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Contents
Abstract
- Urological malignancies are cancers of the urinary system and are common in the UK. Renal cell carcinomas and transitional cell carcinomas are two important urological malignancies discussed in this article.
- Haematuria (blood in the urine) is one of the main presenting complaints in urological malignancies, especially bladder cancer.
- Renal cell carcinomas are adenocarcinomas (cancers of gland-type epithelial cells) arising in the kidney nephron and are the most common renal cancer. They arise from the renal tubular epithelium within the renal parenchyma (the working tissue of the kidney). Some of the risk factors include smoking, obesity, male sex and hypertension.
- Many renal cell carcinomas are found by chance on scans done for other reasons. When there are symptoms, they include haematuria, flank pain (pain in the side, between the ribs and the hip), weight loss, lethargy (unusual tiredness), an abdominal mass and a left-sided varicocele (swollen veins in the scrotum).
- The main investigations for a renal cell carcinoma are urinalysis, ultrasound scan, contrast CT scan and biopsy (taking a small tissue sample). A biopsy is now usually offered for tumours 4 cm or smaller and before ablation (destroying the tumour in place), to confirm the diagnosis and guide treatment.
- Management of renal cell carcinomas includes surgical excision (surgical removal), ablative therapy, active surveillance (monitoring with regular scans) and systemic drug treatment. Surgical excision is by either partial or radical nephrectomy (removing part or all of the kidney). Ablative therapies destroy the tumour in place, by freezing or heating it, without cutting it out. Systemic treatment for advanced disease uses immunotherapy (drugs that help the immune system attack the cancer) and targeted drugs (medicines that slow or stop the cancer growing).
- Transitional cell carcinomas (now usually called urothelial carcinomas) are the main cancer affecting the bladder and are classified by how far the cancer invades into the bladder wall. The three classifications are non-muscle invasive, muscle invasive and locally advanced. Some risk factors include smoking, occupational exposure to carcinogens (substances that cause cancer) and male sex. A long-term catheter also raises the risk of bladder cancer, more often the squamous cell (flat cell) type than transitional cell carcinoma.
- Transitional cell carcinomas present with haematuria, lower urinary tract symptoms, pelvic pain, pelvic mass and weight loss.
- The main investigations for a transitional cell carcinoma are cystoscopy (looking inside the bladder with a thin camera passed up the urethra), ultrasound scan and blood tests. Flexible and rigid cystoscopies are used to investigate transitional cell carcinomas.
- Management of transitional cell carcinomas depends on the TNM (tumour, nodes, metastases) stage and on the tumour’s classification. Treatment includes transurethral resection of bladder tumour (TURBT: removing the tumour through the urethra), intravesical therapy (drugs put into the bladder), chemotherapy, cystectomy (surgical removal of the bladder), radiotherapy and palliative treatment.
Core
The term urological cancer is used to describe cancers of the urinary system, for example kidney and bladder cancer. It also covers cancers of the male reproductive organs, such as the prostate, testes and penis. Urological cancers are fairly common in the UK, and prostate cancer is the most common. This article covers the two main cancers of the urinary system: renal cell carcinomas, which arise in the kidney, and transitional cell carcinomas, which are more common in the bladder.
One of the main presentations of urological malignancy is haematuria, which can be visible or invisible (found on a urinary dipstick). This is important because patients presenting to the GP with unexplained haematuria may need a suspected cancer pathway referral to urology, depending on their age and other features. This is an urgent referral that aims to confirm or rule out cancer within 28 days. NICE recommends this referral for people:
- Aged 45 and over with:
- Unexplained visible haematuria without urinary tract infection, or
- Visible haematuria that persists or recurs after treatment of urinary tract infection.
- Aged 60 and over with:
- Unexplained non-visible haematuria and either dysuria (pain on passing urine) or a raised white cell count on a blood test.
People aged 60 and over with recurrent or persistent unexplained urinary tract infection do not meet these urgent criteria, but NICE advises considering a non-urgent referral for bladder cancer.
Renal cell carcinomas (RCCs) are the most common renal cancer, making up more than 9 in 10 kidney cancers in adults. Other kidney cancers include transitional cell carcinomas of the renal pelvis (which behave like bladder cancers), nephroblastomas (Wilms’ tumours, mainly seen in young children) and squamous cell carcinomas (cancers of flat surface cells).
Most renal cell carcinomas are adenocarcinomas that arise from the proximal renal tubular epithelium. Histologically (under the microscope), about 80 to 90% are clear cell carcinomas, so called because the cells contain abundant glycogen and lipid. Other subtypes include papillary, chromophobe and renal medullary carcinoma. Papillary RCCs also arise from the proximal tubule, but chromophobe RCCs arise from intercalated cells (cells found in the collecting ducts).
They can arise anywhere within the renal cortex and may spread by direct invasion into surrounding tissue, by growing into the renal vein (sometimes as far as the inferior vena cava), and through the lymphatic system and the blood (haematogenous spread).
- Smoking
- Male
- Obesity
- Dialysis
- Hypertension
- Industrial exposure to carcinogens
- Family history - a small number of renal cell carcinomas have a genetic aetiology (cause), for example an inherited condition such as tuberous sclerosis.
- Haematuria - this is one of the main symptoms of renal cell carcinomas. It can either be visible or invisible.
- Flank or loin pain
- Weight loss
- Lethargy
- Fever
- Palpable abdominal mass - if a patient with renal cell carcinoma has a palpable abdominal mass, the cancer is typically quite advanced.
- Paraneoplastic syndromes - these are a group of syndromes that occur as a result of the malignancy and occur in around 20% of patients. In RCCs the main paraneoplastic syndromes are caused by hormone secretion:
- Renin (a hormone made by the kidney that raises blood pressure) - increased renin secretion causes hypertension.
- Parathyroid hormone-related peptide (PTHrP) - increased secretion results in hypercalcaemia (a high blood calcium level).
- Erythropoietin (the hormone that drives red blood cell production) - increased erythropoietin production causes polycythaemia (too many red blood cells).
- Adrenocorticotropic hormone (ACTH, which makes the adrenal glands release cortisol) - results in Cushing’s syndrome (the effects of too much cortisol) due to a raised cortisol level.
- Left-sided varicocele - if a renal cell carcinoma impinges on the left testicular vein then it can cause a build up of blood within the testicular venous plexus causing a varicocele (enlarged, swollen veins in the scrotum).
- This is classically associated with left sided RCCs, as the left gonadal vein drains into the renal vein and can be compressed by a tumour, whereas the right gonadal vein drains directly into the inferior vena cava.
If a patient is suspected to have a renal cell carcinoma then they will be referred to urology. The first-line investigations are blood tests, urinalysis and imaging to identify the site and size of the lesion.
- The main blood tests to undertake are a full blood count, urea and electrolytes, calcium and liver function tests.
- Urinalysis will be used to look for haematuria which is a red flag for urological malignancy. Urine cytology (examining cells from the urine under a microscope) looks for malignant cells shed into the urine. It detects few renal cell carcinomas, so it is more useful for transitional cell carcinomas.
- Many renal cell carcinomas are asymptomatic (cause no symptoms) and are picked up as an incidental finding on imaging.
- Ultrasound, CT and MRI scans are used in the imaging in renal cell carcinoma as they can identify the lesion and can help in carrying out a biopsy of the lesion. A CT scan of the chest, abdomen and pelvis is used to stage the cancer and look for any metastases.
- NICE recommends a multiphase contrast-enhanced CT of the abdomen (scans taken at different stages as contrast dye passes through the kidney) to assess the kidney. An MRI of the abdomen, ideally with contrast, is used if this CT is not possible. The chest and pelvis are then scanned, ideally with contrast, to complete staging.
- Biopsy (taking a small tissue sample with a needle) helps to confirm the diagnosis and plan treatment. NICE recommends offering it for tumours 4 cm or smaller, and considering it for some larger ones. A biopsy must confirm cancer before ablation, and it is also offered to people with suspected metastatic RCC who are not having surgery first. It is not offered if the result would not change management.
- Those who have surgical excision of the tumour will have it sent to pathology so that the type of renal cell carcinoma can be defined.
The TNM staging system is used to stage renal cell carcinomas as this gives an idea about the prognosis of the malignancy. In England, almost 90% of people with stage I kidney cancer survive their cancer for 5 years or more after diagnosis, compared with around 15% of people with stage IV. These figures are for people diagnosed between 2016 and 2020.
The management of renal cell carcinoma depends on the size of the cancer and on the presence of metastases. Those with local disease typically undergo surgical excision of the malignancy. Those with metastatic disease are mainly treated with systemic anticancer therapy (drugs that act throughout the body, such as immunotherapy and targeted drugs). Surgery is used only in selected patients (see below).
- Surgical excision is the main treatment for localised renal cell carcinomas. It is also used for locally advanced ones, which have grown into nearby tissue or blood vessels, or spread to nearby lymph nodes, but not to distant parts of the body. The two main types of surgical excision are:
- Partial Nephrectomy - this is where only part of the kidney is removed. It is either performed by open, laparoscopic (keyhole) or by robotic surgery. Only small RCCs are removed by partial nephrectomy.
- Radical Nephrectomy - this is where the whole kidney is removed, along with the adrenal gland and the fat surrounding the kidney. This can be either open surgery or laparoscopic and is for RCCs that cannot be excised by partial nephrectomy.
- Ablative therapies can be used to destroy a tumour in place, without cutting it out. They are mainly used for smaller tumours in people who cannot have, or do not want, surgery. A biopsy must first confirm that the tumour is a cancer. Ablative therapies include cryoablation (freezing the tumour), radiofrequency ablation and microwave ablation (both heat the tumour). Some small tumours, especially those under 2 cm, can instead be monitored with regular scans (active surveillance).
- Metastatic disease is treated depending on how many metastases there are. Metastatic RCC is called stage IV and has a very poor prognosis. Cure may not be possible, so the aim of treatment is often to slow disease progression, control symptoms and help the patient live longer. Palliative care also helps the patient to remain comfortable.
- A solitary metastatic lesion does not automatically require immediate cytoreductive nephrectomy plus immunotherapy. A specialist multidisciplinary team assesses prognosis, performance status, resectability and the need for systemic treatment. Nephrectomy with complete local treatment of metastases may be considered in selected patients; patients who need prompt systemic treatment may start this first, with delayed nephrectomy considered after clinical benefit.
- If there are widespread metastases then the main treatment is systemic anticancer therapy. Options include targeted drugs such as sunitinib, and immunotherapy, often combined with a targeted drug (for example, nivolumab with cabozantinib). Cytoreductive nephrectomy may be considered later if the cancer has shrunk on treatment and most of what remains is in the kidney. It may also be used to control symptoms such as bleeding or pain.
The urinary system is lined by transitional cell epithelium, the urothelium, so it is at risk of developing a transitional cell carcinoma (TCC), now usually called a urothelial carcinoma. The majority of TCCs are found in the bladder but they can also be found in the upper urinary system, i.e. in the kidney and ureter. This article will focus on bladder transitional cell carcinomas.
Bladder Transitional Cell Carcinomas
Bladder transitional cell carcinomas (TCCs) are the most common type of bladder cancer, making up over 90% of bladder cancers in industrialised countries such as the UK. Bladder cancer is more common in men and in people over 60. Other bladder cancer types include squamous cell carcinomas and adenocarcinomas, though these are less common in the UK.
Bladder cancers are classified by how far the cancer invades into the muscle of the bladder wall. There are three main classifications:
- Non-Muscle Invasive - the bladder cancer stays in the inner layers of the bladder wall and has not grown into the detrusor muscle (the main muscle layer of the bladder wall).
- Muscle Invasive - the bladder cancer penetrates into the deeper layers of the bladder wall but not into surrounding structures.
- Locally Advanced - the bladder cancer penetrates through the entire bladder wall and spreads beyond the bladder, into the surrounding structures.
- Smoking - this is the greatest risk factor for transitional cell carcinoma.
- Occupational exposure - some occupations have an increased risk of bladder cancer because of the carcinogens they are exposed to in the work environment, e.g. rubber/plastic manufacturer, crude oil, smelting, painter, mechanic and hairdresser.
- White ethnicity
- Male
- Chronic irritation - e.g. infection, schistosomiasis (bilharzia, a parasitic worm infection), bladder stones and a long-term catheter. These mainly increase the risk of bladder squamous cell carcinomas, although transitional cell carcinomas can also occur.
- Cyclophosphamide (a chemotherapy drug)
- Haematuria - this may be macroscopic (visible) or microscopic (invisible, picked up on a urinary dipstick). Patients typically present with macroscopic haematuria in bladder cancer.
- Lower urinary tract symptoms - these include nocturia (passing urine at night), urgency, frequency, incomplete emptying, terminal dribble (dribbling at the end of passing urine), hesitancy (difficulty starting to pass urine), straining and post-micturition dribble (leaking just after passing urine).
- Recurrent urinary tract infections
- Pelvic pain - patients may present with pelvic pain if they have locally advanced disease.
- Pelvic mass
- Weight loss
- Loss of appetite
- Urinary retention - patients may present with urinary retention if the tumour obstructs the internal urethral orifice.
- Systemic symptoms of metastases if late stage.
Bladder carcinomas may be an incidental finding on imaging that was done to investigate something else.
Bladder transitional cell carcinomas are investigated by cystoscopy, blood tests, ultrasound scan, MRI and CT scans. Urinalysis is also used to check for blood in the patient's urine as haematuria is an indicator of bladder TCCs.
Cystoscopy is the main investigation used for transitional cell carcinomas. A flexible cystoscopy is used to visualise the bladder and assess for any suspicious lesions, and is usually the first investigation performed if bladder malignancy is suspected. If a suspicious lesion is found then a rigid cystoscopy is performed to remove the lesion and biopsy it. This is a transurethral resection of the bladder tumour (TURBT), which both treats the tumour and provides tissue for diagnosis. The sample should include some of the detrusor muscle, so the pathologist can see whether the cancer has invaded the muscle.
An ultrasound scan can be used to look for any lesions prior to cystoscopy, and is also used to check for urinary retention if indicated. A pelvic MRI or CT scan are used to assess the size of the bladder malignancy and see if it has invaded into the muscle wall or surrounding structures. MRI and CT scans can also be used to look for any metastases.
It is also important to check the patient’s renal function and full blood count (for anaemia and infection). Other blood tests to do include liver function tests and alkaline phosphatase (an enzyme released mainly from bone and liver). A raised alkaline phosphatase may raise suspicion of bone involvement, and further imaging such as a bone scan may be considered in the appropriate clinical context.
The treatment of bladder transitional cell carcinoma depends on whether the tumour has invaded into the muscle wall or if it has metastasised. Bladder TCCs use the TNM staging system to stage the severity of the bladder malignancy.
Non-muscle invasive TCCs are treated by transurethral resection of the bladder tumour (TURBT), which involves going in through the urethra and removing the tumour. The tumour can then be sent off to pathology for further analysis.
- Other treatments for non-muscle invasive TCCs include intravesical cytotoxic chemotherapy (cell-killing drugs put directly into the bladder) and intravesical BCG. NICE recommends a single dose of the chemotherapy drug mitomycin C, put into the bladder at the same time as the first TURBT, to reduce the risk of recurrence. People with intermediate-risk disease are offered a course of at least 6 doses. BCG (Bacille Calmette-Guérin) is the live TB vaccine, which contains a weakened form of the TB bacteria. Put into the bladder, it triggers an immune response against the cancer, so it is a form of immunotherapy. It is offered to people with high-risk disease, as an alternative to removing the bladder, and is given as an initial course followed by maintenance doses.
- Non-muscle invasive bladder tumours have a high rate of recurrence, so patients need regular surveillance with cystoscopy. How often and for how long depends on the risk group. People with low-risk disease have cystoscopy at 3 and 12 months, without routine urine cytology, and are discharged if the cancer has not come back. People with high-risk disease have cystoscopy every 3 months for 2 years, every 6 months for the next 2 years, then once a year.
Muscle invasive TCCs are treated with either cystectomy (removal of the bladder) or chemoradiation (radiotherapy given together with chemotherapy). Cystectomy is the removal of the bladder along with the prostate in men, and the uterus and ovaries in women. Neoadjuvant chemotherapy is often given before the cystectomy as it increases patient survival rate. After cystectomy, patients require regular follow-up with a CT scan.
- After a cystectomy, patients require either an ileal conduit formation or bladder reconstruction. In ileal conduit formation, a short piece of the ileum carries urine from the ureters to a urostomy (an opening on the abdomen), and the urine drains into a bag worn over it. Bladder reconstruction involves using part of the small bowel to form a new bladder (a neobladder). Urine then drains through the urethra, or the patient empties the new bladder using a catheter.
- Chemoradiotherapy is the other treatment for muscle invasive TCCs. Instead of having their bladder removed, patients have a course of radical radiotherapy given with a radiosensitiser (a treatment that makes the cancer cells more sensitive to radiation, such as the chemotherapy drugs mitomycin and fluorouracil).
Metastatic disease is treated with the intention to control symptoms and prolong survival of the patient as metastatic disease is incurable, so is treated palliatively. The management is decided by a multidisciplinary team and is split into measures for local disease and for systemic disease.
- Local treatment aims to relieve symptoms. Palliative radiotherapy to the bladder can ease haematuria, dysuria, frequency and nocturia. Radiotherapy or embolisation (blocking the blood vessels supplying the tumour) can control heavy bleeding. If the tumour blocks the ureters, a nephrostomy (a tube from the kidney out through the skin) or a stent (a tube inside the ureter) can relieve the blockage. In selected patients, radical cystectomy and urinary diversion (redirecting urine away from the bladder) may also be used to relieve symptoms.
- Systemic treatment includes chemotherapy (and, in selected patients, immunotherapy). Radiotherapy is used for local or palliative control of symptomatic metastases rather than as a systemic treatment.
- Patients will have regular follow-ups and reviews for detection and treatment of progressive disease and to treat any new symptoms that may develop.
Edited by: Dr. Maddie Swannack
Reviewed by: Adrian Judge and Dr. Marcus Judge
Quiz
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