Infiltrative Urothelial Carcinoma

The most common tumour of the bladder. There are thirteen recognised variants.


7th most common malignancy in the world.
4 times more common in men than women.
6 times more common in the developed world.
Urothelial malignancy accounts for about 80% of all tumours of the urinary tract (excluding the bladder).
About 75% of urothelial malignancies are non-invasive or only superficially invasive
Urothelial cancer is a much less common cause of urinary tract malignancy in some parts of Africa (Egypt, western Africa), where squamous cell carcinoma makes up about 40% of malignancies. This is due to bladder infection with Schistasomiasis. In other parts of the world squamous cell carcinoma only makes up 2% of malignancies.


  • Smoking is the most strongly associated risk factor for the development of urothelial malignancy, contributing to about 66% of cases in men and 30% of cases in women.
  • Occupational exposure to chemicals is involved in the pathogenesis for about 25% of bladder malignancies. The most commonly associated chemicals are aromatic amines, often used as dyes.
  • A more modern risk factor is pioglitazone, an oral hypoglycaemic. This increases the risk of malignancy by 40-50%.
  • Phenacetin, previously used as an antipyretic, was found to cause a smaller number of bladder malignancies and was withdrawn in 1983. Paracetamol is a safe metabolite of phenacetin.
  • Cyclophosphamide has been implicated in the development of some bladder cancers, usually squamous cell carcinoma or leiomyosarcoma
  • Chronic infection with Schistasomiasis is more commonly indicated in the development of squamous cell carcinoma
  • Low levels of arsenic ingestion have also been shown to cause bladder malignancy


There are several postulated methods by which environmental exposures can lead to bladder malignancy:

  • Aromatic amines are known to cause DNA adducts when they are metabolised. This could lead to loss of tumour suppressor function or genetic instability.
  • Cigarette smoke contains similar aromatic amines used in occupational settings
  • Prolonged exposure leads to accumulation of genetic damage and hyperplasia of the urothelium
  • Further mutation leads to development of carcinoma in situ or high grade, non-invasive papillary urothelial carcinoma
  • These conditions are the precursor lesions of truly invasive carcinoma

Natural History

Pre-Invasive Lesions

There are several pre-invasive lesions that can develop in the urothelium:

  • Urothelial hyperplasia refers to a thickened epithelial layer, with normal structure otherwise preserved. The malignant potential is thought to be low but it is often seen in association with malignant conditions
  • Urothelial dysplasia consists of urothelium with cytological abnormalities that are not sufficient to meet the grade of carcinoma in situ. If seen with non-invasive papillary tumours, it suggest genetic instability and increases the risk of recurrence. About 10% of patients with dysplasia will develop a malignancy in the future; however, the malignancy may not arise from the area of dysplasia!
  • Papillary urothelial neoplasm of low malignant potential (PUNLMP) is an uncommon tumour that is nearly always cured by excision. It has a low rate of recurrence and almost never leads to invasive malignancy.
  • Low grade (Grade 1 - 2) papillary urothelial carcinoma contains significantly different genetic alterations than high grade, in situ or invasive disease. It is usually considered to be low risk for development of further malignancy
  • High grade (Grade 3) papillary urothelial carcinoma contains widespread cytological abnormalities and a disordered growth pattern. They have a tendency to recur or progress to invasive disease
  • Carcinoma in situ is a flattened lesion (not papillary) that shows malignant cells that are not penetrating the basement membrane. They are genetically unstable and may progress to invasive disease.

Natural History

Once invasive disease has developed, it must invade through the basement membrane and lamina propria to reach the muscularis mucosae. It must then invade through the detrusor muscle. The lamina propria of the mucosa is supplied by neurovascular structures which may facilitate spread to regional nodes or haematogenously.
Local invasion into the ureteric orifice can lead to hydronephrosis and renal failure. Alternatively, local invasion outside of the bladder wall can lead to ureteral obstruction. Lymph nodes are typically involved sequentially, with the iliac nodes falling first, followed by retroperitoneal and then mediastinal nodes.
Haematogenous spread commonly occurs to the liver, lungs, or bone. Lymph node involvement is a strong predictor of distant metastatic disease.

Field Effect vs Transcoelemic Spread

Pre-invasive lesions have a high risk of recurrence, often exceeding 50%. There are two main schools of thought:

  • That chronic exposure to carcinogens has led to genetic instability in a large portion of the urothelium - FIELD EFFECT
    • This is supported by the multiclonal nature of non-invasive urothelial malignancies and the delays between recurrent disease
  • That malignant tumours of the urothelium are able to seed the otherwise normal epithelium with malignant cells - TRANSCOELEMIC SPREAD
    • This is supported by the monoclonal nature of invasive malignancies of the urothelium and their recurrences

Regardless of the cause, the high frequency of recurrent disease means that patients who are diagnosed with non-invasive disease often need regular cystoscopies to ensure recurrence has not developed.

Clinical Presentation


For urothelial carcinoma of the bladder, the most common symptom is macroscopic haematuria, present in about 85% of cases at diagnosis. Depending on the tumour location, patients may also complain of difficulty with urination (due to bladder outflow obstruction) or pain. Advanced cases may simply present with cachexia or renal failure.


Rarely, a mass may be palpable or in the abdomen. Bony metastases can be painful. The patient may also be cachectic in very advanced disease.

Blood Findings

Anaemia due to blood loss is not uncommon. There are no helpful tumour markers.

Imaging Findings

A CT Scan of the chest, abdomen and pelvis is most useful in staging disease. A large bladder tumour may be visible within the bladder wall. Local invasion into adjacent structures is seen as a loss of fat planes. Lymph node metastases may be visible on CT imaging, allowing patients to be staged appropriately. Visceral metastases can also be seen.

Tumour Features

There is a broad range of appearances, dependent on the tumour stage.

Urothelial Dysplasia


The lesion may appear normal, or alternatively have an appearance of erythema. Rarely, the lesion may be pale or ulcerated.


Dysplasia consists of:

  • Loss of cellular polarity
  • Increased numbers of cells
  • Nuclear atypia

Mitoses are uncommon. If they occur in the upper layers then carcinoma in situ is the usual diagnosis.


When present with non-invasive papilloma, dysplasia suggests the epithelium is unstable and prone to further anaplasia. About 10% of patients with dysplasia will go on to develop invasive malignancy; this malignancy might not arise from the dysplastic area however!

Urothelial Carcinoma In Situ


These lesions may not be visible. They may also appear as erythematous or swollen areas. Mucosal ulceration is unusual.


Unlike dysplasia, carcinoma in situ possesses marked anaplasia, with mitoses through all levels of the epithelium, hyperchromatic nuclei and polymorphism. There is no invasion through the basement membrane. Carcinoma in situ does not form papillary lesions.


Cells from carcinoma in situ are typically poorly cohesive as part of their anaplasia. They can be seen in > 95% of urine cytology specimens if carcinoma in situ is present.


Carcinoma in situ in the absence of invasive disease has a 5 year survival of 85%; if invasion is present then survival falls dramatically. 40% of cases develop into invasive carcinoma after 15 years.

Non-Invasive Papillary Urothelial Neoplasia

There are four grades of non-invasive papillary urothelial neoplasia:

  • Papillomas are benign growths of tissue that are covered by normal urothelium
  • Papillary Urothelial Neoplasia of Low Malignant Potential (PUNLMP)
  • Low Grade Papillary Urothelial Neoplasia
  • High Grade Papillary Urothelial Neoplasia


These lesions have a variety of macroscopic appearances. The 'classic' appearance is of polyps that extend off the bladder wall, often tan to red in colour. Other appearances includes sessile polyps.


The fronds in a benign papilloma are covered by a normal urothelium and do not fuse. Mitoses are very rare and confined to the basal layer. There is no increased cellularity.
PUNLMP has an increased number of cells compared to the benign papilloma, but is otherwise the same. There is no cellular atypia. Mitoses remain on the basal layer.
Unlike PUNLMP, the cells of low grade papillary urothelial neoplasia have some mild anaplastic features, with some loss of nuclear polarity and a low number of mitoses present throughout most layers. The fronds may fuse together to a small degree.
High grade papillary urothelial neoplasia is lined by epithelium reminiscent of carcinoma in situ (above). They typically have significant anaplasia with loss of polarity and pleomorphism. Invasion is common in these lesions which possess a poorer prognosis.


PUNLMPs only progress in 4% of cases but can recur in 25% of patients.
Low grade papillary urothelial neoplasms progress in 10% of patients. They have a 50% risk of recurrence.
High grade lesions progress with much greater frequency (65%)

Infiltrating Urothelial Carcinoma


Urothelial malignancies can have a wide range of macroscopic appearances, with exophytic papillae/nodules, an invasive mass that extends through the bladder wall, ulcerated areas or a combination of features. The tumour is particularly firm to palpation.


Invasive urothelial malignancies can possess a wide range of cytological features. There are no specific features to urothelial carcinoma. Malignant cells are usually anaplastic, large and with significant cellular and nuclear polymorphism. Growth occurs in nests or strands. Urothelial malignancy often contains areas of divergent differentiation:

  • About 1 in 5 malignancies will show areas of squamous differentiation (distinct from squamous cell carcinoma of the bladder which has a different aetiology in most cases). This is a poor prognostic feature.
  • 1 in 20 malignancies will show regions of glandular differentiation, occasionally with mucin production
  • Sarcomatoid, micropapillary, nested, rhabdoid or lymphoepithelial variants are associated with a poorer prognosis.
  • The presence of a small cell (or 'neuroendocrine component') overrides the diagnosis of urothelial carcinoma. These tumours should be considered as per the small cell carcinoma of the bladder page suggests.

The tumor is often associated with a dense desmoplastic stroma.


Staging depends on the site of disease:

TNM Staging for Bladder Cancer

T Stage

T stage Characteristics
T0 No tumour identified
Ta Non-invasive papillary neoplasm
Tis Carcinoma in situ
T1 Invasion into the lamina propria but not detrusor
T2a Invasion through the inner half of detrusor
T2b Invasion through the outer half of detrusor, but not beyond
T3a Microscopic invasion beyond detrusor
T3b Macroscopic invasion beyond detrusor
T4a Invasion of prostate (men) or uterus/vagina (women)
T4b Invasion of abdominal or pelvic wall

N Stage

N Stage Characteristics
N0 No lymph nodes
N1 Single external/internal iliac lymph node
N2 More than one external/internal iliac node
N3 Involvement of common iliac nodes

M Stage

M Stage Characteristics
M0 No distant metastases
M1 Distant metastases

Final Stage

Stage T N M
0a Ta N0 M0
0is Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T3-4a N0 M0
IV T4b N0 M0

TNM Stage for Ureter or Renal Pelvis Malignancy

T Stage

The T staging is the same as for the bladder, except:

  • T2 is a single stage representing invasion into, but not through, the muscularis
  • T3 represents invasion into the fat around the structure, or the renal parenchyma
  • T4 represents invasion into adjacent organs, or through the entire kidney to the perinephric fat

N Stage

N Stage Characteristics
N0 No lymph nodes
N1 Single regional node < 2 cm in size
N2 Multiple nodes < 5 cm in size, or single node 2-5 cm in size
N3 Single or multiple nodes > 5 cm in size

M Stage

Same as for bladder

Final Stage

Final staging is the same as bladder, with the presence of nodal or distant metastases resulting in Stage IV

TNM Staging of Urethral Malignancy

T Stage

T stage Characteristics
T0 No tumour identified
Ta Non-invasive papillary neoplasm
Tis Carcinoma in situ
T1 Invasion into the lamina propria
T2 Invasion of corpos spongiosum, prostate or periurethral muscle
T3 Invasion of corpos cavernosum, anterior vagina, periprostatic tissue, bladder neck
T4 Invasion of adjacent organs not covered above

N Stage

N Stage Characteristics
N0 No lymph node involvement
N1 Single node < 2 cm in size
N2 Single node > 2 cm in size, or multiple nodes

M Stage

As for bladder/ureter/renal pelvis malignancy

Final Stage

Stage T N M
0a Ta N0 M0
0is Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T1-2 N1 M0
III T3 N0-1 M0
IV T4 N0-1 M0