Urothelial carcinoma

by Jason Wasserman MD PhD FRCPC
March 25, 2023

What is urothelial carcinoma?

Urothelial carcinoma is a type of cancer that starts in a part of the body called the urinary tract. The urinary tract includes the bladder, ureters, urethra, and kidneys. It is the most common type of bladder cancer. Urothelial carcinoma arises from specialized urothelial cells that cover the inside surface of these organs and create a barrier called the urothelium.

What causes urothelial carcinoma?

Studies have shown that a wide variety of toxins, medications, and infections are associated with an increased risk of developing urothelial carcinoma. Toxins that can cause urothelial carcinoma include tobacco smoke, opium, benzidine-based dyes, aromatic amines, arsenic, and aristolochic acid produced by Aristolochia plants (which are commonly used in herbal medications). Chronic (long-term) inflammation in the bladder caused by infections such as the Schistosoma haematobium and prolonged indwelling catheter use are also associated with an increased risk of developing urothelial carcinoma in the bladder. Some medical treatments including radiation to the pelvis and chemotherapy with chlornaphazine or cyclophosphamide have also been shown to increase the risk of developing urothelial carcinoma in the bladder.

Which genetic syndromes are associated with an increased risk of developing urothelial carcinoma?

The risk of developing urothelial carcinoma is increased in both Lynch syndrome and Costello syndrome. In people with Lynch syndrome, the tumours tend to develop in the upper part of the urinary tract, for example, the kidneys or the ureters. People with Costello syndrome are more likely to develop a tumour in the bladder.

What are the symptoms of urothelial carcinoma?

Symptoms of urothelial carcinoma include blood in the urine, pain when urinating, or the need to urinate more frequently. Large tumours or those that start in the ureters may block the flow of urine which can lead to back or abdominal pain.

How is the diagnosis of urothelial carcinoma made?

The diagnosis of urothelial carcinoma is usually made by looking at a urine sample under a microscope. The diagnosis can also be made after a small sample of tissue is removed from the urinary tract during a procedure called a biopsy. For larger tumours that involve the bladder or kidney, part or all of the organ may need to be removed in a procedure called a resection.

What does grade mean and why is the grade important for urothelial carcinoma?

Pathologists divide urothelial carcinoma into two grades – low grade and high grade – based on how the tumour cells look when examined under the microscope. However, the vast majority of tumours are considered high-grade. Low-grade tumours are made up of cells that look more like normal urothelial cells while high-grade tumours are made up of more abnormal-looking cells that tend to be larger, darker, and less organized than normal urothelial cells.​ The grade is important because high-grade tumours are more likely to re-grow after treatment and spread to other parts of the body.​

What does it mean if urothelial carcinoma shows squamous differentiation?

Squamous differentiation in urothelial carcinoma means that some of the cells in the tumour have changed to look like the specialized squamous cells that are normally found in the skin. Up to 40% of urothelial carcinomas will show squamous differentiation.

What does it mean if urothelial carcinoma shows glandular differentiation?

Glandular differentiation in urothelial carcinoma means that some of the cells in the tumour have started to connect together to form round structures called glands. The glands may look similar to the glands normally found in the colon.

What is a variant of urothelial carcinoma and why are variants important?

A variant of urothelial carcinoma is a tumour that is made up of cells that grow or stick together in a way that makes the tumour different from conventional urothelial carcinoma. Variants are important because some variants, such as micropapillary, plasmacytoid, sarcomatoid, and poorly differentiated, are aggressive tumours that are more likely to spread to other parts of the body.

Micropapillary urothelial carcinoma

In the micropapillary variant of urothelial carcinoma, the tumour cells connect to form very small finger-like projections that pathologists describe as “micropapillary”. The groups of tumour cells are often found in open spaces called “lacunae”. The micropapillary variant of urothelial carcinoma is considered an aggressive variant that commonly spreads to lymph nodes and other parts of the body.

Nested urothelial carcinoma

In the nested variant of urothelial carcinoma, the tumour cells connect together to form small groups called “nests”. Because the nests of tumour cells can look very similar to normal structures found in the bladder, it may be difficult for your pathologist to diagnose this variant on a small tissue sample such as a biopsy.

Tubular and microcystic urothelial carcinoma

The tubular and microcystic variants of urothelial carcinoma are related and are typically thought of as a single variant. The tumour cells in this variant connect together to form small round structures called “tubules” or “microcysts”.

Large nested urothelial carcinoma

In the large nested variant of urothelial carcinoma, the tumour cells connect together to form large groups of cells called nests. As the name implies, the nests in the “large nested” variant of urothelial carcinoma are larger than the nests in the “nested variant”. The large nested variant of urothelial carcinoma is considered an aggressive variant that commonly grows outside of the bladder and spreads to lymph nodes and other parts of the body.

Plasmacytoid urothelial carcinoma

In the plasmacytoid variant of urothelial carcinoma, the tumour cells look very similar to a type of immune cell called a plasma cell. Unlike other variants of urothelial carcinoma, the tumour cells in the plasmacytoid variant do not stick together as the tumour grows. Pathologists describe this pattern of growth as “discohesive”. The plasmacytoid variant of urothelial carcinoma is considered an aggressive variant that commonly grows outside of the bladder and spreads to lymph nodes and other parts of the body.

Sarcomatoid urothelial carcinoma

In the sarcomatoid variant of urothelial carcinoma, the tumour cells look similar to a type of cancer called a sarcoma. The sarcomatoid variant of urothelial carcinoma is an aggressive variant that commonly spreads to other parts of the body including the lungs and the bones. Occasionally, the tumour cells in the sarcomatoid variant of urothelial carcinoma may look like the cells normally found in bone, muscle, cartilage, or blood vessels. This is called heterologous differentiation and tumours that show heterologous differentiation are associated with a worse prognosis than those that do not show this change.

Lymphoepithelioma-like urothelial carcinoma

In the lymphoepithelioma-like variant of urothelial carcinoma, the tumour cells do not resemble normal urothelial cells. In contrast, the tumour cells are often described as undifferentiated because they do not look like any normal type of cell. In this variant, the tumour cells are often surrounded by immune cells called lymphocytes.

Clear cell urothelial carcinoma

In the clear cell variant of urothelial carcinoma, the tumour cells are filled with a material called glycogen which gives the tumour cells a “clear” look when examined under the microscope.

Poorly differentiated urothelial carcinoma

In the poorly differentiated variant of urothelial carcinoma, the tumour cells look very different from the urothelial cells normally found in the urinary tract. Pathologists often need to perform a test called immunohistochemistry to confirm that the cells originated in the bladder and to make the diagnosis.

What does invasion mean and why is it important for urothelial carcinoma?

Invasion is a word pathologists use to describe the spread of tumour cells from the place where the tumour started into surrounding tissues. All urothelial carcinomas start in a thin layer of tissue called the urothelium that covers the inside surface of the urinary tract. As the tumour grows, the tumour cells spread into the layers of tissue below the urothelium. These layers include the lamina propria, muscularis propria, and perivesical soft tissue.

The distance that the tumour cells have spread is called the depth of invasion and it can only be determined after the tumour is examined under the microscope. The depth of invasion is very important because tumours that invade deeper into the surrounding tissue are more likely to spread to other parts of the body. The depth of invasion is also used to determine the pathologic tumour stage (pT).

What is lymphovascular invasion and why is it important?

Lymphovascular invasion means that tumour cells were seen inside a blood vessel or lymphatic vessel. Blood vessels are long thin tubes that carry blood around the body. Lymphatic vessels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. Lymphovascular invasion is important because tumour cells can use blood vessels or lymphatic vessels to spread to other parts of the body such as lymph nodes or the lungs.

Were lymph nodes examined and did any contain tumour cells?

Lymph nodes are small immune organs located throughout the body. Tumour cells can travel from the tumour to a lymph node through lymphatic channels located in and around the tumour (see Lymphovascular invasion above). The movement of tumour cells from the tumour to a lymph node is called metastasis.

Your pathologist will carefully examine all lymph nodes for tumour cells. Lymph nodes that contain tumour cells are often called positive while those that do not contain any cancer cells are called negative. Most reports include the total number of lymph nodes examined and the number, if any, that contain tumour cells. Lymph nodes on the same side as the tumour are called ipsilateral while those on the opposite side of the tumour are called contralateral.

The number of lymph nodes found to contain tumour cells is used to determine the pathologic nodal stage (pN). Finding tumour cells in a lymph node is associated with a worse prognosis and may require additional treatment.

What is a margin?

A margin is the normal tissue that surrounds a tumour and is removed with the tumour at the time of surgery. A negative margin means that no tumour cells were seen at the cut edge of the tissue. A margin is called positive when there is no distance between the tumour and the cut edge of the tissue. A positive margin is associated with a higher risk that the tumour will grow back (recur) in the same location after treatment.

How is urothelial carcinoma staged?

​The pathologic stage for urothelial carcinoma is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. This system uses information about the primary tumour (pT), lymph nodes (pN), and distant metastatic disease (pM)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. In general, a higher number means more advanced disease and a worse prognosis.

Tumour stage (pT) for urothelial carcinoma

Urothelial carcinomas are given a tumour stage from 1 to 4 based on the depth of invasion.

• T1 – The tumour cells have entered the lamina propria just below the urothelium.
• T2 – The tumour cells have spread into the muscularis propria.
• T3 – The tumour cells are in the perivesical soft tissue.
• T4 – The tumour cells have invaded surrounding organs such as the prostate, uterus, or pelvic wall.​

Nodal stage (pN) for urothelial carcinoma

Urothelial carcinoma is given a nodal stage between 0 and 3 based on the number of lymph nodes that contain cancer cells and the location of those lymph nodes.

• ​N0 – No tumour cells are seen in any of the lymph nodes examined.
• N1 – Tumour cells are found in one lymph node in the pelvis.
• N2 – Tumour cells are found in more than one lymph node in the pelvis.
• N3 – Tumour cells are found in the common iliac lymph nodes which are located outside of the pelvis.
• NX – No lymph nodes were sent for pathologic examination.

Metastatic stage (pM) for urothelial carcinoma

Urothelial carcinoma is given a metastatic stage of 0 or 1 based on the presence of tumour cells at a distant site in the body (for example the lungs). The metastatic stage can only be determined if tissue from a distant site is submitted for pathological examination. Because this tissue is rarely present, the metastatic stage cannot be determined and is listed as MX.