-fluorouracil, mitomycin C, cisplatin, or weekly gemcitabine. While this may control disease in some patients, cure rates are lower than with cystectomy
[36].
For those unable to receive chemotherapy, definitive radiotherapy alone at radical doses may improve survival compared with no treatment, but outcomes remain limited and often palliative
[44]. Due to high local recurrence risk, close surveillance with cystoscopy and imaging is essential, and salvage cystectomy should be considered if patient fitness improves
[36, 55].
Adjuvant radiotherapy (ART) after radical cystectomy is being revisited because loco-regional recurrence rates for ≥pT3 disease remain high, and salvage is difficult. Modern intensity-modulated techniques have reduced historical toxicity, enabling safer postoperative treatment. High-risk features associated with loco-regional failure include pT3–4, pN+, positive margins, and limited lymph-node dissection (<10 nodes) [58] [59].
Phase II–III and retrospective studies consistently show substantial reductions in pelvic relapse with ART or chemoradiotherapy compared with observation or chemotherapy alone, especially in ≥pT3/4 or margin-positive disease [60] [61].
With IMRT/VMAT, severe GI toxicity is markedly lower than in historical 2D RT: grade ≥3 GI events ~3–6%, though grade 2 GI symptoms are common. Phase II trials show acceptable urinary toxicity even in neobladder patients [62].
Reviews and guidelines suggest that ART is reasonable for selected high-risk MIBC, especially with positive margins, pT3–4, pN+, or suboptimal node dissection, and where access to salvage or immunotherapy is limited [63]. Large databases show no consistent OS benefit overall, but a possible benefit in marginally-positive patients [64] [65]. International consensus CTV guidelines now recommend including the cystectomy bed and common iliac nodes for high-risk cases [66].
Most work on neoadjuvant radiotherapy (RT) in bladder cancer is in mixed or predominantly urothelial histology. For pure bladder squamous cell carcinoma (SCC), evidence is largely indirect, coming from older series or reviews that pool histologies. A systematic review of bladder SCC notes that preoperative RT + radical cystectomy (RC) appears to improve survival compared with RC alone, but the data are from small, older series and are insufficient for firm recommendations. The same review highlights SCC’s high local-recurrence risk and suggests neoadjuvant or adjuvant RT (± systemic therapy) may reduce recurrence, but emphasizes the lack of randomized SCC-only trials [36].
Contemporary reviews of perioperative RT in muscle-invasive bladder cancer argue that preoperative RT is attractive in very high-risk, locally advanced disease to sterilize microscopic extension and improve pathologic response, but call the evidence “preliminary” and non-definitive [67]. Current neoadjuvant RT trials (often with immunotherapy such as nivolumab or durvalumab) are in urothelial carcinoma, not SCC; they explore feasibility and pathological complete response but do not yet guide SCC practice [68].
For operable, locally advanced SCC, RC remains standard; neoadjuvant RT can be considered only in selected very high-risk cases, extrapolating from mixed-histology data and acknowledging the lack of SCC-specific proof [36] [38]. For patients unfit for RC, management usually shifts to definitive chemoradiation, not “neoadjuvant” RT, again extrapolated from urothelial MIBC paradigms rather than SCC trials [69].
For bladder squamous cell carcinoma, radical cystectomy remains standard; chemoradiation is mainly a bladder-sparing or non-surgical option and appears less effective for survival but can offer local control when surgery is not feasible.
A large NCDB study of 828 patients with localized muscle-invasive pure SCC (cT2–3N0M0) compared RC ± perioperative chemotherapy, chemotherapy alone, radiation alone, and definitive chemoradiation. RC (with or without chemo) had the best survival; chemoradiation carried a higher death risk (HR 1.61 vs RC alone) but was better than radiation alone or chemotherapy alone [37]. A systematic review of non-bilharzial SCC concluded RC is the gold standard; radiotherapy alone gives poor outcomes, while multimodality approaches (pre-op RT + RC, or RC + systemic therapy) may help, but evidence is low-level and heterogeneous [36].
Variant histology (including SCC) shows worse survival after bladder-preserving RT than pure urothelial carcinoma, highlighting more aggressive biology and the need for intensification or surgery when possible [55].
Indications of chemoradiation in Bladder SCC:
Regimens generally mirror urothelial protocols: conventional or hypofractionated pelvic RT (≈55–64 Gy) with concurrent cisplatin, gemcitabine, or 5-FU/mitomycin C as radiosensitizer [56]. Given chemotherapy resistance concerns in SCC, systemic control may still be suboptimal, and close surveillance or consideration of combined RC, where feasible, is important [36] [55].
Chemotherapy has limited proven benefit in pure bladder SCC and is not currently a standard curative modality outside of surgery-based approaches. Large NCDB analysis of 828 localized, muscle-invasive pure SCC (cT2–3N0M0) found radical cystectomy (RC) with or without “perioperative” chemotherapy had the best survival, while chemotherapy alone, radiation alone, and chemoradiation were all significantly worse (HR for death vs RC alone: chemo alone 2.43, chemoradiation 1.61). Addition of neoadjuvant or adjuvant chemotherapy to RC did not improve overall survival compared with RC alone (HR 1.33 for neoadjuvant + RC; 1.11 for adjuvant + RC, both NS) [37]. A systematic review of non-bilharzial SCC concluded there is little evidence that chemotherapy improves survival over RC and that SCC appears relatively chemotherapy-resistant [36].
Variant-histology NAC data show SCC is the least responsive: lower clinical-to-pathologic downstaging and significantly worse cancer-specific survival after NAC+RC vs pure urothelial carcinoma [41]. NCDB and institutional series of invasive SCC found no survival advantage to neoadjuvant chemotherapy before RC; downstaging may increase but OS is unchanged [70]. Cisplatin-based regimens (MVAC, GC) yield poor pCR and high recurrence in SCC compared with urothelial carcinoma [36] [70].
Prospective non-urothelial trial (including 8 SCC) showed ifosfamide–paclitaxel–cisplatin had activity (median survival 8.9 months; 2 complete remissions among SCC) but numbers are very small [36]. Recent institutional data in metastatic SCC using gemcitabine/platinum or taxane/platinum show modest responses with short median PFS (~3–5 months) and universal progression [71].
Platinum regimens (mainly cisplatin-based) are standard for urothelial MIBC, but bladder SCC/marked squamous differentiation responds less well and derives smaller survival benefit. Direct data for pure bladder SCC are extremely limited; most studies pool urothelial carcinoma with squamous differentiation (UCSD) or other variants. In a small neoadjuvant series, UCSD showed no pathologic complete responses to cisplatin-based NAC vs 34.5% in pure UC, with much poorer DFS and OS, indicating relative cisplatin resistance [71]. A large Japanese NAC cohort found squamous differentiation carried a worse prognosis, though some such tumors still benefited from cisplatin-based NAC, underscoring biological heterogeneity [72]. In metastatic disease treated with gemcitabine–platinum, patients with variant histology (most commonly squamous differentiation) had similar response rates but shorter PFS and OS vs pure UC [73].
For bladder SCC, neither neoadjuvant nor adjuvant chemotherapy has proven a survival advantage over surgery alone; evidence does not clearly favor one sequence over the other. NCDB study of 828 localized pure SCC (T2–3N0M0) found radical cystectomy (RC) alone, RC+neoadjuvant (NAC), and RC+adjuvant (AC) chemotherapy had similar overall survival; perioperative chemotherapy (NAC or AC) did not improve outcomes versus RC alone [37]. Another NCDB analysis in 671 SCC patients showed no survival benefit for NAC+RC vs RC alone (HR 1.17; OS curves overlapping) [47]. Multi-institutional variant-histology series (283 SCC) reported worse cancer-specific survival and less downstaging after NAC than in pure urothelial carcinoma, supporting relative chemoresistance [41]. A systematic review of NAC in variant histologies concluded SCC is less sensitive to NAC; three NCDB-based SCC studies all showed no significant OS gain with NAC+RC vs RC alone [70].
SCC-focused datasets rarely distinguish NAC from AC in detail; the large comparative-effectiveness SCC study reports RC+NAC and RC+AC both comparable to RC alone, without a clear difference between NAC and AC [37]. Variant-histology reviews describe possible but unproven benefit of perioperative chemotherapy in SCC; no data demonstrate AC superior to NAC in SCC [70].
NCDB cohort (671 pure SCC) found no overall survival advantage from neoadjuvant chemotherapy (NAC) before cystectomy (HR 1.17; p=0.46) [47]. A larger SEER/RC series of 1018 SCC patients showed no cancer-specific or overall survival benefit from perioperative chemotherapy in node-negative (T2–4aN0M0) disease; benefit appeared only in T4b/N+/M+ subsets [40]. Comparative-effectiveness analysis of 828 pure SCC reported RC alone, RC+NAC, and RC+adjuvant chemotherapy had similar OS, while chemo-only or chemoradiation were inferior to RC-based approaches [37].
Multi-institutional variant-histology series showed SCC had the lowest effect of NAC, with markedly worse cancer-specific survival and significantly less clinical-to-pathologic downstaging than urothelial carcinoma (UC) [41]. In another cohort, urothelial tumors with squamous differentiation had 0% pathologic complete response to cisplatin-based NAC vs 34.5% in pure UC, and much worse DFS/OS [74]. A Western pure SCC series reported no objective responses in 4 patients given NAC and limited benefit from adjuvant chemotherapy [75].
Most SCC data are retrospective registry or small single-center series, often mixing pure and mixed SCC, lacking regimen detail, and with selection bias [36] [41]. A systematic review concluded there is little evidence supporting chemotherapy in non-bilharzial SCC, and its efficacy relative to cystectomy is unknown [36].
Immune checkpoint inhibitors are promising for bladder squamous cell carcinoma, but evidence is indirect and based mainly on biomarker and small-cohort data. Pure and mixed squamous bladder cancers frequently express PD-L1 at levels comparable to conventional urothelial carcinoma, and up to ~20% of pure SCC would meet FDA CPS≥10 eligibility for pembrolizumab first-line use [76]. Quantitative immune profiling shows many squamous tumors are “hot”, with high CD8⁺/perforin⁺ T-cell and macrophage infiltration, especially when PD-L1 is high, suggesting potential sensitivity to ICIs[77].
Neoadjuvant pembrolizumab trials in MIBC that included variant histologies reported modest activity in SCC variants, with response rates similar across non-urothelial types but based on very small numbers. Retrospective series of advanced non-urothelial BC (including SCC and UC with squamous differentiation) show overall response rates ~22–26% to PD-1/PD-L1 inhibitors, comparable across variants, but numbers for pure SCC are limited and heterogeneous [78]. A case of UC with squamous differentiation treated with nivolumab showed an excellent metastatic response, supporting activity in squamous-containing tumors[76].
Across metastatic bladder cancer, PD-1/PD-L1 inhibitors achieve response in ~20–30% and improve survival after platinum, with avelumab maintenance now standard in responders [79] [80]. High TMB and inflamed microenvironment—features seen in many bladder cancers—correlate with ICI response in large meta-analyses [81].
Bladder SCC (pure and with squamous differentiation) frequently expresses PD-L1 and often shows an inflamed tumor microenvironment, providing a strong biologic rationale for PD-1/PD-L1 blockade. Direct outcome data on ICI response in this histology are limited to small series and extrapolation from broader urothelial cohorts.
In non-schistosomal bladder SCC/UC with squamous differentiation, PD-L1 positivity on tumor and/or immune cells ranges from ~5–60% depending on antibody and scoring system, with no major difference between pure SCC and mixed UC/SCC. Using FDA-style CPS scoring, up to ~20% of pure SCC would meet CPS ≥10 eligibility for first-line pembrolizumab, similar to conventional urothelial carcinoma[76].
A focused review of schistosomal and non-schistosomal SCC reports PD-L1 positivity in ~65% of primary pure SCC in one cohort, frequently associated with basal/squamous-like molecular subtype and CDKN2A alterations[82].
Quantitative profiling of 68 pure SCC and 46 mixed tumors shows many are “hot” tumors: high intratumoral CD8⁺/perforin⁺ T cells and CD68⁺/CD163⁺ macrophages; perforin⁺ CD8⁺ density predicts better overall survival. High PD-L1 (CPS ≥10) strongly associates with higher CD3⁺, CD8⁺, and CD163⁺ densities and proliferative (Ki-67-high) tumor cells, defining a subgroup that “might pose a promising subgroup for clinically successful ICI therapy”[77].
Real-world immunotherapy in non-urothelial bladder cancer: activity is present but generally lower than in urothelial carcinoma, with limited data. The most direct real-world series is PEMBROBLAD, a 24-center retrospective cohort of 139 patients with advanced bladder cancer carrying histological variants (UC-V) or pure non-urothelial cancers (NUC) treated with checkpoint inhibitors after platinum failure[83].
Most patients received pembrolizumab; serious treatment-related AEs occurred in 9.3%, with 5% discontinuation, similar to pivotal mUC trials[83].
A systematic review of neoadjuvant/adjuvant ICI in MIBC notes preliminary activity of pembrolizumab in non-urothelial variants, including squamous and lymphoepithelioma-like, and summarizes two retrospective series in advanced non-urothelial BC reporting ORR 22–26% to PD-1/PD-L1 inhibitors across mixed variants[78].
A broader narrative review dedicated to non-urothelial and variant bladder cancers concludes that accumulating case series and small cohorts “suggest that immune checkpoint inhibition might have a role,” but emphasizes the lack of robust, prospective histology-specific data and the need for dedicated trials[84].
Most interventional work in bladder SCC occurs either via the dedicated AURORA (atezolizumab) trial or by including SCC within broader “non-urothelial/variant” or all-comers bladder cancer immunotherapy trials. First prospective ICI trial dedicated to advanced urinary tract SCC (UTSCC); allows mixed histology if no urothelial component. Primary endpoint ORR (Simon 2-stage). Translational work includes PD-L1 and immune biomarkers
[85]. Stage-1 analysis showed ORR 15.8% (3/19) and trial was closed for insufficient activity as monotherapy[86].
A recent narrative review on non-urothelial bladder cancers summarizes that SCC and other variants are commonly excluded from phase III urothelial trials, but some perioperative and metastatic ICI trials now allow limited numbers of non-urothelial/variant histologies (squamous, adenocarcinoma, small cell)[87]. A systematic analysis of 2899 global bladder cancer trials shows that PD-1/PD-L1 immunotherapy dominates the modern trial landscape, but histology-specific breakdown (e.g., pure SCC) is rarely specified; non-urothelial tumors are a small fraction of enrolled patients[88].
A systematic review of SCC of the bladder up to 2016 found no immunotherapy trials specifically in SCC, and recommended explicitly including SCC in future ICI protocols, given PD-1/PD-L1 success in urothelial cancer and other squamous tumors
[36]. More recent SCC-focused reviews reiterate that most ongoing ICI work still extrapolates from urothelial carcinoma, and that prospective SCC-only trials remain largely absent aside from AURORA[26, 89, 90].
Large neoadjuvant and perioperative ICI trials (e.g., durvalumab+cisplatin/gemcitabine in NIAGARA; various nivolumab, pembrolizumab, atezolizumab neoadjuvant trials) form the bulk of current immunotherapy development in muscle-invasive bladder cancer, but either exclude non-urothelial histologies or include only very small variant cohorts without SCC-specific reporting[91, 92].
For muscle‑invasive bladder squamous cell carcinoma (SCC), radical cystectomy is the mainstay; evidence for chemo‑ or immunotherapy is limited and extrapolated from urothelial cancer.
Multiple reviews identify radical cystectomy (RC) with pelvic lymph node dissection as the “gold-standard” for bladder SCC, including muscle-invasive disease[36, 93].
A 2020 NCDB study of 828 patients with clinical T2–3N0M0 pure SCC compared RC ± perioperative chemotherapy with chemotherapy alone, radiation alone, or chemoradiation. RC (with or without chemotherapy) had significantly better overall survival; chemo alone HR 2.43, RT alone HR 4.78, chemoradiation HR 1.61 vs RC[37].
Case-based data suggest partial cystectomy can control carefully selected, solitary muscle-invasive SCC with negative margins, but requires lifelong cystoscopic follow-up due to high late-recurrence risk[93].
The large SCC systematic review found little evidence that cisplatin-based chemotherapy improves outcomes in non-bilharzial SCC, and its benefit relative to RC is unknown. Preoperative radiotherapy plus RC may improve survival versus RC alone in historical series, whereas definitive RT alone is associated with poor outcomes in SCC[36].
Contemporary MIBC guidelines and perioperative reviews that shape current practice are almost entirely based on urothelial carcinoma; they acknowledge that variant histologies (including SCC) often respond less well and are under-represented in trials[94, 95].
The SCC systematic review states that immunotherapy for bladder SCC “has yet to be investigated” in dedicated trials[36].
Current ICI use is extrapolated from urothelial carcinoma reviews and guidelines, not SCC-specific data[96].
For metastatic bladder SCC, treatment is palliative and largely extrapolated from metastatic urothelial cancer; cisplatin‑based chemotherapy remains standard, with immunotherapy used empirically in selected patients.
A recent focused review on metastatic SCC of the bladder highlights very poor outcomes and limited responsiveness to systemic therapy and radiotherapy [90].
Retrospective and small prospective data show that cisplatin-based combinations (MVAC, CMB, gemcitabine/cisplatin) and 5-FU/mitomycin C with radiotherapy can produce partial responses, but response rates are lower than in conventional urothelial carcinoma, and long-term survivors are rare [36, 90].
One prospective non-urothelial study (including 8 pure SCC) found that ifosfamide–paclitaxel–cisplatin was active, with a median OS of 8.9 months and 2 complete remissions among SCC cases [36].
For metastatic/locally advanced SCC, radiotherapy alone is generally palliative, but combinations such as 5-FU/mitomycin C + RT or cisplatin-RT yielded occasional durable responses in small series [90].
In oligometastatic bladder cancer more broadly, multidisciplinary groups support metastasis-directed radiotherapy plus systemic therapy for carefully selected patients, though not SCC-specific [97].
The systematic SCC review states that immunotherapy “has yet to be investigated” specifically for bladder SCC; any ICI use is extrapolated from urothelial data [36].
Meta-analyses and reviews in advanced bladder cancer show overall-survival benefit and better tolerability of ICIs vs chemotherapy in unselected advanced bladder carcinoma, supporting their use after or instead of chemotherapy in appropriate patients [98].
(if fit): cisplatin‑based combination (e.g., GC or MVAC), acknowledging modest and uncertain benefit in SCC.
carboplatin‑gemcitabine or PD‑1/PD‑L1 inhibitor (especially PD‑L1–positive), with palliative intent.
PD‑1/PD‑L1 inhibitor; consider avelumab‑style maintenance if disease control on platinum, though SCC evidence is absent.
Management should be individualized in a multidisciplinary setting, with clinical‑trial enrollment strongly encouraged whenever available.
Bilharzial and non‑bilharzial bladder SCC share a surgical standard (radical cystectomy), but differ in epidemiology, biology, and the extent of radiotherapy integration into treatment.
Bilharzial SCC (B-SCC) arises in Schistosoma haematobium–endemic regions, often in the 5th decade, predominantly male, usually well- to moderately differentiated but muscle-invasive at diagnosis[26, 36].
Non-bilharzial SCC (NB-SCC) is rare in Western and many Asian settings (<5% of bladder cancers), presents later (6th–7th decade), and is more often poorly differentiated, bulky T3 tumors linked to chronic irritation (catheters, stones, infections)[26, 36, 99].
Both subtypes have low distant metastasis rates, with death mainly from uncontrolled pelvic disease rather than systemic spread[99, 100].
a.Local Therapy (Non-metastatic)
Across both B-SCC and NB-SCC, radical cystectomy (RC + pelvic lymphadenectomy) is the accepted “gold standard” for resectable, non-metastatic disease, offering substantially better survival than TURBT, radiotherapy (RT) alone, or chemotherapy alone
[36, 99]. NB-SCC series and registry analyses confirm surgery-based approaches provide the longest overall survival, with RT-only strategies associated with poor outcomes[36, 44, 99, 100].
b.Role of Radiotherapy and Chemoradiation
In bilharzial SCC, preoperative radiotherapy followed by radical cystectomy may enhance long-term survival, and this approach has been routinely used in some endemic areas. In contrast, evidence for non-bilharzial SCC is limited and mainly based on extrapolation[36, 99, 101].
Definitive radiotherapy or chemoradiation typically targets patients who are not suitable for surgery, providing occasional local control but is generally associated with a poor prognosis[99, 100].
In bilharzial SCC, adjuvant radiotherapy is more frequently employed to lower pelvic recurrence, whereas in non-bilharzial cases, it might be considered for patients with high-risk features, though a clear survival benefit remains unproven[36, 99, 101].
c.Systemic Therapy & Immunotherapy
For both B-SCC and NB-SCC, evidence for chemotherapy is weak; cisplatin-based regimens show limited and inconsistent benefit, mainly in small NB-SCC series or mixed SCC cohorts[36, 99, 100].
A systematic SCC review notes that immunotherapy has not been specifically studied in either B-SCC or NB-SCC; any use is extrapolated from urothelial carcinoma[36].
In bilharzial-endemic settings, patients are younger but often present with extensive local disease; RC is frequently combined with neoadjuvant or adjuvant RT in high-volume centers, informed by historical B-SCC data[36, 102].
In non-bilharzial disease, guidelines and series emphasize RC alone as standard, with RT or chemoradiation reserved for non-surgical candidates or within multimodal protocols whose benefit is unproven[36, 99, 100].
Elderly or frail patients with bladder SCC face major therapeutic challenges because standard curative options (radical cystectomy and cisplatin‑based therapy) are often poorly tolerated; care must be individualized using frailty‑based, not age‑based, decisions.
Under-representation and undertreatment: Older bladder cancer patients (median diagnosis ~73 years) are frequently excluded from trials and receive less curative treatment, leading to worse disease-specific outcomes than younger patients [103–106].
High comorbidity and frailty: Multimorbidity, reduced organ function, and geriatric syndromes increase surgical and chemotherapy toxicity risk, especially in those >70–80 years [103–106].
Aggressive SCC biology with limited systemic options: SCC is more chemoresistant than urothelial carcinoma, with poor response to neoadjuvant chemotherapy and no proven survival benefit from NAC before cystectomy [89, 90].
Metastatic SCC responds poorly to chemotherapy and radiotherapy, with median survivals often around 1 year or less [90].
Radical cystectomy: Perioperative mortality and complications rise sharply with age, yet selected fit elderly can achieve meaningful survival; age alone should not be an exclusion, but frailty strongly predicts complications and death[103, 106].
Urinary diversion: Non-continent diversion (e.g., ileal conduit) reduces operative time and complications and is usually preferred in frail elderly; orthotopic neobladder is reserved for highly selected, robust patients[103].
Radiotherapy/chemoradiation: Many older/frail patients are unfit for full-course chemoradiation; ultra-hypofractionated or short palliative RT regimens can control hematuria and pain with acceptable toxicity[103, 105, 107, 108].
Systemic therapy & immunotherapy: Cisplatin eligibility is often limited by renal and performance status; carboplatin-based or non-platinum regimens are less effective. Checkpoint inhibitors show similar efficacy and tolerability in older vs younger metastatic bladder cancer patients and may be preferable in cisplatin-unfit patients, though SCC-specific data are sparse[90, 103, 107].
Use comprehensive geriatric assessment/frailty tools (e.g., G8, GA) to guide treatment intensity, not chronological age. Discuss goals of care and quality of life early; integrate palliative care from diagnosis of metastatic SCC or when curative therapy is not feasible[103, 105, 107, 108].
For advanced bladder SCC, palliation focuses on local symptom control (especially bleeding and pain) with radiotherapy and careful use of systemic therapy, alongside early, specialist palliative care.
Advanced SCC behaves similarly to other aggressive bladder cancers, with death often from uncontrolled pelvic disease rather than distant spread [36, 90].
Palliative bladder RT provides high short-term relief of haematuria (~70–75%), pain, and irritative urinary symptoms, with schedules ranging from single 8 Gy to 21 Gy/3 fx or 30–36 Gy in 5–6 fx [109].
Meta-analysis shows higher RT dose does not improve the initial haematuria/frequency response, though it may prolong haematuria control at the cost of more toxicity [110].
Narrative and recent reviews emphasize hypofractionated RT (e.g., 21 Gy/3 fx, weekly 6 × 6 Gy) as a practical standard for frail, symptomatic patients [109].
Single 8 Gy or short hypofractionated course gives rapid, often durable control [109].
21 Gy/3 fx or 30–36 Gy in 5–10 fx improves pain, dysuria, frequency [109].
RT effective for bone pain, spinal cord compression, brain mets as in other cancers [109].
Metastatic bladder SCC responds poorly to standard chemotherapy and RT; survival after metastasis is often only a few months in small series [36, 90].
For metastatic bladder cancer overall, palliative platinum-based chemotherapy (gemcitabine–cisplatin or –carboplatin) improves median OS to ~9–14 months versus <1 year without treatment, but with substantial toxicity [111, 112].
Real-world data show sequential chemotherapy then immunotherapy yields mOS ~19 months, and immunotherapy alone is comparable to chemotherapy as first- or second-line palliative therapy [112].
Checkpoint inhibitors (e.g., pembrolizumab, atezolizumab, avelumab) are standard palliative options in metastatic bladder cancer and may be particularly valuable for cisplatinineligible patients, though SCC-specific benefit remains unproven [36]. Emerging data and case reports support combining RT with immune checkpoint inhibitors for symptomatic control and possiblesystemic benefit (abscopal-like effects) [113, 114].
Only ~4% of US patients with advanced bladder cancer receive specialist palliative care, despite clear benefits [115, 116].
In advanced/metastatic bladder cancer, early palliative care alongside oncologic treatment improves quality of life, reduces fatigue and psychological distress, and increases family satisfaction over 6 months [117].
General oncology literature confirms that structured symptom assessment and palliative care optimize control of pain, breathlessness, nausea/vomiting, and fatigue and can improve treatment adherence and sometimes survival [118, 119].
Symptom control and patient‑centred, early palliative care are central to preserving quality of life in bladder SCC, which shares most QoL issues with other bladder cancer subtypes.
Large QoL cohorts in bladder cancer (all histologies) show that Global HRQoL is substantially worse than in the general population and other pelvic cancers, driven more by age/comorbidities than stage or treatment type [120]. Most patients report problems in ≥1 domain (pain, mobility, self-care, usual activities, anxiety/depression) [120].
During systemic therapy, the most problematic symptoms correlating with worse QoL are anxiety, sadness, fatigue, poor concentration, and feeling discouraged, more than urinary symptoms alone [120].
Common treatment-related symptoms include frequent urination, pain, fatigue, dry mouth, limb swelling, and hospitalizations; over half of patients fail to complete planned chemo/immunotherapy, underscoring the need for better supportive care [121].
Physical: Urinary/bowel symptoms, pain, fatigue, sexual dysfunction[120–122].
Psychological: Anxiety, depression, fear of death/recurrence, body-image concerns[121, 123, 124].
Social/practical: Financial toxicity, reduced social life, dependence on caregivers[120, 123].
Information/support: High rates of unmet needs for symptom management, treatment information, and emotional support[125].
Current major bladder cancer guidelines (EAU, NCCN, SITC) recognize pure squamous cell carcinoma (SCC) of the bladder as high-risk and biologically distinct, but evidence is weak and most recommendations are extrapolated from urothelial carcinoma. There are no level I, SCC-specific trials, and several reviews explicitly state that formal, high-evidence guidelines for SCC are lacking[26, 36, 89].
| Guideline/source | Key statements relevant to SCC | Reference |
|---|---|---|
|
EAU bladder cancer guidelines |
Classify any variant histology, including SCC, as high‑risk bladder cancer; recommend upfront radical cystectomy (RC) + lymph‑node dissection for non‑metastatic SCC; no neoadjuvant chemo for pure SCC |
[26, 90] |
|
NCCN bladder cancer guidelines |
Provide specific sections for nonurothelial histologies but base systemic therapy on urothelial data; for non‑muscle‑invasive T1 SCC, data favor early RC over BCG. |
[90, 129] |
|
Recent SCC reviews |
Conclude there is insufficient evidence to give definitive treatment algorithms; RC is de facto standard, multimodal approaches and immunotherapy still investigational. |
[26, 36, 89, 90] |
Multiple population-based and institutional series show radical cystectomy provides the best survival for non-metastatic SCC compared with radiotherapy, chemoradiation, or observation [44].
EAUaligned reviews and NCCNbased discussions therefore recommend:
Upfront radical cystectomy with pelvic lymph-node dissection for non-metastatic pure SCC (including many pT1 cases), rather than bladder-preservation or BCG [26, 90].
For T1 SCC and schistosomal-associated SCC, early RC improves cancer-specific survival compared with conservative strategies [90].
Large registry and NCDB analyses show no overall-survival benefit from neoadjuvant chemotherapy in localized, muscle-invasive SCC [37, 90].
Adding perioperative chemotherapy (neo- or adjuvant) to RC does not clearly improve survival versus RC alone, though numbers are small and retrospective [37, 90].
Radiotherapy alone, or chemoradiation without surgery, is consistently associated with worse survival than RC in non-metastatic SCC [37, 43, 44].
For schistosomal SCC, some regional practice and older data support neoadjuvant RT before cystectomy, but guidelines note insufficient high-quality evidence to recommend routine adjuvant RT or chemotherapy [26, 36].
EAU guidance and contemporary reviews:
For metastatic SCC, there is no standard systemic regimen; outcomes with chemo or RT are poor, and treatment should be individualized [90].
Systemic therapy generally follows urothelial cancer paradigms (platinum-based chemotherapy, then immune checkpoint inhibitors), but SCC-specific efficacy is unproven, and evidence is limited to small series and case reports [89, 90].
The role of radical cystectomy for bladder adenocarcinomas has been found to be the cornerstone of reducing the overall mortality[130].
External beam radiotherapy (EBRT) alone is not the preferred treatment option for bladder cancer patients, as it is considered inferior to radical cystectomy. However, the addition of chemotherapy enhances outcomes, and chemoradiation can be used as a radical treatment alternative for patients with adenocarcinoma who are either unfit or unwilling to undergo cystectomy[130].
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