Early-Invasive Urothelial Bladder Carcinoma and Instillation Treatment of Non-muscle-Invasive Bladder Cancer
Stage T1 non-muscle-invasive bladder cancer (NMIBC) is a very special subentity of urothelial bladder carcinoma showing progression in up to 50% within 5 years after first diagnosis. This chapter recalls recommended diagnosis and treatment of early-invasive bladder cancer in special and conservative adjuvant instillation treatment of NMIBC in general. In the end, indications of immediate and early cystectomy of NMIBC are discussed.
KeywordsEarly-invasive bladder cancer Stage T1 Prognosis Intravesical chemotherapy Bacillus Calmette-Guérin Early cystectomy
Early-invasive urothelial bladder cancer is a non-muscle-invasive bladder tumor at stage T1 with various clinical outcomes. While one third shows never recurrence, another third of patients recurs under progression and must be cystectomied to prevent death of disease that occurs at the level of stage T2 disease (Shahin et al. 2003).
Diagnosis of Stage T1 Bladder Cancer
Diagnostic assessment of stage T1 bladder cancer includes several steps that require increasing invasiveness and result in the histopathological verification of the urothelial carcinoma. The clinical suspicion has to lead to further investigation, as screening for bladder cancer is not recommended (Krogsboll et al. 2015).
Hematuria is the leading symptom in patients with bladder cancer, with the majority of the patients presenting with asymptomatic macroscopic hematuria (Kamat et al. 2016). Only 2–4% of the patients presenting with mircoscopic hematuria have bladder cancer (Sharp et al. 2013). Nonetheless, recurring microhematuria in combination with one of the known risk factors (past or current smoking, male sex, exposure to chemicals, etc.) demands further investigation (Sharp et al. 2013). Patients without hematuria suffer from a delayed diagnosis (Mansson et al. 1993). Other symptoms that may indicate towards bladder cancer are: urgency or dysuric symptoms.
Physical examination cannot reveal stage T1 bladder cancer (Babjuk et al. 2016), but it should be performed to reveal a potential hydronephrosis through flank pain. Papillary or solid stage T1 tumor in or near the ureteral orifice can cause a hydronephrosis.
Transabdominal ultrasound is recommended to detect visible intraluminal tumors of the bladder (Babjuk et al. 2016). Furthermore, differential diagnoses of hematuria like renal tumor, renal stone, or a hydronephrosis, as a result of obstruction by urolithiasis or urothelial carcinoma, can be detected.
Radiologic imaging should be used in selected cases and is not recommended in routine diagnosis of bladder cancer (Babjuk et al. 2016). Multidetector-row CT (MDCT) has a sensitivity of 79%, specificity of 94% and accuracy of 91% and is not recommended for routine use in the detection of primary bladder cancer (Babjuk et al. 2016; Jinzaki et al. 2016). Intravenous urography (IVU) or computed tomography (CT) is able to detect papillary tumors of the upper urinary tract but not recommended due to the low incidence of findings (Babjuk et al. 2016; Goessl et al. 1997; Palou et al. 2005; Holmäng et al. 1998). The MDCT-scan of the abdomen has the highest sensitivity (93.5–95.8%), specificity (94.8–100%), and accuracy (94.2–99.6%) in detection of upper urinary tract urothelial carcinoma (UTUC) and thus should be the first option (Babjuk et al. 2016; Jinzaki et al. 2016). The IVU is inferior concerning sensitivity (75.0–80.4%), specificity (81.0–86.0%), and accuracy (80.8–84.9%) (Jinzaki et al. 2016). The MDCT can show smaller masses, is not impaired by intraabdominal gas, and can distinguish tumors from blood clots or stones (Jinzaki et al. 2016). Further information that can be acquired through MDCT is lymph node status and intrarenal tumors. Thus the IVU is recommended as an alternative if CT is not available (Babjuk et al. 2016; Nolte-Ernsting and Cowan 2006). MDCT and retrograde urography have similar sensitivity and specificity with MDCT being a not invasive procedure (Razavi et al. 2012). In case of contrast allergy, pregnancy or in young patients MRI of the abdomen can be performed but has several limitations like a poorer resolution, various artefacts, and large studies comparing MRI to MDCT are missing (Vikram et al. 2009).
Imaging of the upper urinary tract should be considered in case of bladder tumor in the trigone, which has an incidence of 7.5% concomitant UTUC (Palou et al. 2005) and in follow-up of multiple and high risk tumors (Millán-Rodríguez et al. 2000).
Examination of voided urine or bladder-washing specimens is performed to detect exfoliated tumor cells. The quality of urinary cytology depends on several parameters. The sensitivity depends on tumor grade, as the reported sensitivity for high grade or G3 tumors is 84%, for low grade or G1 tumors is 16% and for CIS is 60%, respectively (Yafi et al. 2015; Casey et al. 2015). Furthermore, evaluation of urinary cytology has high interobserver variability but specificity can raise up to 90% in experienced observers (Babjuk et al. 2016; Raitanen et al. 2002). Thus cytology can be considered in patients with CIS, G3, or high grade tumors in addition to cystoscopic evaluation. Negative urinary cytology does not exclude bladder cancer, whereas an urothelial carcinoma anywhere in the urothelial tract can result in a positive urinary cytology.
Voided first morning urine should not be used due to cytolysis because of the long contact to toxic substances within the urine (Layfield et al. 2004). The urine specimen should be collected 3–4 h after the last voiding and processed as soon as possible (Layfield et al. 2004). Urine washings with sterile isotonic solution concomitant to cystoscopy can also be used (Layfield et al. 2004). Intravesical infections, stones, intravesical instillation therapy, and low cell count can affect the quality of evaluation (Babjuk et al. 2016).
Urinary Marker Tests
Sensitivities and specificities of the different urinary tests (adapted from (Babjuk et al. 2016))
Sensitivity for high grade tumors (%)
Nuclear matrix protein (NMP) 22
To date, none of the urinary marker tests is recommended in the routine diagnosis of (primary) bladder cancer and none can reduce follow-up cystoscopies (Babjuk et al. 2016). As outlined above, there is also no application of these tests in bladder cancer screening. Few indications remain – especially for low or intermediate risk tumors – where urinary tests may give additional information to the golden standard cystoscopy. As the early-invasive T1 bladder cancer always displays a high risk tumor, follow-up should always include frequent cystoscopy and cytology and urinary marker tests are irrelevant in this situation (Babjuk et al. 2016).
Despite the improvement in urine tests or imaging, cystoscopy remains the golden standard in the diagnosis of bladder cancer. Cystoscopy is regularly performed in an outpatient setting. Flexible instruments are recommended for the examination in men (Babjuk et al. 2016; Aaronson et al. 2009). In symptoms suggestive for bladder cancer, the visual examination of the bladder through cystoscopy can reveal papillary or solid lesions that have to be followed by transurethral resection of the bladder (TUR-B) and histological evaluation. Cystoscopy should be performed schematically and subtle to make every area visible. If concomitant Cis is suspected – usually displayed by a flat and red lesion – cystoscopy and histological evaluation should be complemented by urinary cytology and multiple biopsies (Kurth et al. 1995).
Treatment of Stage T1 Bladder Cancer
After detection of papillary, solid or flat lesions via cystoscopy, transurethral resection of the bladder (TURB) always is the first step in bladder cancer treatment. It should clarify the diagnosis and macroscopically remove the complete tumor burden (Babjuk et al. 2016). There are different strategies to resect bladder tumors: small masses should be cut out en bloc, while larger ones are resected in fractions separated in the exophytic part of the tumor, the detrusor muscle, and the tumor surrounding areas. Random biopsies should be taken in cases of suspect cytology without macroscopic tumors from the four bladder walls, the trigone, and dome of the bladder to assess macroscopically hardly detectable carcinoma in situ (CIS). In our days, random biopsies were replaced by photodynamic diagnosis (PDD) that could show an increase of 23% in detection of CIS (Kausch et al. 2010). For exophytic non-muscle-invasive bladder cancer (NMIBC) PDD results in a statistically significantly better recurrence-free survival over all NMIBC risk groups and due to decrease of hospitalization in a reduction of tumor-related costs (Otto et al. 2009).
High rates of residual tumor burden in stage T1 bladder cancer of up to 65% and the danger of under-staging in initial TURB of 20% demonstrate the need of second resection in this patient group 2–6 weeks after initial TURB (Patschan et al. 2017; Hautmann et al. 2009). Due to high risk of recurrence and progression in early-invasive bladder cancer in every case of stage T1 bladder cancer, further treatment is essential.
Further Treatment Options
The guidelines of the leading international associations of urology recommend at least some sort of instillation therapy in every case of NMIBC. This applies especially for stage T1 bladder cancer, where at least long-term immunotherapy by intravesical Bacillus Calmette-Guérin (BCG) treatment should be performed and in some circumstances even early cystectomy is demanded, e.g., in high-grade stage T1 bladder cancer with associated CIS (Denzinger et al. 2008). Today European Organization for Research and Treatment of Cancer (EORTC) risk factors are decisive for prognostification of NMIBC.
EORTC risk calculator for disease recurrence and progression. (Adapted from Sylvester et al. 2006)
Number of tumors
Prior recurrence rate
Probability of disease recurrence and progression according to EORTC score. (Adapted from Babjuk et al. 2016)
Probability of recurrence at 1 year (%)
Probability of recurrence at 5 years (%)
Probability of progression at 1 year
Probability of progression at 5 years (%)
0.2 (0–0.7) %
1 (0.4–1.6) %
5 (4–7) %
Considering grading, there is evidence that well-differentiated G1 tumors do not exist in stage T1 bladder cancer (Mikulowski and Hellsten 2005; Otto et al. 2011). Furthermore, in early-invasive bladder cancer at stage T1, the WHO1973 classification, that discriminates G1, G2, and G3 tumors is more suitable in prognosis prediction than the two-armed WHO2004/2016 classification that discriminates between low-grade and high-grade tumors (Otto et al. 2011; May et al. 2010).
Interobserver-variability leads to 40–50% nonconforming results regarding staging Ta vs. T1 and grading (May et al. 2010; Murphy et al. 2002; Bol et al. 2003; van Rhijn et al. 2010a). The reproducibility of the WHO2004/2016 classification is not superior to the WHO1973 classification (May et al. 2010; Rhijn et al. 2010b; Mangrud et al. 2014).
Indeed EORTC risk factors remain the only established parameters in supporting the treatment decision of NMIBC. Whether intravesical chemotherapy or immunotherapy should take place depend on the probability of recurrence or progression. Where recurrence is the foremost risk of patients, intravesical chemotherapy is recommended. Patients with low risk of recurrence only demand an immediate instillation of chemotherapy, which reduces the 2-year recurrence rate statistically significant (Hinotsu et al. 1999). Further instillation treatment is not suitable in these cases.
For patients with intermediate or high risk of recurrence, adjuvant intravesical chemotherapy is recommended. Advantage of chemotherapy with foremost mitomycin C (MMC) instillations was proven for tumor recurrence but not progression in initial and recurrent NMIBC (Huncharek et al. 2000; Huncharek et al. 2001). There is no clear recommendation concerning duration of intravesival chemotherapy, mostly continued for 1 year (Sylvester et al. 2008).
Especially for high risk NMIBC concerning recurrence and progression various meta-analyses could show that Bacillus Calmette-Guérin (BCG) is superior to MMC instillation treatment and other substances for intravesical treatment, e.g., epirubicin (Järvinen et al. 2009; Sylvester et al. 2010). Early-invasive bladder cancer should be treated by BCG instillations after reresection. Six weekly instillations should be mandatory, maintenance therapy is recommended (Böhle et al. 2003). Only these patients could show a statistically significant reduction of progression rate, but a distinct schedule could not be established yet. Indeed it should endure at least 1 year with up to 27 instillations up to 3 years (Lamm et al. 2000).
BCG Failure and Early Cystectomy
Immediate and early cystectomy describes radical cystectomy that is performed in patients with NMIBC either without instillation treatment or after NMIBC recurrence after failure of intravesical therapy. Based on the classification described above, stage T1 early-invasive bladder cancer always displays a high risk or even highest risk situation, where early cystectomy at least should be considered as an alternative to the bladder sparing approach by instillation therapy. Besides the clinical and pathological parameters indicative for early cystectomy, this is an individual decision that has to integrate patient’s age, physiological and mental status. It has to be considered that more than 30% of the T1 tumors are understaged in TURB (Patschan et al. 2017; Hautmann et al. 2009; Denzinger et al. 2008). Established indications for early cystectomy are: BCG-failure, T1G3 recurrence after BCG-treatment, refusal of BCG-treatment, and T1G3 tumor in diverticulum because of the lack of muscle layer (Babjuk et al. 2016; Golijanin et al. 2003).
Early cystectomy for early-invasive bladder cancer should always include lymph node dissection, due to understaging and about 9–18% lymph node metastases in radical cystectomy specimens of T1G3 bladder cancer (Kulkarni et al. 2010).
Besides these indications, morbidity and mortality of radical cystectomy have to be considered. Early cystectomy for stage T1 bladder cancer provides the best oncological safety, which is dearly bought by incontinence, sexual dysfunctions and a perioperative 90-day mortality of up to 9% (Aziz et al. 2014). The lack of strong suggestive parameters for immediate or early cystectomy in combination to the side effects results in an individual treatment decision in high risk or highest risk T1 bladder cancer.
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