Bladder cancer: An overview

Bladder cancer is a prevalent disease with substantial morbidity and mortality that requires multidisciplinary medical
and surgical management

Bladder cancer is the 10th most common cancer diagnosed worldwide,¹ and it is the most common urinary tract neoplasm, with urothelial carcinoma (UCC) being the most common histologic type (approximately 90 per cent).⁸ Metastatic urothelial cancer is the 13th most common cancer in Ireland and has a five-year survival rate of 5 per cent.14 In Ireland bladder cancer affects approximately 490 people annually.³

Bladder cancer has a higher incidence in men than women: The age-standardised incidence rate per 100, 000 person-years is 9.5 for men and 2.4 for women worldwide, and in the EU, 20 for men and 4.6 for women.²

The incidence of bladder cancer increases with age. Approximately 70 per cent of patients diagnosed with bladder cancer in Ireland are over 65 years of age and up to 15 per cent are diagnosed with metastatic disease at initial presentation.¹⁴

Tobacco smoking is the main risk factor, accounting for nearly 50 per cent of cases, followed by occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons, which are responsible for approximately 10 per cent of all cases.^2,4 The incidence of bladder cancer in smokers is almost twice that of non-smokers.³

While family history seems to have little impact, genetic predisposition has an influence on the incidence of bladder cancer via its impact on susceptibility to other risk factors.⁵

Other risk factors include the parasitic infection schistosomiasis; medications including pioglitazone for the management of type 2 diabetes (associated with a small increase in bladder cancer); cyclophosphamide (a chemotherapy agent used in the management of haematological malignancies); and pelvic radiation.³

Symptoms and diagnosis

Common presenting bladder cancer symptoms include microscopic haematuria, gross haematuria and infection, or obstruction.8 The most common presenting symptom seen in over 80 per cent of bladder cancer patients is painless haematuria.14 Other less common symptoms include dysuria, frequency or urgency, constitutional symptoms such as fatigue, weight loss, and rarely bone or flank pain due to metastases. There are no screening tests for the early detection of bladder cancer. Gross haematuria correlates with advanced disease stage.⁸

Diagnostic modalities include imaging, ultrasound, intravenous urography (IVU), CT, MRI, cystoscopy, and biopsy.⁸

Diagnostic methods used for bladder cancer are cystoscopy and urine cytology. Cystoscopy is an invasive tool and has low sensitivity for carcinoma in situ and is considered the gold standard for the initial management of bladder cancer. Direct visualisation of the bladder is necessary in all cases of haematuria, where there is a concern for bladder cancer, and no imaging modality is sensitive enough to replace the cystoscope.³ Urine cytology is non-invasive, cost-effective, and has a high specificity, but low sensitivity for low-grade urothelial tumours.¹¹

The main role of imaging in the assessment of haematuria is to evaluate the kidneys and ureters. Ultrasound or CT may be used and guidelines differ in their recommendation regarding imagery. Ultrasound of the kidneys will identify most renal tumours; however, it can miss a small percentage of upper tract urothelial cancers which can be detected with CT scanning.³

Types of bladder cancer⁶

The urinary bladder wall is composed of four layers: mucosa, submucosa, muscularis, and serosa. There are three main types of bladder cancer:

Urothelial carcinoma (UCC): UCC accounts for approximately 90 per cent of all bladder cancers and also for 10-to-15 per cent of kidney cancers diagnosed in adults. It begins in the urothelial cells found in the urinary tract. UCC is sometimes also referred to as transitional cell carcinoma or TCC.

Squamous cell carcinoma (SCC): Squamous cells develop in the bladder lining in response to irritation and inflammation. Over time, these cells may become cancerous. Squamous cell carcinoma accounts for about 4 per cent of all bladder cancers.

Adenocarcinoma: Adenocarcinoma accounts for about 2 per cent of all bladder Ta. CIS is a cancer that is found on or near the surface of the bladder (stage Tis).⁶

Non-muscle-invasive: Non-muscle-invasive bladder cancer (NMIBC) has grown into the lamina propria, but not into the muscle. NMIBC is also referred to as superficial cancer, although this term may incorrectly suggest that the cancer is not serious. NMIBC has the possibility of spreading into the bladder muscle or to other parts of the body.⁶

Muscle-invasive: Muscle-invasive bladder cancer (MIBC) has grown into the bladder wall muscle and sometimes into the fatty layers or surrounding tissues or organs outside the bladder.⁶

Staging and grading^7,9

The stage of a cancer describes its size, position and whether it has spread. The TNM system is a commonly used staging system. T refers to how far the tumour has grown into the bladder, and how far it has spread into the surrounding tissues. N describes whether the tumour has spread to the nearby lymph nodes. M refers to secondary or metastatic cancer if the tumour spreads to another part of the body.⁷ CIS or Tis means very early, high grade cancer cells are only in the innermost layer of the bladder lining.

T – Tumour⁹

Ta: The cancer is just in the innermost layer of the bladder lining.

T1: The cancer has started to grow into the connective tissue beneath the bladder lining.

T2: The cancer has grown through the connective tissue into the muscle. T2 is divided into T2a and T2b.

• T2a: The cancer has grown into the superficial muscle.
• T2b: The cancer has grown into the deeper muscle.

T3: The cancer has grown through the muscle into the fat layer. T3 is divided into T3a and T3b.

• T3a: The cancer in the fat layer can only be seen under microscopic invasion.
• T3b: The cancer in the fat layer can be seen on tests, or under macroscopic invasion.

T4: The cancer has spread outside the bladder. T4 is divided into T4a and T4b.

• T4a: The cancer has spread to the prostate, uterus or vagina.
• T4b: The cancer has spread to the wall of the pelvis or abdomen.

N – Lymph nodes

N0 means there are no cancer cells in any lymph nodes

• N1 means there are cancer cells in one lymph node in the pelvis.
• N2 means there are cancer cells in more than one lymph node in the pelvis.
• N3 means there are cancer cells in one or more lymph nodes just outside the pelvis.

M – Metastasis

• M0 means the cancer has not spread to other parts of the body.
• M1 means the cancer has spread to other parts of the body, such as the bones, lungs, liver, or lymph nodes. M1 can be divided into M1a and M1b:
• M1a means the cancer has spread to the lymph nodes outside the pelivs.
• M1b means the cancer has spread to other parts of the body, for example, bones ,lungs and liver.

Grading for bladder cancer may be referred to as:^{7, 10}

Grade 1: The cancer cells look very like normal cells. They are called low grade or well differentiated. They tend to grow slowly and generally stay in the lining of the bladder.

Grade 2: The cancer cells look abnormal. They are called moderately differentiated. They are more likely to spread into the deeper muscle layer of the bladder or to come back after treatment.

Grade 3: The cancer cells look very abnormal. They are called high grade or poorly differentiated. They grow more quickly and are more likely to come back after treatment or spread into the deeper muscle layer of the bladder.

Grading may also be referred to as low-grade or high-grade:

Low-grade: The cancer cells are slow-growing and are less likely to spread

High-grade: The cancer cells grow more quickly and are more likely to spread. CIS is always classed as high-grade.

Pathology plays a crucial role in the management of bladder cancer. At initial diagnosis, most patients present with NMIBC, which correlates with better overall survival and prognosis. The most important factor in the pathological assessment of UC is identifying the extent of invasion for proper staging. Bladder cancers can be unifocal or multifocal. The majority of cases present as multifocal. Multifocal tumours may be multiple independent or arise from a common origin. The pathology report should include the tumour location, grade, depth, presence or absence of CIS, and whether the detrusor muscle is present in the examined specimen. The pathology report should also include the presence of LVI or variant histology. In complex cases, review by an experienced genitourinary pathologist is recommended.⁸

Management of NMIBC

NMIBC is the most common diagnosed bladder cancer and refers to bladder cancers confined to the mucosa (pTa) or lamina propria (Pt1), without invasion of the bladder wall muscle. CIS, a high grade fat tumour confined to the mucosal layer, is also included in this group. pTa and pT1 appear as papillary type lesions and the number and size of tumours are important predictors for the risks of progression and reoccurrence. CIS tumours can appear as velvety changes on the bladder mucosa and often present with lower urinary tract symptoms rather than haematuria.³

Management of NMIBC includes transurethral resection of bladder tumour (TURBT), a diagnostic and therapeutic procedure that allows the collection of samples to determine the grade and stage of bladder cancer. The samples are sent for histological assessment. NMBIC has the potential to reoccur or progress to MIBC.

The European Organisation for Research and Treatment of Cancer (EORTC) has developed a scoring model for predicting recurrence and progression. The scoring system is based on assigning points for- number of factors; tumour diameter; prior recurrence rate; category; concurrent CIS; and World Health Organisation (WHO) 1973 tumour grade. Surveillance after treatment such as TURBT uses different modalities including regular cystoscope evaluation, CT scan and cytology. Intravesical treatments including chemotherapy agents mitomycin, epirubicin and BCG are important in the reduction of recurrence and progression rates of NMBIC.³

Management of MIBC

While most patients presenting with bladder cancer have NMIBC, up to 25 per cent have MIBC, where cancer cells are detected in the muscularis mucosa at the time of TURBT. Tumours that extend to the muscle layer are staged T2, to the perivesical fat T3, and those that invade other organs or the pelvic side wall, T4.³

MIBC cannot be cured with endoscopic treatments alone and requires radical therapy. Even with radical treatments the five-year survival rate is approximately 50 per cent. Treatment options for MIBC include radical cystectomy, neoadjuvant chemotherapy (NAC), urinary reservoir reconstruction, trimodal therapy, radiotherapy, and endoscopic management.³

In radical cystectomy the prostate gland and seminal vesicles are also removed in men and the urethra is removed if a tumour is detected on urethral biopsy. In women the uterus, urethra and adjacent vaginal tissues are removed, however, the ovaries can usually be left in situ. Regional lymph nodes are also removed in both men and women.³

The addition of NAC has been shown to account for a 5 per cent improvement in overall survival with radical cystectomy. NAC should be commenced as soon as possible and followed by surgery usually within six weeks.

Ileal conduit is the most common method of urinary reservoir reconstruction in Ireland and the UK. The Studer neobladder is another technique, but is contraindicated when a tumour has spread to the urethra.³

Trimodal therapy utilises TURBT, radiotherapy and chemotherapy. In carefully selected patients, results from trimodal therapy can match those of radical cystectomy. External beam radiotherapy should not be offered as a primary therapy and only be considered in patients unfit for cystectomy.

Endoscopic resection and diathermy for patients with un-resectable disease can improve quality-, but not quantity-of-life.³ Standard first-line treatment for metastatic urothelial cancer is gemcitabine/cisplatin (GC) or MVAC (methotrexate, vinblastine, adriamycin and cisplatin). About 50 per cent of patients are unfit for cisplatin-containing chemotherapy due to poor hearing, impaired renal function or comorbidity.

Patients who are unable to receive cisplatin may be offered palliative chemo in the form of carboplatin/gemcitabine. This is the preferred option as it is better tolerated than methotrexate/carboplatin/vinblastine (MCAVI), but without a statistically significant difference in overall and progression-free survival.

Patients unfit for platinum-based therapy have the option of single agent taxane or gemcitabine. Although a significant number of patients have an objective response to first-line therapy, most eventually progress and require subsequent lines of therapy.¹⁴

Options for treatment in the second-line setting and beyond include immunotherapy, targeted treatment or chemotherapy. Immunotherapy has been approved by the US FDA in the second-line setting for patients with metastatic urothelial cancer who progressed on previous platinum chemotherapy. In the Irish setting, however, chemotherapy is currently the only funded treatment, and treatment options for patients who progress on chemotherapy are limited. Patients may be able to access immunotherapy or erdafitinib
via compassionate access schemes, however these applications require time and are subject to approval from pharmaceutical companies.¹⁴

In summary

Bladder cancer is a prevalent disease with substantial morbidity and mortality that requires multidisciplinary medical and surgical management. Bladder cancer should be considered as two distinct diseases. NMIBC can be completely managed endoscopically with the occasional use of intravesical treatments. Strict adherence to surveillance is necessary to help prevent recurrence or progression. MIBC is more progressive and treated with radical cystectomy/radical cystoprostatectomy and ileal conduit formation following NAC. Long-term follow-up is required to monitor recurrence and functional deterioration.³

The prognosis of UC depends on multiple factors. TNM stage is the most important prognostic factor of urinary bladder carcinoma. The five-year overall survival for pT1 is 75 per cent, for pT2 is 50 per cent, and for pT3 is 20 per cent.8 Up to 45 per cent of patients will develop complications following radical cystectomy and ileal conduit formation. The main complications include vitamin B12 deficiency, metabolic acidosis, and deterioration of renal function, urinary tract infections, and anastomotic complications.

Advanced and metastatic bladder cancer has a poor prognosis and median survival even with cisplatin-based chemotherapy is approximately 14 months.³

Treatment of patients with advanced disease is, however, undergoing rapid changes as immunotherapy with checkpoint inhibitors (ICI), targeted therapies and antibody-drug conjugates have become options for certain patients with various stages of disease.¹² The advent of ICI has transformed the treatment landscape of bladder cancer. Novel ICI have successfully shown improved outcomes in metastatic disease to such an extent that the standard of care paradigm has changed, leading to the development of different trials with the aim of determining whether ICI may have a role in early disease.¹³

With ongoing clinical trials increasingly showing an overall survival benefit with immunotherapy and targeted treatment for bladder cancer, it is important that Ireland keeps pace with evolving practice in order to provide the best possible care and outcomes for these patients.¹⁴

References

. International Agency for Research on Cancer. Estimated number of new cases in 2020, worldwide, both sexes, all ages. World Health Organisation, Geneva, Switzerland

2. Compérat E, Gontero P, Liedburg F, et al. 2021. European Association of Urology Guidelines on non–muscle-invasive bladder cancer (Ta, T1, and Carcinoma in Situ). Available at: www.sciencedirect.com/science/article/pii/S0302283821019783#bib0015
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   factors in bladder cancer management. Hospital Professional News. Issue 88; September 2021
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9. Cancer Research UK (2018).
   Stages bladder cancer. Available at:
   www.cancerresearchuk.org/about-cancer/bladder-cancer/types-stages-grades/stages
10. Cancer Research UK (2018). Grades of bladder cancer. Available at: www.cancerresearchuk.org/about-cancer/bladder-cancer/types-stages-grades/grades
11. Oeyen E, Hoekx L, De Wachter S, Baldewijns M, Ameye F, Mertens I. Bladder cancer diagnosis and follow-up: The current status and possible role of extracellular vesicles. Int J Mol Sci. 2019 Feb; 20(4): 821. Published online 2019 Feb 14. doi: 10.3390/ijms20040821
12. Andrew T, Lenis M, Patrick M, Lec M, Karim C, et al. Bladder cancer a review. JAMA. 2020; 324(19):1980-1991. doi:10.1001/jama.2020.17598
13. Cancer treatment reviews (2021). Recent advances in neoadjuvant immunotherapy for urothelial bladder cancer: What to expect in the near future. Available at: www.cancertreatmentreviews.com/article/S0305-7372(20)30181-X/fulltext#relatedArticles
14. Chew S, Darwish W, Carroll H, McCaffrey J. (2020). Updates on management of metastatic bladder cancer. Hospital Professional News. Available at: https://hospitalprofessionalnews.ie/wp-content/uploads/2020/09/Updates-on-management-of-metastatic-bladder-cancer.pdf