Schinzari.

3 - Oncology [MR2] Page 1 of 10

Urothelial Carcinoma and Urinary Tract Cancers

29/11/24 Gaia e Angelo

Transitional carcinoma, also known as urothelial carcinoma, arises from the transitional
epithelium, a specialized type of epithelium lining the urinary tract. The transitional
epithelium allows for structural changes, such as expansion and contraction, depending on
urine volume. This unique adaptability is key to its function but also contributes to its
susceptibility to carcinogenic influences.

Epidemiology and Risk Factors

The most frequent site of urothelial carcinoma is the bladder, followed by other parts of the
urinary tract, such as the renal pelvis and ureters. The median age of onset for bladder
cancer is around 64 years, and several risk factors increase susceptibility:
• Chemical exposures: Professional exposure to carcinogens such as aromatic amines,
particularly in industrial workers, is a significant factor. For example, pathologists
previously exposed to carcinogens like aminobenzidine, used in immunohistochemical
staining, have an increased risk of developing urothelial carcinoma.
• Lifestyle factors: Smoking is a well-established risk factor due to prolonged exposure
to carcinogenic compounds in tobacco.
• Chronic irritation: Prolonged urinary retention increases the bladder’s exposure to
carcinogens, providing more time for these substances to act on the urothelium.

Pathogenesis

Urothelial carcinoma arises from the urothelial lining and is influenced by continuous
exposure to carcinogens in urine. The bladder, acting as a reservoir, provides a prolonged
contact time for these carcinogens, leading to higher susceptibility.

Two primary subtypes of bladder cancer are:

1. Non-muscle-invasive bladder cancer (NMIBC): This subtype remains confined to the
mucosa or submucosa and has a lower metastatic potential.
2. Muscle-invasive bladder cancer (MIBC): This subtype invades the detrusor muscle,
often exhibiting greater metastatic potential due to increased vascularization.

Clinical Presentation

The primary symptom of urothelial carcinoma is hematuria, which may be macroscopic

(visible blood in the urine) or microscopic (detected via urine analysis). Other symptoms,
such as pain, typically indicate advanced or metastatic disease.
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For renal cell carcinoma, diagnosis is often incidental, as the disease is usually asymptomatic
in early stages. Symptoms, if present, include pain or hematuria, particularly when
metastatic disease develops.

Diagnostic Approach

1. Urine Analysis: Red blood cells in the urine without an obvious cause should raise
suspicion for urothelial carcinoma.
2. Imaging Studies: Techniques such as ultrasound, CT, or MRI are used to identify
masses or structural changes.
3. Histological Examination: This remains the gold standard for diagnosis, allowing for
molecular classification to refine understanding of incidence and prognosis.

Staging and Classification

Bladder cancer staging is essential for determining treatment strategies. Tumors are
classified into muscle-invasive and non-muscle-invasive groups, which differ in terms of
metastatic potential and therapeutic approaches. Muscle-invasive cancers, being more
vascularized, have a higher likelihood of hematogenous spread.

Metastatic Spread

Urothelial carcinoma primarily metastasizes through regional lymphatic and hematogenous

pathways. The most common sites of metastasis include:
1. Pelvic lymph nodes: The primary lymphatic drainage of the bladder.
2. Retroperitoneal lymph nodes: Often involved in advanced disease.
3. Lungs: A frequent site of hematogenous spread.
4. Bone: Particularly in cases of advanced metastatic disease.
5. Liver: Another potential site for distant metastasis.

Muscle-invasive bladder cancer (MIBC) has a higher metastatic potential due to the
vascularized nature of the detrusor muscle, facilitating hematogenous spread. In contrast,
non-muscle-invasive bladder cancer (NMIBC) rarely metastasizes, as it remains confined to
the superficial layers of the bladder wall.

Diagnostic Workflow

1. First-line Investigations:
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• Urine analysis: Essential for detecting hematuria (macroscopic or microscopic).

• Complete blood count (CBC): To evaluate signs of infection, anemia, or systemic
inflammation.
• Vital signs and physical examination: Assess overall patient health and exclude other
conditions.
2. Imaging Studies:
• Ultrasound (US): A non-invasive first-level imaging technique to evaluate masses in
the bladder wall.
• Cystoscopy: A critical endoscopic procedure to directly visualize the bladder mucosa
and identify lesions. It also allows for biopsy and resection of tumors.
• Second-level imaging: CT urography or MRI to evaluate the upper urinary tract and
exclude secondary tumors, such as synchronous urothelial carcinomas in the renal
pelvis or ureters.
3. Cytology:
• Urine cytology is often performed alongside imaging. It can detect exfoliated cancer
cells, particularly in high-grade tumors, although sensitivity is lower for low-grade
lesions.
4. Advanced Diagnostics:
• Histopathological examination: After tumor resection, tissue analysis confirms
diagnosis, determines grade, and provides staging information.
• Staging imaging: CT or PET scans may be necessary to assess metastatic spread,
especially when symptoms or findings suggest systemic involvement.

Treatment Approach

• Transurethral Resection of Bladder Tumor (TURBT):

• This endoscopic procedure is the cornerstone for diagnosing and treating non-
muscle-invasive bladder cancer. It involves resection of visible tumors for histological
evaluation and initial management.
• TURBT is performed under sedation and may require the use of rigid or flexible
instruments.
• Further Management:
• Non-muscle-invasive disease: Intravesical therapy with Bacillus Calmette-Guérin
(BCG) or chemotherapy is often used to prevent recurrence.
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• Muscle-invasive disease: Radical cystectomy, often combined with chemotherapy or

radiotherapy, is indicated.
• Follow-up:
Regular cystoscopic surveillance is necessary, particularly in non-muscle-invasive cases, due
to the high recurrence rate.

Clinical Considerations

• While bladder cancer predominantly affects older adults, young patients with risk
factors (e.g., smoking, occupational exposure) may also develop the disease. Diagnostic
evaluation should not be limited by patient age.
• Emerging molecular markers may further refine the diagnosis and classification of
urothelial carcinoma, aiding in personalized treatment strategies.

In conclusion, urothelial carcinoma requires a structured diagnostic and therapeutic

approach to manage localized and advanced disease effectively. TURBT remains a critical
intervention, and advancements in imaging and molecular diagnostics continue to improve
patient outcomes.
To properly assess the progression and management of carcinoma, it is crucial to establish
whether the tumor has invaded muscular tissue. Histological analysis alone cannot
determine this; excision and examination of the tumor tissue, especially the muscular layer,
are mandatory. Differentiation between superficial (non-muscle invasive) and muscle-
invasive carcinoma significantly influences treatment strategies, as their potential for local
spread and metastasis varies.

Histopathological Evaluation and Staging

When diagnosing superficial carcinoma, pathologists classify tumors into “TRUE T1” or
“TRUE T2” based on the presence of muscular tissue in the sample and its invasion status.
In “TRUE T1,” the tumor invades subepithelial connective tissue without muscular
involvement. However, if no muscular tissue is included in the specimen, a repeat biopsy is
necessary to confirm staging. Incomplete or unclear staging can compromise subsequent
treatment planning and risk assessment.

Management of Non-Muscle-Invasive Bladder Carcinoma (NMIBC)

Superficial bladder carcinoma does not exhibit a risk of systemic spread but is prone to
recurrence. Adjuvant intravesical therapy, typically with Bacillus Calmette-Guérin (BCG), is
employed to reduce recurrence risk and prolong disease-free intervals. BCG therapy, a form
of immunotherapy introduced in the 1970s, leverages an immune-mediated mechanism to
target residual cancer cells. The standard protocol involves six weekly intravesical
instillations, followed by monthly administrations. While effective, this regimen was
established based on clinical practicality rather than specific biological evidence.

Muscle-Invasive Bladder Carcinoma (MIBC)

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In muscle-invasive carcinoma, the risk of systemic spread necessitates more aggressive

treatment. Intravesical therapies like BCG are ineffective due to the tumor’s potential to
metastasize beyond the bladder. The gold standard for MIBC is radical cystectomy with
pelvic lymphadenectomy, often combined with urinary reconstruction using the
gastrointestinal tract. Reconstruction options include creating a neobladder or using an ileal
conduit to divert urine. While these procedures are life-saving, they are associated with
complications such as infection and potential functional limitations.

In cases of direct ureterostomy, infections are common due to the continuous exposure of
sterile urine to external contaminants. Ileal conduits mitigate this risk by providing a more
controlled urine flow but still pose challenges due to bacterial colonization and the
complexity of the procedure.

Bladder Cancer Management

29/11/24 Angelo e Gaia

The management of bladder cancer varies significantly depending on whether the disease is
non-muscle-invasive or muscle-invasive.

For non-muscle-invasive bladder cancer (NMIBC), the standard treatment involves

intravesical Bacillus Calmette-Guérin (BCG) therapy.

This regimen typically consists of six weekly administrations followed by monthly

maintenance doses. Interestingly, the choice of six weekly doses is not rooted in biological
evidence but rather in practical considerations from the initial studies. Researchers used six-
vial packages of BCG, administering one vial per week. Despite this arbitrary origin, the
protocol has proven effective and remains widely used for superficial bladder cancers.

However, intravesical therapy, whether immunotherapy like BCG or chemotherapy, is

ineffective for muscle-invasive bladder cancer (MIBC). Once the cancer invades the muscle
layer, it has the potential to spread beyond the bladder, rendering localized treatments
insufficient. In these cases, systemic and radical approaches are necessary.

The cornerstone of treatment for MIBC is radical cystectomy combined with pelvic
lymphadenectomy. This surgery entails the complete removal of the bladder and nearby
lymph nodes to achieve thorough local control.

Following cystectomy, the patient requires urinary diversion, as the bladder's removal
eliminates its storage function.
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Options for urinary diversion include the creation of an ileal conduit, which uses a segment
of the intestine to channel urine to an external urostomy bag, or the construction of a
neobladder.

The neobladder is a reservoir fashioned from intestinal tissue, designed to restore some
degree of urinary continence.

A less common option is ureterostomy, where the ureters are directly connected to the
skin, though this method carries a high risk of infection due to the exposure of sterile urine
to external pathogens.

These surgical interventions, while often life-saving, come with significant challenges.

For instance, the use of intestinal tissue in urinary diversion introduces bacteria into the
urinary system, increasing the risk of infection. Despite this, techniques such as the ileal
conduit have become the preferred method due to their reliability and lower complication
rates compared to alternatives.

SYSTEMIC TREATMENT IN MIBC

For patients with muscle-invasive disease, systemic treatments are crucial to address the
risk of micro metastatic spread.

Adjuvant chemotherapy following radical surgery is one such approach aimed at

improving survival outcomes. However, its application is not without challenges. A critical
issue is the timing of chemotherapy; patients require a recovery period of at least two
months after radical cystectomy before initiating systemic treatment.

This delay, coupled with the physical toll of the surgery, often reduces the feasibility and
effectiveness of adjuvant therapy. Postoperative complications can further hinder the ability
to administer chemotherapy promptly.

Interestingly, the role of adjuvant therapy differs from that of primary tumor reduction. In
the context of MIBC, the primary tumor is already removed during surgery. The purpose of
adjuvant therapy is to target any residual microscopic disease that could lead to recurrence
or metastasis. While it does not aim to cure the disease outright, it significantly enhances
survival rates by mitigating the risk of systemic spread.

Bladder cancer management exemplifies the complexities of balancing local and systemic
treatments. Radical cystectomy achieves excellent local control, but the systemic threat
posed by micro metastases necessitates additional measures. Although adjuvant
chemotherapy offers promising survival benefits, its effectiveness is tempered by the
practical challenges of surgery recovery and treatment timing.
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Advancing surgical techniques, optimizing recovery protocols, and refining systemic

therapies may help bridge these gaps, offering patients a better chance at improved
outcomes and quality of life.

Challenges in Clinical Trials:

The evidence supporting adjuvant chemotherapy is limited by historical challenges in clinical

trials, many of which were prematurely closed or underpowered. Consequently, clinicians
often face uncertainty about the true survival benefits of these treatments. Recent studies
have aimed to evaluate newer systemic therapies, including chemotherapy and
immunotherapy, in the adjuvant setting to better define their role in improving survival
outcomes.

Pathological Response as a Surrogate Marker:

A critical goal of adjuvant therapy is achieving a pathological complete response (pCR),

where no evidence of residual cancer is found during post-surgical evaluation. A strong
association exists between pCR and improved survival outcomes, making it an essential
endpoint in clinical trials and practice. However, current therapies achieve pCR in only about
25% of patients, leaving considerable room for improvement.

Systemic Treatments and Bladder Preservation:

Systemic treatments, particularly those involving platinum-based chemotherapies, remain

the cornerstone for addressing micro metastatic disease.

Cisplatin is the preferred agent due to its efficacy in creating DNA damage that leads to
tumor cell death. However, its use is limited by significant nephrotoxicity, which makes it
unsuitable for patients with impaired kidney function. In such cases, carboplatin, which is
less nephrotoxic but more neurotoxic, may be used as an alternative. Unfortunately, the
efficacy of carboplatin is often considered inferior to cisplatin.

Efforts are also underway to explore bladder-preserving strategies for select patients. In
cases of a single, localized muscle-invasive lesion without extension to the perivascular
tissue, bladder-sparing approaches such as wide resection combined with chemoradiation
may offer a viable alternative to radical cystectomy. This approach aims to maintain bladder
function while controlling the disease.

Innovations and Ongoing Challenges:

The divide between cisplatin-eligible and cisplatin-ineligible patients highlights the need for
novel treatments that can cater to a broader range of individuals. Immunotherapy, targeted
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therapies, and newer agents are being studied as potential alternatives to traditional
chemotherapy, particularly for patients who cannot tolerate cisplatin.

In conclusion, the management of MIBC requires a delicate balance between aggressive

local control via surgery and systemic therapy to prevent disease recurrence. Challenges
such as treatment timing, patient eligibility, and the limited efficacy of current therapies
underscore the need for ongoing research and innovation to improve outcomes in this
complex disease.

ADVANCED BLADDER CANCER MANAGEMENT

The management of advanced bladder cancer has undergone significant advancements,

with systemic treatments playing an increasingly pivotal role alongside surgical
interventions. The treatment landscape is defined by innovations in drug mechanisms,
clinical trial findings, and the necessity to tailor approaches based on patient-specific factors.

Cisplatin remains the standard of care for eligible patients with muscle-invasive and
advanced bladder cancer. Its mechanism of action involves inducing DNA crosslinks that
result in cancer cell death. However, its administration is challenging due to its
nephrotoxicity.

To mitigate kidney damage, patients require substantial hydration, typically involving

several liters of intravenous fluids. This poses a problem for those with compromised
ventricular function, as excessive fluid administration can lead to pulmonary edema.

Consequently, the eligibility for cisplatin therapy is strictly defined, excluding patients with
poor renal function or high creatinine levels.

In cases where cisplatin is not an option, alternative systemic treatments are considered.
Second-line therapies include vinflunine, though it is increasingly being replaced by
immunotherapies such as atezolizumab and pembrolizumab. These drugs target the PD-
1/PD-L1 pathway, effectively reactivating the immune system to attack cancer cells.

Another breakthrough in systemic therapy is the development of antibody-drug conjugates

like enfortumab vedotin. These innovative drugs target specific proteins, such as nectin-4,
on bladder cancer cells. By delivering a cytotoxic agent directly to the tumor, they reduce
systemic toxicity while enhancing treatment precision. However, their use is not without
challenges, as premature release of the cytotoxin can cause unintended systemic effects.
Moreover, severe adverse reactions, including toxic epidermal necrolysis (Stevens-Johnson
syndrome), necessitate close monitoring.
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Combination therapies are an emerging focus, aiming to improve treatment efficacy by

pairing immunotherapies with chemotherapy or other novel agents.

For instance, the combination of checkpoint inhibitors with cisplatin and gemcitabine has
demonstrated promising early results, signaling a potential shift toward multi-modal
regimens.

These strategies not only aim to enhance tumor control but also address the challenge of
resistance seen with monotherapy.

EARLIER PHASES TREATMENT

The role of systemic therapies is expanding beyond advanced disease to include earlier
treatment phases. In the neoadjuvant setting, these therapies are used to reduce tumor
size before surgery, improving the likelihood of successful resection and reducing the risk
of recurrence.

Ongoing trials are exploring the integration of immunotherapies into both neoadjuvant and
adjuvant settings, potentially reshaping the standard treatment protocols.

Unique clinical scenarios, such as tumors arising in the bladder diverticulum, add further
complexity to management.

These tumors lack a muscular layer, increasing the risk of direct extension and
carcinomatosis. Such cases require meticulous surgical planning to prevent recurrence or
metastasis, underscoring the need for individualized approaches in bladder cancer care.

The future of bladder cancer treatment lies in balancing innovation with practicality. While
therapies like antibody-drug conjugates and immunotherapy show unparalleled potential,
their integration into clinical practice must account for patient eligibility, toxicity, and cost.
As research progresses, the emphasis will remain on improving survival outcomes while
ensuring the quality of life for patients facing this challenging disease.

MANAGEMENT OF UROTHELIAL CARCINOMA

The management of urothelial carcinoma, particularly in cases involving the upper urinary
tract or unique anatomical locations, presents significant challenges due to the complexity
of treatment decisions and the aggressive nature of the disease. Surgery and systemic
therapy remain the mainstays of treatment, tailored to the stage and individual patient
factors.

Surgery and Adjuvant Chemotherapy

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In cases where nephrectomy is performed, it is generally followed by systemic therapy if the

disease is advanced (pT2 or higher). While nephrectomy itself is not a particularly complex
procedure for surgeons, it often leaves patients with only one kidney, which necessitates
careful consideration of adjuvant therapy. Cisplatin, the preferred chemotherapeutic agent
for its superior efficacy, is less commonly used in this context due to its nephrotoxicity.
Instead, carboplatin is frequently employed as a safer alternative. Although slightly less
effective than cisplatin, carboplatin still provides a meaningful survival benefit.

For patients with localized (pT1) disease, there is typically no indication for systemic
treatment, and they are managed with surgery alone. However, in advanced stages (pT2 or
more), adjuvant chemotherapy with carboplatin or cisplatin remains the standard of care to
improve survival outcomes.

Aggressive Squamous Cell Carcinomas

Penile squamous cell carcinoma and similar aggressive squamous carcinomas of the urinary
tract exhibit a very poor prognosis, with a median survival of only one to two years. These
cancers often spread through lymphatic channels, involving pelvic and supraclavicular lymph
nodes, and later metastasize to the lungs and mediastinum.

Systemic treatment options for these cases have historically been limited and include a
combination of platinum-based chemotherapies such as cisplatin or carboplatin with other
agents like 5-fluorouracil. However, these regimens yield modest results at best. Recent
advancements include immunotherapies like cemiplimab, an anti-PD-1 antibody initially
developed for squamous cell carcinoma of the skin. While still under investigation,
cemiplimab has shown promise in treating advanced squamous carcinomas, offering a new
potential avenue for managing these aggressive tumors.

Treatment Challenges and Future Directions

The management of these cancers highlights the need for tailored approaches that account
for individual patient factors, such as renal function, anatomical considerations, and the
disease's aggressiveness. Advances in immunotherapy and targeted therapies are beginning
to reshape the treatment landscape, but challenges remain, especially in ensuring
accessibility and managing toxicities.

In urothelial carcinoma, as in many cancers, the goal is not only to extend survival but also
to improve the quality of life. Striking this balance requires a nuanced understanding of the
disease and a multidisciplinary approach to care.