Bladder cancer

Bladder cancer is the 10th most common cancer in the UK (8th most common male cancer and 16th most common female cancer). There are multiple histological subtypes of bladder cancer of which urothelial carcinoma (UC) is the most common.

🦴 Anatomy

A cross-section of the bladder wall indicates there are 4 layers of the bladder to be aware of:

1. Urothelium - this is stratified transitional epithelium that lines the renal pelvis, ureters, bladder and proximal urethra. There are 3 types of cells present: umbrella cells, intermediate cells and basal cells. It has a role in barrier function of the bladder to prevent absorption of urine’s toxic substances (such as acid and urea) and to defend against pathogen entry from the external environment.
2. Lamina propria - the connective tissue layer. In between the urothelium and lamina propria there is a basement membrane.
3. Muscularis propria - this is the detrusor muscle layer.
4. Fatty connective tissue

Pathophysiology

Carcinogenic substances (such as nitrosamines) get excreted by the kidneys and collect in the bladder where they remain a while before getting excreted with urination. This prolonged exposure to such substances is likely to cause malignant changes of the urothelial cells of the bladder.

70% of bladder cancers are multifocal and synchronous (meaning that there are multiple tumours occurring at the same time). Recurrences happen at different times in about 60% of patients (metachronous recurrence). These recurrences are often at sites that are different to the primary site which promotes the idea of the field effect.

The field effect in cancer refers to the idea that exposure of a particular tissue or organ to carcinogens or other cancer-promoting factors can lead to widespread molecular and cellular changes beyond the visibly affected tumor site. Instead of viewing cancer as a localized and isolated event, the field effect suggests that the entire field of tissue exposed to a carcinogenic insult undergoes molecular alterations, making it more susceptible to the development of multiple tumors.

In the context of bladder cancer, for example, the field effect proposes that the urothelium exposed to certain carcinogens undergoes changes that can lead to the initiation and development of cancer in various areas of the urinary tract. This could result in the formation of multiple tumors, either simultaneously or at different times, even though they may be physically separate and distinct.

While the field effect is believed to explain the multiple tumors in bladder cancer, studies suggest that most tumors originate from a single cell. Both ideas, however, have practical applications: a single genetic mutation may kickstart the process, giving a growth advantage to cells that eventually become cancerous. This might explain why new tumors often develop close to each other and why cancer cells might spread downstream from upper tract tumors or after surgical removal.

⚠️ Risk factors

🔢 Classification and types

Types of bladder cancer:

We can identify the following types of bladder cancer based on its histology:

1. Urothelial carcinoma - also known as a transitional cell carcinoma. It makes up 90% of the cases.
2. Squamous cell carcinoma - 5% of cases. Associated with schistosoma infection (bilharzia).
3. Adenocarcinoma - 2%
4. Sarcoma and small cell bladder cancer - rarer subtypes.

We can stage bladder cancer using the TNM staging system. This staging can help us further classify the disease:

• Non-muscle invasive bladder cancer - this makes up 70-80% of bladder cancers. As the name suggests, it is when the cancer does not penetrate into the muscular layer of the bladder. This means that it solely involves the urothelial layer. It is referred to as the T stage.

There are 3 T stages of non muscle invasive bladder cancer:

1. Carcinoma in situ (CIS) - also known as TIS. The cancer cells in CIS are flat and remain at the level of the urothelium. They appear as velvety patches when seen under a microscope.
2. Papillary bladder cancer - this is also known as Ta. It is the most common subtype. The cancer cells appear as papillary structures that seem like mushrooms. They grow into the bladder cavity.
3. T1 - T1 tumours are the early malignant stages that can grow out of the urothelium and into the lamina propria.
• Muscle-invasive bladder cancer - this is when the tumour penetrates deeper into the bladder wall, past the lamina propria and into the muscular layers. They carry a higher risk of metastasis and need to be treated more aggressively. It includes T2a/b, T3a/b, T4a/b.
• Locally advanced bladder cancer - this means the tumour has gone through the bladder and into the nearby tissues including the vagina, womb, ovaries, prostate, and colon/rectum as well as into local lymph nodes.
• Advanced/metastatic bladder cancer - this is when there has been involvment of the abdomen and/or pelvis as well as distant lymph nodes. There may be metastasis (often bone, lungs and liver).

⭐️ The most common bladder cancer is a urothelial non-muscle invasive papillary/Ta bladder cancer.

😷 Presentation

The cardinal sign of bladder cancer is painless haematuria (visible or non-visible). If it is present it is considered renal/bladder cancer until proven otherwise.

Other features of bladder cancer include:

• Storage LUTS - such as frequency, urgency, urge incontinence, nocturia and nocturnal enuresis.
• Recurrent UTIs
• Hydronephrosis
• Neuropathic pain on the medial thigh - due to invasion of the obturator nerve.
• Unintended weight loss
• Night sweats

✍️ Referral criteria

NICE states that patients who meet the following criteria are elegible for a 2-week wait referral:

1. Aged ≥45 with:
1. Unexplained visible haematuria (in the absence of UTI) OR
2. Visible haematuria that persists after successful treatment of UTI.
2. Aged ≥60 with non-visible haematuria AND dysuria/raised white cell count.

NICE also recommends considering a non-urgent referral in people over 60 with recurrent, unexplained UTIs.

🔍 Investigations

• ⭐️ If suspecting bladder cancer we should do an urgent flexible or rigid cystoscopy. A flexible cystoscopy is initially done (usually) under local anaesthesia.
• If a tumour is visualised with flexible cystoscopy → rigid cystoscopy + biopsy under a general anaesthesia.
• Urine cytology - is not routinely done due to its poor sensitivity and specificity. It can be used to identify cancerous cells in the urine. If cancerous cells are found with cystoscopy showing seemingly normal epithelium then random biopsies at cystoscopy should be done.

🧰 Management

Let’s take a look a look at the management of non-muscle invasive bladder cancer, muscle-invasive bladder cancer, locally advanced/metastatic bladder cancer.

🧰

Management of muscle-invasive bladder cancer:

🏆 Most muscle-invasive bladder cancers require radical cystectomy.

After doing a radical cystectomy, we have to find alternative methods to drain the urine, such as:

• Urostomy with ileal conduit - this is the most common option. It is used to drain urine from the kidney while bypassing the ureters, bladder and urethra. A section of the ileum, around 15-20cm long, is removed. An end-to-end conduit is created within the bowel. The ureters are anastomosed to one end of the removed ileum while a stoma is formed with the other end. The urine drains into a urostomy bag.

The urostomy bag needs to fit tightly around the stoma to avoid contamination as urine is acidic and can cause irritation and skin damage.

• Continent urinary diversion - this involves the formation of a pouch within the abdomen from a section of the ileum along with a stoma formation. The urine does not drain from the stoma directly and the patient needs to insert a catheter to drain the urine.
• Neobladder reconstruction - a segment of the bowel is used to form a new bladder which is drained via catheter or urethrally.
• Ureterosigmoidostomy - this is rarely done. It involves attaching the ureters directly to the sigmoid colon where it subsequently drains urine. The rectum may be then expanded to create a space for urine to collect. The patient can then drain urine by relaxing the anal sphincter (the same way they normally open their bowels). This is known as a Mainz II procedure. It is rarely done nowadays due to infection of the kidneys, electrolyte imbalances and secondary cancer formation at the anastomosis between the ureters and sigmoid colon.

Most patients will also need:

• Neo-adjuvant chemotherapy - using cisplatin-based regimen.
• Follow-up:
• Routine CT imaging
• Routine bloods - especially B12 and folate levels after performing an ileal resection.