Non-invasive diagnostic tests for bladder cancer: a review of the literature

Transitional cell carcinoma of the bladder is the second most common malignancy of the genitourinary tract. Cystoscopy and urine cytology are the traditional most used techniques for diagnosis and surveillance of superficial bladder cancer. Urine cytology is specific for diagnosis of bladder cancer but sensitivity results not high, particularly in low-grade disease. Voided urine can be easily obtained and therefore additional diagnostic urine tests would be ideal for screening or follow-up of transitional cell carcinoma. A number of studies have focused on the evaluation of urinary markers that hold promise as non-invasive adjuncts to conventional diagnostic or surveillance techniques. In this review we discuss several new urinary markers (test for bladder tumor antigen, NMP22, fibrin degradation products, telomerase, fluorescence in situ hybridization test, flow cytometry) and their role in detection and follow-up of bladder cancer. Most of these markers have higher sensitivity than urine cytology, but voided urine cytology has the highest specificity.     

Urine cytology. It is still the gold standard for screening?

Urine cytology remains the gold standard for bladder cancer screening. It is the test against which all others are compared when evaluating potential bladder tumor markers. The answer to whether urine cytology possess the optimal combination of sensitivity and specificity to retain consideration as the best screening device depends on the goals of the clinical practice. Urine cytology has excellent specificity with few false-positive cases. Its overall sensitivity is poor, but this drawback is explained for the most part by poor criteria for identifying well-differentiated, low-grade TCC. The natural history of such lesions is the occurrence of multiple superficial recurrences in 70% to 80% of patients, with only a minority (10% to 15%) progressing to muscle invasive or metastatic disease. Because patients with low-grade TCC are at low risk for progression, they are monitored primarily for the development of a subsequent tumor. One might argue that the detection of new low-grade lesions is of secondary importance to the early detection of disease progression. The performance characteristics of urine cytology in this regard are much improved. Urine cytology often results in the identification of high-grade malignant cells even before a cystoscopically distinguishable gross lesion is present. Routinely diagnosing grade I TCC may be clinically irrelevant. Ancillary techniques to improve the sensitivity of urine cytology have been insufficiently additive to have much clinical value. Several promising bladder tumor markers have been investigated as potential screening tools and are summarized in Table 3. BTA, nuclear matrix proteins, and fibrin/fibrinogen degradation products share lower specificities than urine cytology and may have high rates of false positivity. Telomerase is highly sensitive and highly specific but is not readily available as a point-of-service test. Hyaluronidase and hyaluronic acid are promising prognostic markers, but hyaluronidase does not detect grade I TCC. Early results from studies of this marker await verification. Combining some of these new markers may optimize their performance status, allowing the advantages of one test to correct the shortcomings of another. Likewise, their combination with urine cytology may prove beneficial. Although adding urine cytology has not increased the sensitivity of some point-of-service tests, few studies have addressed the effect on specificity. Until an obvious winner is declared in the race to find a bladder tumor marker, urine cytology will remain the gold standard screening method because of its comfortable familiarity.     

Urine markers for detection and surveillance of bladder cancer

ObjectivesBladder cancer detection and surveillance includes cystoscopy and cytology. Urinary cytology is limited by its low sensitivity for low-grade tumors. Urine markers have been extensively studied to help improve the diagnosis of bladder cancer with the goal of complementing or even replacing cystoscopy. However, to date, no marker has reached widespread use owing to insufficient evidence for clinical benefit.Material and methodsPubmed/Medline search was conducted to identify original articles, review articles, and editorials regarding urine-based biomarkers for screening, early detection, and surveillance of urothelial carcinoma of the bladder. Searches were limited to the English language, with a time frame of 2000 to 2013. Keywords included urothelial carcinoma, bladder cancer, transitional cell carcinoma, biomarker, marker, urine, diagnosis, recurrence, and progression.ResultsAlthough several urinary markers have shown higher sensitivity compared with cytology, it remains insufficient to replace cystoscopy. Moreover, most markers suffer from lower specificity than cytology. In this review, we aimed to summarize the current knowledge on commercially available and promising investigational urine markers for the detection and surveillance of bladder cancer.ConclusionsWell-designed protocols and prospective, controlled trials are needed to provide the basis to determine whether integration of biomarkers into clinical decision making will be of value for bladder cancer detection and screening in the future.     

Urine markers for detection and surveillance of non-muscle-invasive bladder cancer

Context

Bladder cancer diagnosis and surveillance includes cystoscopy and cytology. The limitation of urinary cytology is its low sensitivity for low-grade recurrences. As of now, six urine markers are commercially available to complement cystoscopy in the detection of bladder cancer. Several promising tests are under investigation.

Objective

In this nonsystematic review, we summarize the existing data on commercially available and promising investigational urine markers for the detection of bladder cancer.

Evidence acquisition

A PubMed search was carried out. We reviewed the recent literature on urine-based markers for bladder cancer. Articles were considered between 1997 and 2011. Older studies were included selectively if historically relevant.

Evidence synthesis

Although different studies have shown the superiority of urine markers regarding sensitivity for bladder cancer detection as compared with cytology, none of these tests is ideal and can be recommended unrestrictedly.

Conclusions

Urine markers have been studied extensively to help diagnose bladder cancer and thereby decrease the need for cystoscopy. However, no marker is available at present that can sufficiently warrant this. Several urinary markers have higher but still insufficient sensitivity compared with cytology. Urinary cytology or markers cannot safely replace cystoscopy in this setting. To identify an optimal marker that can delay cystoscopy in the diagnosis of bladder cancer, large prospective and standardized studies are needed.     

Molecular markers in bladder cancer: a critical appraisal

The diagnosis of both primary and recurrent bladder tumors currently relies upon the urine cytology and cystoscopy. Neither of these diagnostic tools is completely accurate. Prognostication of bladder cancer is largely based on pathologic tumor grade and stage. Over the past 2 decades, there is accumulating evidence that like many other cancers, bladder cancer, too, has a distinct molecular signature that separates it from other cancers and normal bladder tissue. Bladder tumors of different grades and stages even possess unique, and specific genotypic and phenotypic characteristics. Although recognition of several of these molecular alterations is possible by analyzing tumor tissue, urine, and serum samples, few if any of these "molecular markers" for bladder cancer are widely used in clinical practice. These markers include some that can be applied during the diagnostic work-up of symptoms (e.g., hematuria), those under surveillance for recurrence of superficial disease and forecasting long-term prognosis, or response to chemotherapy. In this review of molecular markers for bladder cancer, effectiveness of markers in each of these categories that are identifiable in the urine of patients with bladder cancer was examined. Many of the diagnostic markers appear to hold an advantage over urine cytology in terms of sensitivity, especially for the detection of low-grade superficial tumors. However, most markers tend to be less specific than cytology, yielding more false-positives. This result is more commonly observed in patients with concurrent bladder inflammation or other benign bladder conditions. Although there are several candidate markers for assessing prognosis or response to chemotherapy, studies of large patient populations are lacking. Further studies involving larger numbers of patients are required to determine their accuracy and widespread applicability in guiding treatment of bladder cancer.     

Urine based markers of urological malignancy

PURPOSE: A number of urine based markers have been and are being investigated for the diagnosis and prognostication of urological conditions. A majority of these markers have been evaluated in urological neoplasms, particularly bladder cancer. The diagnosis of bladder cancer currently relies on identifying malignant cells in the urine and subsequently visualizing the tumor on cystoscopy. This diagnosis is further confirmed by transurethral resection or biopsy. While urine cytology is specific, it is not sensitive, especially for detecting low grade disease. This characteristic has prompted the search for more accurate markers of bladder cancer. In this review we critically examine the results of studies evaluating various markers for bladder cancer. MATERIALS AND METHODS: The published literature on urine based markers for all urological diseases, particularly bladder cancer, was identified using a MEDLINE search and critically analyzed. The sensitivity, specificity, positive and negative predictive values of the various markers were compared. The benefit of using combined markers rather than a single marker was also analyzed from published reports. RESULTS: Most published literature on urine based markers for urological malignancies involve such markers for diagnosing and prognosticating bladder cancer. Hence, we focused mainly on urine based markers in bladder cancer. Most markers appear to have an advantage over urine cytology in terms of sensitivity, especially for detecting low grade, superficial tumors. However, most markers tend to be less specific than cytology, yielding more false-positive results. This scenario is more common in patients with concurrent bladder inflammation or other benign bladder conditions. However, there is reason to be optimistic about several new markers that appear to provide better specificity. Few urine based markers have been identified and investigated in other urological tumors. CONCLUSIONS: Detecting bladder cancer using diagnostic markers still presents a challenge. A number of new markers are currently available that appear to be significantly more accurate than cytology. However, further studies involving a larger number of patients are required to determine their accuracy and widespread applicability for diagnosing bladder cancer. Urine based markers do not appear to have a significant role in the diagnosis or prognosis of other urological malignancies, such as prostate, kidney or testicular cancer.     

Molecular markers for detection, surveillance and prognostication of bladder cancer

Many markers for the detection of bladder cancers have been tested and almost all urinary markers reported are better than cytology with regard to sensitivity, but they score lower in specificity. Currently molecular and genetic changes play an important role in the discovery of new molecular markers for detection, prognostication and surveillance. The purpose of this review is to highlight the most important urinary molecular biomarker developments that have been studied and reported recently. In the current review we have summarized the most recent and relevant published reports on molecular urinary markers. The results of this review show that the first generation of urinary markers did not add much to urinary cytology. The current generation of markers is better, but additional clinical trials are needed. Our knowledge of molecular pathways in bladder cancer is growing and new methods of marker development emerge, but the perfect marker is still to be found. Currently, there are not clinically usable molecular markers that can guide us in diagnosis or surveillance, nor guide us in lowering the frequency of urethrocystoscopy in bladder cancer.     

Comparison of the ImmunoCyt test and urinary cytology with other urine tests in the detection and surveillance of bladder cancer

Despite several new urine markers urinary cytology remains the gold standard for the non-invasive detection of bladder carcinoma. The use of monoclonal antibodies against tumor associated antigens offers a promising approach to improve urinary cytology. The aim of this study was to compare fluorescence immunocytology (ImmunoCyt/Ucyt+ test), alone and in combination with the conventional cytology, with other urine markers. Urine samples from 126 patients undergoing cystoscopy were included in the study. Among them, 42 patients had urothelial carcinoma, two dysplasia, two other malignancies, and 78 had no evidence of bladder cancer. Urine samples were taken before any manipulation. We used the ImmunoCyt test and Papanicolaou staining for conventional cytology. The ImmunoCyt slides were examined under a fluorescence microscope. Evaluations of the tests were blinded to clinical and pathological data and were carried out by three independent observers. The results of cytology and ImmunoCyt were compared with the BTAstat, NMP22, Lewis X, 486p3/12, and Urovision tests. The sensitivity for the ImmunoCyt test was 78.3% and for conventional cytology 84.6%. The combination of ImmunoCyt and cytology showed a sensitivity of 89.1%. The specificity was 73.8% for the ImmunoCyt alone, 80.0% for the cytology, and 72.5% for the combination of ImmunoCyt and cytology. Sensitivities for the other tests were 68.8% for (FISH), 66.6% (BTA-Stat), 68.8% (486p3/12), 95.5% (Lewis X), and 71.1% for (NMP22). Specificity was 89.1% for (FISH), 78.2% (BTA-Stat), 76.4% (486p3/12), 32.8% (Lewis X), and 65.5% for (NMP22). Urinary cytology can be improved by immunostaining with monoclonal antibodies against tumor-associated antibodies. The combination of ImmunoCyt with conventional cytology offers a superior sensitivity to other commercial tests. The ImmunoCyt test provides a useful supplement to urinary cytology in the diagnosis of bladder cancer.M.I. Toma, M.G. Friedrich contributed equally to this study     

Defining the role of NMP22 in bladder cancer surveillance

Despite advances in treatment and knowledge of its pathogenesis, urothelial carcinoma of the bladder remains a significant cause of morbidity and mortality. Experience with the natural course of bladder cancer has revealed that early diagnosis of primary and recurrent disease improves patient prognosis. In this regard, cystoscopy (usually in combination with urinary cytology) has long been regarded as the gold standard for the diagnosis and surveillance of bladder cancer. However, the disadvantages inherent to cystoscopy, including invasiveness and cost, have stimulated a search for alternative methods for detecting urothelial malignancy. The ideal alternative test would duplicate the high accuracy of cystoscopy for detecting bladder tumors while eschewing its invasiveness, attendant morbidity, and high cost. The vast majority of bladder cancers arise from the urothelium, which continually sheds cells as well as intracellular contents into the urine, thereby providing a potential source of cancer-specific markers. Voided cytology and urinalysis are established tests that have been the standard tools for detection of such substances. The last decade has seen the rise of a myriad of novel urine-based bladder tumor markers, including bladder tumor antigen, urinary bladder cancer antigen, fibronectin, telomerase, and nuclear matrix proteins (e.g., NMP22). The NMP22 assay in particular has been the subject of considerable study and has demonstrated some promise as a potential adjunct to cystoscopy and cytology. Through a critical review of the literature, we seek to define the role, if any, of NMP22 in the follow-up of patients with a previous history of urothelial carcinoma of the bladder.     

Significance of atypical urinary cytology in the evaluation of patients with end‐stage renal disease for kidney transplantation – a retrospective study

To determine what percentage of renal transplant candidates have atypical urinary cytology, what proportion have urothelial carcinoma and whether cystoscopy is necessary with atypical cytology. All end‐stage renal disease (ESRD) patients (703) presenting for renal transplantation at our institution were retrospectively reviewed. Individuals producing sufficient urine were screened with urine cytology and those with atypical cytology or risk factors for bladder cancer underwent cystoscopy. Four hundred and thirty patients had available urinary cytology and, of these, 151 (35%) had atypical cytology. Of patients with atypical cytology, three were identified to have urothelial carcinoma. However, three additional patients with urothelial carcinoma did not present with atypical cytology. In total, 6 of 703 (0.85%) patients had bladder cancer. All were treated with transurethral resection and eventually underwent renal transplant. One patient has had disease progression post‐transplant to distant metastases. This is the largest study to date evaluating the incidence of urothelial carcinoma in ESRD patients presenting for transplant workup. We found the incidence of bladder cancer to be higher than in the general Canadian population, however, most lesions were low grade. We found atypical cytology in transplant candidates to be a poor predictor for these low‐grade lesions and do not recommend routine cystoscopy for atypical cytology.     

Urinary markers in bladder cancer

OBJECTIVES: Many markers for the detection of bladder cancers have been tested. Almost all urinary markers reported are better than cytology with regard to sensitivity, but they score lower in specificity. The purpose of this review is to highlight the most important urinary biomarkers studied and reported recently. METHODS: Literature on bladder cancer markers has been reviewed regularly in the last few years. In the current review we have tried to summarise the most recent literature of urinary markers. RESULTS: The results of this review show that the first-generation urinary markers did not add much to urinary cytology. The current generation of markers is promising but larger clinical trails are needed. The future of marker development is bright with new techniques emerging, but the perfect marker is still to be found. CONCLUSION: Currently, no single marker can yet guide us in surveillance and lower the frequency of urethrocystoscopy.     

Routine follow-up cystoscopy in detection of recurrence in patients being monitored for bladder cancer

BACKGROUND AND AIMS: Cystoscopy and urine cytology are the standard tools for monitoring superficial bladder cancer. The sensitivity of cystoscopy is, however, limited to the tumours that can be visualised, and the sensitivity of cytology is relatively low in low-stage/low-grade tumours. Therefore, new tumour markers have been developed. BTA stat has been reported to have high sensitivity in detecting both primary and recurrent bladder tumours, and may have the potential to detect tumours that cannot be visualised by routine cystoscopy including recurrences in upper tract. The objective of the study was to analyse the reliability of routine follow-up cystoscopy by further investigating patients with positive marker status, BTA stat Test and urine cytology, but negative cystoscopy. MATERIAL AND METHODS: 446 consecutive patients being followed for bladder cancer were analysed in a prospective multicenter study. A voided urine sample was obtained prior to cystoscopy and split for culture, cytology and BTA stat testing. In the case of positive marker status, BTA stat Test or urine cytology, but negative cystoscopy patients were further investigated by i.v. urography or renal ultrasound and random biopsies. The sensitivity of routine follow-up cystoscopy is reported. RESULTS: Of 446 patients 131 (29.4%) had a bladder cancer recurrence at routine cystoscopy. Of the remaining 315 patients not having recurrent tumour at cystoscopy, 56 patients (17.8%) had positive BTA stat Test result, 6 (1.9%) had positive cytology and 5 were positive by both tests. Nine recurrences that were missed at routine follow-up cystoscopy were detected by further investigations making the total number of bladder confined recurrent tumours 140 (140/446, 31.4%). Five of these 9 recurrences were high grade lesions (1 T1G3, 4 CIS), of which 4 were detected by positive cytology. The overall sensitivity of cystoscopy was 93.6%. CONCLUSIONS: We found that routine follow-up cystoscopy may miss over five percent of the recurrent tumours. Although cystoscopy remains the gold standard for bladder cancer follow-up, it is suggested that even with negative cystoscopy patients with positive marker status, BTA stat Test and especially urine cytology, should be considered at risk for coexisting, and in some case even high grade recurrence.     

¿Cuál es el valor de la biopsia aleatoria en el seguimiento del carcinoma uroterial superficial de vejiga?

IntroductionTransitional cell carcinoma of the bladder represents a disease of entire urothelial tract. The follow up is very important to detect any lesion that might represent a progression or a local recurrence. Some authors recommend randomized biopsies as a routine workup, others recommend cystoscopies and urinary cytology as the main part of superficial bladder cancer follow up.Patients and MethodsForty nine patients with superficial bladder cancer were followed up during a ten-year period. Randomized biopsies and urinary cytology were harvested according to the international cancer protocol on bladder cancer.Results15 (1%) out of 1.489 randomized biopsies found to be positive to transitional cell carcinoma. Four out (10.5%) of 35 biopsies targeted to suspicious areas were positive to transitional cell carcinoma. 50 (17.4%) out of 288 cystoscopies with urinary cytology found to be positive to transitional cell carcinoma. Sensitivity and Specificity of biopsies (including randomized and targeted) were 31% and 85.2% respectively. Sensitivity and specificity of cystoscopies with urinary cytology were 48% and 86.5% respectively.ConclusionRandomized biopsies did not show to detect more local recurrence or progression when compared to the urinary cytology. Cystoscopies with urinary cytology have good sensitivity and specificity for detection of tumor recurrence during follow up of transitional cell carcinoma.     

Bladder carcinoma in situ in 2003: state of the art

Carcinoma is situ (CIS) of the bladder is a high-grade non-invasive malignancy with a high tendency of progression and transitional cell carcinoma outside the bladder. The diagnosis is a combination of abnormal cytology and cystoscopy with biopsies. Although cytology has clear limitations in low-grade lesions, such as a low inter- and intra-observer reproducibility, high-grade lesions and CIS should be diagnosed with a high degree of sensitivity and specificity. Currently available urinary markers do not (yet) seem to match cytology. The cystoscopic diagnosis is more difficult, since flat lesions are often difficult to see. The application of fluorescence cystoscopy and resection clearly improves the detection of the number of CIS lesions per patient and also the number of patients with CIS. For treatment of CIS (maintenance) BCG remains the golden standard. BCG appears to be able to prevent or delay progression to muscle invasive disease. BCG refractory patients are at high risk for progression and cancer death, and cystectomy is the treatment of choice. Alternatives for BCG refractory CIS patients, like intravesical chemo-immunotherapy, new chemotherapeutic drugs or photo-dynamic therapy, remain highly experimental. Last but not least, the danger for CIS patients is failure to respond to therapy and a high subsequent chance of progression and cancer-specific death. Unfortunately, despite much research, this prediction is not yet possible with molecular markers in daily practice.     

Vascular endothelial growth factor and its correlation with superficial bladder cancer recurrence rates and stage progression

Because of the heterogeneous behavior of superficial bladder cancer, the development of additional simple diagnostic and prognostic tests will be invaluable. The authors have demonstrated significantly elevated levels of urinary VEGF in patients with active bladder cancer. The sensitivity and specificity of urinary VEGF for diagnosing primary or recurrent bladder cancer were superior when compared with the results of cytology, which remains the most widely used noninvasive diagnostic investigation. These results and the authors' previous findings at the mRNA and protein level strongly implicate VEGF in the pathogenesis of bladder cancer recurrence and progression. The potential exists for anti-VEGF strategies in the treatment of, or prophylaxis against, recurrent superficial bladder cancer.     

Clinical application of NMP22 and urinary cytology in patients with hematuria or a history of urothelial carcinoma

For evaluation of the clinical application of immunoassay for nuclear matrix protein 22 (NMP22 immunoassay) and urinary cytology for early diagnosis and detection of bladder cancer in patients with hematuria and/or a previous history of bladder cancer, 209 urine samples obtained from 137 patients presenting episodes of hematuria or a history of bladder cancer were assayed for NMP22 levels and/or prepared for cytology examination. Biopsy was performed when any visible tumor was identified during cystoscopy examination. The median NMP22 concentrations measured in samples taken from patients with active bladder cancer, from patients with a history of bladder cancer but no active disease, from patients with hematuria, and from healthy volunteers were 18.95, 5.45, 6.39, and 3.75 U/ml, respectively. The urinary NMP22 level recorded for patients with urothelial carcinoma was significantly higher than that noted for individuals without active disease. The sensitivity of the NMP22 assay and of urinary cytology in diagnosing bladder cancer was 69% and 67%, respectively. In contrast, the specificity of these two diagnostic modalities reached 72% and 93%, respectively. The NMP22 assay is slightly more sensitive but less specific than urinary cytology in detecting bladder cancer. This study indicates that determination of urinary NMP22 levels is a useful and noninvasive tool for the detection of bladder cancer because of its high sensitivity. The urinary NMP22 assay may be used as a first-line routine screening method; however, it cannot replace the use of urinary cytology because of its lower specificity.     

Role of lymphadenectomy in the management of urothelial carcinoma of the bladder and the upper urinary tract

The role of lymphadenectomy has been controversial in urological malignancies. Urothelial carcinoma of the bladder and upper urinary tract has a high potential to spread through the lymphatic network compared with other malignancies, including renal cell carcinoma or prostate cancer. In urothelial carcinoma of the bladder, lymphadenectomy of pelvic nodes had been considered as the standard procedure when radical cystectomy was carried out. Recently, many investigators have examined the influence of its extent, and the majority of the studies have supported the beneficial role of extended lymphadenectomy in accurate staging or in improving patient survival. Although randomized controlled trials are required to establish a greater level of evidence, more urological surgeons have already noticed the necessity for extended lymphadenectomy in bladder cancer. In contrast to bladder cancer, there have been far fewer studies on urothelial carcinoma of the upper urinary tract. This might be because of the smaller number of the patients with urothelial carcinoma of the upper urinary tract and the lack of understanding of regional nodes. However, studies of lymph node mapping and the retrospective analyses with respect to the benefit of lymphadenectomy have been carried out in urothelial carcinoma of the upper urinary tract by some investigators, although the results are still controversial. However, the results from multi‐institutional studies by high volume centers have supported the beneficial role of lymphadenectomy in urothelial carcinoma of the upper urinary tract, as it has been proposed in bladder cancer. Thus, lymphadenectomy for urothelial carcinoma of the bladder and the upper urinary tract might have a potential role in staging and improving the oncological outcomes.     

Urinary markers in screening patients with hematuria

Hematuria is a common presenting symptom of urothelial malignancy. Although conventional urine analysis is very sensitive in detecting the presence of hematuria, it is not specific in detecting bladder cancer or other urinary-tract cancers. The noninvasive urinary tests NMP22 and UroVysion have been approved by the U.S. Food and Drug Administration for bladder cancer screening. These tests have better sensitivity than cytology for detecting bladder cancer in patients who present with hematuria. The positive predictive values of both tests increase in individuals with hematuria who have risk factors for bladder cancer. Evaluating hematuria with sensitive markers, such as NMP22 and UroVysion, in high-risk populations offers an opportunity to develop effective strategies for bladder cancer screening.     

Recent clinical trials in superficial bladder cancer

The present review addresses literature regarding the management of superficial bladder cancer published since March 2000. There is no definitive winner among urinary markers of bladder cancer, because they lack specificity or are insufficiently tested. Pathologists continue in their efforts to improve prediction of evolution of superficial bladder cancer to recurrent or infiltrative disease. A few studies have confirmed the value of previously described prognostic factors for recurrence and progression, and have added some refinements. Transurethral resection is not as complete as was believed. Fluorescence detection of flat bladder carcinoma has been demonstrated to improve diagnosis and treatment. The necessity to perform a repeat transurethral resection in high-grade superficial bladder cancer became evident. Identification of the working mechanisms of bacille Calmette-Guérin on superficial bladder cancer remains an important objective, and may help to improve treatment schedules and avoid the morbidity associated with bacille Calmette-Guérin administration. Patients who are at high risk may benefit from long-term maintenance bacille Calmette-Guérin therapy. Valrubicin and keyhole limpet haemocyanin appear to be promising agents in the treatment of superficial bladder cancer.     

Molecular pathways of urothelial development and bladder tumorigenesis

Bladder cancer is the fifth most common human malignancy and the second most frequently diagnosed genitourinary tumor after prostate cancer. The majority of malignant tumors arising in the urinary bladder are urothelial carcinomas. Clinically, superficial bladder tumors (stages Ta and Tis) account for 75% to 85% of neoplasms, while the remaining 15% to 25% are invasive (T1, T2–T4) or metastatic lesions at the time of initial presentation. Several studies have revealed that distinct genotypic and phenotypic patterns are associated with early vs. late stages of bladder cancer. Early superficial disease appears to segregate into 2 main pathways: (1) superficial papillary bladder tumors, which are characterized by gain-of-function mutations affecting oncogenes such as H-RAS, FGFR3, and PI3K, and deletions of the long arm of chromosome 9 (9q); (2) Carcinoma in situ, a “flat” high grade lesion considered to be a precursor of invasive cancer, is characterized by loss-of-function mutations affecting tumor suppressor genes, such as p53, RB, and PTEN. Based on these data, a model for bladder tumor progression has been proposed in which 2 separate genetic pathways characterize the evolution of early bladder neoplasms. Several molecular markers have been correlated with tumor stage, but the rationale for these 2 well-defined genetic pathways still remains unclear.Normal urothelium is a pseudo-stratified epithelium that coats the bladder, composed of 3 cell types: basal, intermediate, and superficial (“umbrella”) cells. We have identified a series of markers that are differently expressed in these distinct cells types, and postulated a novel model for urothelium development and configuration. Briefly, it is our working hypothesis that 2 distinct progenitor cells are responsible for basal/intermediate cells and “umbrella” cells, respectively. Basal and intermediate cells are characterized by a p63 positive phenotype, as well as expression of high molecular weight cytokeratins (CKs), such as CK5, CK10, and CK14. On the contrary, “umbrella” cells display a p63 negative phenotype and are characterized by expression of 2 specific low molecular weight CKs: CK18 and CK20. Neither urothelial stem cells nor bladder cancer stem cells have been identified to date. In this review, we will further expand on the issues discussed above.