by Jason Wasserman MD PhD FRCPC and Zuzanna Gorski MD
January 4, 2024
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. This type of cancer sometimes arises from a non-invasive type of cancer called urothelial carcinoma in situ.
This article will help you understand your diagnosis and your pathology report for urothelial carcinoma.
The urinary tract is a system designed to help remove waste and excess water from the body through the production of urine. The urinary tract includes the kidneys, ureters, bladder, and urethra. Urine made in the kidneys flows into the bladder by way of the ureters. The bladder stores the urine until it is released from the body by way of the urethra. The inside surface of the entire urinary tract is lined by specialized urothelial cells that form a barrier called the urothelium.
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 this type of cancer 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, prolonged indwelling catheter, and some medical treatments including radiation to the pelvis and chemotherapy with chlornaphazine or cyclophosphamide have also been shown to increase the risk of developing this type of cancer.
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.
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.
Urothelial carcinoma starts from the urothelial cells normally found in the urothelium, a thin layer of tissue that covers the inside surface of the urinary tract. Although this tumour is most commonly found in the bladder, it can arise anywhere along the length 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, fat, and serosa. Your pathologist will try to determine how far the tumour cells have spread into the layers of tissue below the urothelium and the deepest level of invasion will often be described in your pathology report. This information is very important because is it used to determine the pathologic tumour stage (pT) and because tumours that invade deeper into the surrounding tissue are more likely to spread to other parts of the body. The depth of invasion may also impact the treatment options available for you.
The diagnosis 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. After the diagnosis is made, the entire tumour is usually removed in a procedure called transurethral resection (TURBT). 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.
Pathologists divide urothelial carcinoma into two grades – low grade and high grade – based on how the tumour cells look when examined under the microscope. Despite this, the vast majority of tumours are considered high grade because the tumour cells look very abnormal when compared to healthy urothelial cells. In contrast, low grade tumours are made up of cells that look more like normal urothelial cells. The grade is important because high grade tumours are more aggressive cancers that are more likely to re-grow after treatment and spread to lymph nodes and other parts of the body.
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 these tumours will show squamous differentiation.
Glandular differentiation in urothelial carcinoma means that some of the cells in the tumour have started to connect to form round structures called glands. The glands may look similar to the glands normally found in the colon.
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 look different from the typical (or conventional) type of 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. The most common variants are described in the sections below.
Micropapillary urothelial carcinoma is made up of tumour cells connected 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 is considered an aggressive variant that quickly spreads to lymph nodes and other parts of the body.
Nested urothelial carcinoma is made up of the tumour cells connected 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 urothelial carcinoma and microcystic urothelial carcinoma look similar when examined under the microscope and are typically thought of as a single variant. The tumour cells in this variant connect to form small round structures called “tubules” or “microcysts”.
Large nested urothelial carcinoma is made up of tumour cells connected to form large groups of cells called nests. As the name implies, the nests in the “large nested” variant are larger than the nests in the “nested variant”. The large nested variant 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 is made up of tumour cells that look very similar to immune cells called plasma cells. Unlike other variants, 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 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 is made up of tumour cells that look similar to a type of cancer called sarcoma. The sarcomatoid variant 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 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 is made up of tumour cells that look very different from normal urothelial cells. 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 is made up of tumour cells filled with a material called glycogen which gives the tumour cells a “clear” look when examined under the microscope.
Poorly differentiated urothelial carcinoma is made up of tumour cells that 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.
Lymphovascular invasion occurs when cancer cells invade a blood vessel or lymphatic channel. Blood vessels, thin tubes that carry blood throughout the body, contrast with lymphatic channels, which carry a fluid called lymph instead of blood. These lymphatic channels connect to small immune organs known as lymph nodes, scattered throughout the body. Lymphovascular invasion is important because it enables cancer cells to spread to other body parts, including lymph nodes or the lungs, via the blood or lymphatic vessels.
Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small lymphatic vessels. For this reason, lymph nodes are commonly removed and examined under a microscope to look for cancer cells. The movement of cancer cells from the tumour to another part of the body such as a lymph node is called a metastasis.
Cancer cells typically spread first to lymph nodes close to the tumour although lymph nodes far away from the tumour can also be involved. For this reason, the first lymph nodes removed are usually close to the tumour. Lymph nodes further away from the tumour are only typically removed if they are enlarged and there is a high clinical suspicion that there may be cancer cells in the lymph node.
If any lymph nodes were removed from your body, they will be examined under the microscope by a pathologist and the results of this examination will be described in your report. “Positive” means that cancer cells were found in the lymph node. “Negative” means that no cancer cells were found. If cancer cells are found in a lymph node, the size of the largest group of cancer cells (often described as “focus” or “deposit”) may also be included in your report. Extranodal extension means that the tumour cells have broken through the capsule on the outside of the lymph node and have spread into the surrounding tissue.
The examination of lymph nodes is important for two reasons. First, this information is used to determine the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment such as chemotherapy, radiation therapy, or immunotherapy is required.
In pathology, a margin refers to the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.
Pathologists typically assess margins following a surgical procedure like an excision or resection, aimed at removing the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.
Pathologists examine margins to check if tumour cells are present at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some cancer may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.
The pathologic stage for urothelial carcinoma is based on the TNM staging system, an internationally recognized system 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 a more advanced disease and a worse prognosis.
Urothelial carcinomas are given a tumour stage from 1 to 4 based on the depth of invasion.
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.
This article was written by doctors to help you read and understand your pathology report. Contact us if you have any questions about this article or your pathology report. Read this article for a more general introduction to the parts of a typical pathology report.