(From WebMD Professional Resources and Editors@urotoday.com)
Bladder cancer is a disease that affects the organ responsible for collecting urine before it is expelled. It is a relatively common condition, especially among adults and older individuals, and it can present in different forms depending on its extent and aggressiveness. Understanding the main risk factors, symptoms, diagnostic tests, and treatment options can help patients better navigate the care pathway and collaborate more consciously with the healthcare team.
RISK FACTORS
Smoking is the strongest risk factor for bladder cancer, both in superficial forms and in muscle-invasive disease, with a well-established causal relationship. Data indicate that smoking accounts for 50–65% of cases in men and 20–30% in women. The risk of bladder cancer is proportional to smoking intensity, and passive exposure to tobacco smoke also increases the risk.
Occupational exposure (particularly in jobs involving paints, dyes, textiles, rubber, and leather) is considered a risk factor, though generally less impactful than tobacco smoking. Similarly, radiotherapy performed for mainly pelvic malignancies has been associated with an increased risk of secondary bladder cancers, but tobacco smoking remains the strongest risk factor. Although certain foods, such as processed and red meats, have been linked to an increased risk of bladder cancer, further research is needed to fully evaluate and establish the relationship between dietary habits and bladder cancer risk. No increased risk has been demonstrated with coffee consumption or artificial sweeteners.
According to researchers, the main precursor of muscle-invasive bladder cancer (the most severe form) is flat carcinoma in situ (CIS), whereas most non–muscle-invasive bladder tumors arise from normal mucosa. However, over time, if neglected, even non–muscle-invasive bladder cancer can progress to muscle-invasive disease, especially in tumors that invade the lamina propria, the layer immediately beneath the bladder mucosa. Urothelial papilloma and glandular cystitis are generally considered non-precursors of muscle-invasive bladder cancer. Urothelial papilloma is a rare neoplasm covered by normal urothelium, while glandular cystitis typically occurs following chronic urinary tract infections or continuous irritation. Villous adenoma is also generally benign but can develop into a cancerous lesion; nevertheless, it is not usually considered a precursor of muscle-invasive bladder cancer.
SYMPTOMS
The European Association of Urology (EAU) specifies that the predominant symptom of bladder cancer is hematuria, that is, the usually sudden presence of blood in the urine. This bleeding is generally not associated with painful symptoms, unlike what is seen in hemorrhagic cystitis. Other common symptoms include urinary urgency, increased frequency, and dysuria. Pelvic pain and symptoms of urinary tract obstruction usually occur only in patients with more advanced tumors.
DIAGNOSTIC TESTS
From a diagnostic standpoint, urinary cytology remains the most accurate non-invasive test for bladder cancer in routine clinical use, with a sensitivity of 80–90% and a specificity of 98–100% for detecting high-grade lesions and carcinoma in situ (CIS). The disadvantages of urinary cytology are that it is relatively ineffective in detecting low-grade malignancies, and benign inflammatory conditions can lead to false-positive results.
The most accurate diagnosis, however, is achieved through cystoscopy, which allows the urologist to directly observe the inside of the bladder using a thin instrument inserted through the urethra. When performed under anesthesia, it is not uncomfortable at all and is the fundamental procedure for identifying lesions and, if necessary, obtaining tissue samples. Despite the high diagnostic capability of standard cystoscopy, flat cell carcinoma (carcinoma in situ, CIS) may sometimes escape detection. In contrast, a specific type of contrast-enhanced cystoscopy (using aminolevulinic acid) has demonstrated high tumor specificity by illuminating the lesion with a specific wavelength of light to produce fluorescence.
DISEASE PROGRESSION
High-grade bladder cancer (CIS or muscle-invasive disease) has the potential over time to metastasize to distant sites. According to a recent review, the most common metastatic sites are bone, lymph nodes, liver, and lungs, while muscle and renal metastases are considered rare. In the presence of metastatic spread, collected data indicate that the estimated median survival in patients with metastatic disease is approximately 15 months.
Bladder tumors, like all cancers, are classified according to the TNM system, where T stands for primary tumor, N for lymph node metastases, and M for distant metastases.
Primary tumor (T) classification for bladder cancer:
- CIS – Carcinoma in situ, high-grade dysplasia confined to the epithelium
- Ta – Papillary tumor confined to the epithelium
- T1 – Tumor invasion into the lamina propria
- T2 – Tumor invasion into the muscularis propria:
- T2a, superficial muscularis propria
- T2b, deep muscularis propria
- T3 – Tumor involvement of perivesical fat:
- T3a, microscopic invasion
- T3b, macroscopic invasion
- T4 – Tumor involvement of adjacent organs:
- T4a, invasion of prostatic stroma, seminal vesicles, uterus, or vagina
- T4b, invasion of the pelvic or abdominal wall
Lymph node (N) classification:
- N0 – No regional lymph node metastases
- N1 – Metastasis in a single lymph node in the true pelvis
- N2 – Metastases in multiple regional lymph nodes in the true pelvis
- N3 – Metastases in common iliac lymph nodes
Distant metastasis (M) classification:
- M0 – No distant metastasis
- M1a – Non-regional lymph nodes
- M1b – Other distant metastases
It is important to note that over 70% of all newly diagnosed bladder cancers are non–muscle-invasive, but they may become muscle-invasive over time. This highlights the importance of early diagnosis and treatment. Indeed, 50–70% of these tumors are confined to the mucosa, 20–30% have already invaded the lamina propria, and only about 10% are CIS.
If histological diagnosis of tissue obtained during endoscopic resection (TURB) demonstrates CIS or muscle-invasive tumor, subsequent diagnostic steps include CT scan or MRI of the abdomen, pelvis, and chest, as well as blood tests (alkaline phosphatase). Evaluation of the skeletal system (bone scan, PET) is recommended only if there is concern for bone metastases, suggested by bone pain or elevated alkaline phosphatase.
THERAPEUTIC TREATMENT
In bladder cancer therapy, it is necessary to distinguish less aggressive lesions—non–muscle-invasive and non-CIS—from more aggressive forms. In the former case, endoscopic resection of the lesion, usually accompanied by intravesical chemotherapy administered immediately after surgery and repeated according to a defined protocol, can definitively resolve the disease.
In muscle-invasive bladder cancer, the two main therapeutic options are radical cystectomy or so-called trimodal therapy (bladder-sparing), which consists of:
- Transurethral resection of the bladder tumor
- Concomitant radiotherapy
- Systemic chemotherapy
Based on retrospective data, guidelines have set the optimal maximum tumor size for bladder preservation in muscle-invasive disease at 6 cm. A recent review has instead defined the optimal patient characteristics for trimodal therapy, including predominant urothelial carcinoma histology, visibly complete transurethral tumor resection, clinical stage T2 to T3a, absence of extensive carcinoma in situ, absence of hydronephrosis, and good bladder function.
Each approach has its proponents.
Drs. Chedgy* and Black** argue that radical cystectomy should be considered the standard treatment for muscle-invasive bladder cancer. They cite recommendations from European and U.S. guidelines, as well as published literature showing a 5-year cancer-specific survival of 75% across all stages treated with cystectomy. In contrast, published literature on trimodal therapy shows evidence of lower survival and frequent treatment failures, with nearly one-third of patients eventually requiring salvage cystectomy.
Nevertheless, Chedgy and Black consider cystectomy and trimodal therapy to be complementary. They note that many patients deemed unfit for radical cystectomy may be candidates for trimodal therapy, especially when radiosensitization is performed with 5-fluorouracil and mitomycin.
Dr. Mitin*** recommends considering trimodal therapy as the first option for patients with muscle-invasive bladder cancer, reserving radical cystectomy for those who cannot or do not wish to undergo bladder preservation, as well as for salvage in cases of local recurrence. Mitin cites literature demonstrating similar or better outcomes compared with cystectomy and excellent quality of life, with low rates of radiation-induced adverse effects.
However, trimodal therapy carries a significant rate of local recurrence, requiring thorough and frequent cystoscopic surveillance. Local recurrence requiring salvage cystectomy is usually identified within the first 3 years. Morbidity and mortality rates with salvage cystectomy are surprisingly similar to those with upfront radical cystectomy, but reconstructive options may be limited due to the presence of irradiated bowel, which may be unacceptable for a continent reservoir or neobladder creation.
Dr. Shore**** has recently proposed a new therapeutic hypothesis for high-risk bladder cancer, defined as CIS, T1 invasion, and high-grade papillary tumors, as well as those with very high-risk features such as prostatic urethral involvement. He argues that for BCG-unresponsive patients, the field now offers several therapies beyond traditional radical cystectomy, with the current availability of two FDA-approved intravesical immunotherapies: nadofaragene firadenovec and nogapendekin alfa.
In the future, treatment selection for muscle-invasive bladder cancer will likely be based on tumor biomarker testing to indicate treatment sensitivity.
* Spire Southampton Hospital, UK
** Consultant Urological Surgeon, UK
*** Massachusetts General Hospital, Boston, USA
**** Carolina Urologic Research Center, Atlantic Urology Clinics, USA
