High-grade papillary urothelial carcinoma is a type of cancer that starts in the urothelial cells that line the inside of the urinary tract. The word papillary means the tumor grows as finger-like projections that stick out from the lining. The term high grade means the tumor cells look very different from normal urothelial cells under the microscope.
High-grade papillary urothelial carcinoma most often starts in the bladder, but it can also start in the kidney, the ureters, or the urethra. Many of these tumors are found while the cancer cells are still confined to the lining, which is called non-invasive. Others have already grown beyond the lining into the bladder wall, which is called invasive. Compared with low-grade tumors, high-grade tumors are more likely to grow deeper into the bladder wall and to spread.
This article explains how high-grade papillary urothelial carcinoma is diagnosed and what your pathology report says about the grade, invasion, and stage of the tumor. It also explains why treatment and close follow-up are needed even when the cancer has not invaded.
High-grade papillary urothelial carcinoma is mainly a disease of older adults, and the typical age at diagnosis is in the early 70s. It is about four times more common in men than in women. It is uncommon before the age of 40.
Smoking is the most important cause of high-grade papillary urothelial carcinoma, because chemicals from tobacco smoke are filtered into the urine and damage the lining of the bladder. Long-term exposure to certain industrial chemicals, such as aromatic amines once used in dye and rubber manufacturing, also increases risk. Other causes include arsenic in drinking water and earlier treatment with radiation to the pelvis or with the chemotherapy drug cyclophosphamide.
A small number of urothelial carcinomas are linked to an inherited condition called Lynch syndrome. This link is strongest for tumors that start in the kidney or ureter. Stopping smoking lowers the chance of new tumors forming in the bladder after treatment.
The most common symptom of high-grade papillary urothelial carcinoma is blood in the urine, which is usually painless and may come and go. Some people notice the blood themselves, while in others it is found only on a urine test. Other symptoms include burning during urination and needing to urinate often or urgently. Pain in the side or lower back can occur if a tumor blocks urine flow.
The diagnosis of high-grade papillary urothelial carcinoma usually begins after blood is found in the urine. A doctor may send a urine sample for cytology, a test in which a pathologist looks for cancer cells. Urine cytology is good at finding high-grade cancer cells because they look so different from normal cells. Our article on cytology explains this type of test.
A urologist then looks inside the bladder with a thin camera, a procedure called cystoscopy. If a tumor is seen, it is removed through the urethra in a procedure called a transurethral resection of bladder tumor, or TURBT. Our article on the TURBT pathology report explains the procedure and what pathologists examine.
Under the microscope, a pathologist sees thin projections called papillae, each with a central stalk of tissue and blood vessels called a fibrovascular core. In high-grade papillary urothelial carcinoma, the cells covering these papillae are large, vary in shape, and are arranged in a disorderly way. Many of the cells are dividing. The pathologist then decides whether the cancer cells have grown below the lining.
The pathologist also checks whether the thick muscle layer of the bladder wall, called the muscularis propria, is present in the sample. For a high-grade tumor, this is especially important, because these tumors can reach the muscle. Your TURBT report will describe the muscle layer in one of these ways:
Imaging, such as a CT scan, is often used to check the kidneys and ureters for other tumors. If the cancer is invasive, scans are also used to look for spread to lymph nodes and other organs.
The grade of a papillary urothelial carcinoma describes how different the tumor cells look from normal urothelial cells. For high-grade papillary urothelial carcinoma, grade is one of the most important findings in your report. It helps predict tumor behavior, and your team uses it to plan treatment and follow-up. Papillary urothelial carcinoma has two grades:
Some papillary urothelial carcinomas contain both low-grade and high-grade areas. Under the World Health Organization (WHO) classification, 5th edition (2022), the tumor is graded as high grade when the high-grade areas make up 5% or more of the tumor. Your report may describe the tumor as high grade even if most of it looks low grade.
Some reports, especially in Europe, also assign a grade from 1 to 3 using an older 1973 WHO system. This grade is optional, and it is given alongside the low and high grade rather than replacing it. Most high-grade tumors are grade 3 in the older system, and some are grade 2.
For high-grade papillary urothelial carcinoma, the next most important finding after grade is whether the cancer cells have grown below the lining. This process is called invasion. Your report will name the deepest layer of the bladder wall that contains cancer cells.
When high-grade papillary urothelial carcinoma invades the lamina propria, the pathologist will usually describe how much of this layer is involved, if measurable. The report may give the size or depth of the invasive area in millimeters. It may also say whether the cancer is above or below a thin band of muscle within the lamina propria, called the muscularis mucosae. More extensive invasion is linked to a higher chance that the cancer will grow into the muscle later.
When a high-grade tumor is invasive, the pathologist will also look for subtypes of urothelial carcinoma, such as the micropapillary, nested, or plasmacytoid subtype. These subtypes are listed in the College of American Pathologists (CAP) protocol and the WHO classification. Finding one in a pT1 tumor places the cancer in a higher-risk group, and your team may discuss removing the bladder early. Our article on urothelial carcinoma describes each subtype.
Your report may also mention urothelial carcinoma in situ in the lining near the papillary tumor. This flat, high-grade, non-invasive form of the cancer is common alongside high-grade papillary tumors and can be hard to see during cystoscopy. When it is present, the risk of the cancer coming back or growing into the muscle is higher.
Lymphovascular invasion means cells from the high-grade papillary urothelial carcinoma are seen inside a small blood vessel or a lymphatic channel. Your report may call this “lymphatic and/or vascular invasion,” and it is reported as present, not identified, or cannot be determined. It can only happen once the cancer has invaded below the lining, so it is not seen in non-invasive tumors. When it is present in a pT1 tumor, the risk of spread is higher, and your team may discuss removing the bladder early.
A TURBT removes high-grade papillary urothelial carcinoma in many small pieces, so the pathologist cannot tell which edges were cut during surgery. For this reason, we do not report margins on a TURBT specimen. A second TURBT is often done to make sure no tumor remains. If the bladder is later removed in an operation called a cystectomy, the margins are reported as described in our article on the radical cystectomy pathology report.
Biomarker testing for high-grade papillary urothelial carcinoma looks for features of the cancer cells that can guide treatment. Most reports do not include these tests for non-invasive or pT1 tumors. They are usually done only if the cancer becomes advanced, comes back after surgery, or if a clinical trial is being considered. They can be performed on tissue from an earlier TURBT.
FGFR3 is a gene that makes a protein involved in cell growth. Changes in FGFR3 are less common in high-grade than in low-grade papillary urothelial carcinoma, but they are still found in some tumors. Testing is done with a molecular test such as next-generation sequencing (NGS). The test looks for a mutation or a fusion with another gene.
HER2 is a protein on the surface of some cancer cells that helps them grow. In urothelial carcinoma, clinicians test for it by immunohistochemistry, mainly when the cancer is advanced. Results are scored from 0 to 3+.
PD-L1 is a protein that some cancer cells use to hide from the immune system. In urothelial carcinoma, it is tested by immunohistochemistry and usually reported as a combined positive score (CPS) or as positive or negative. For most current immunotherapy treatments for urothelial carcinoma, including those used for high-risk non-invasive tumors, a PD-L1 result is not required. If your report includes a PD-L1 result, your oncologist can explain whether it affects your treatment. Our article on PD-L1 testing in cancer explains how the test works.
Mismatch repair proteins fix mistakes that happen when a cell copies its DNA. Testing looks for four proteins called MLH1, PMS2, MSH2, and MSH6. For high-grade papillary urothelial carcinoma, it is done most often on tumors from the kidney or ureter, because of their link to Lynch syndrome.
Our article on mismatch repair across cancer types explains these results in more detail. For more information on tumor testing, visit our Biomarkers and Genetic Testing section.
The pathologic stage for high-grade papillary urothelial carcinoma of the bladder is assigned using the TNM system from the AJCC Cancer Staging Manual, 8th edition. The tumor stage (pT) describes how deeply the cancer has grown. The nodal stage (pN) describes spread to lymph nodes and is assigned only when lymph nodes are removed. Spread to distant organs (M) is usually determined by imaging rather than by the pathology report.
A TURBT can show whether the cancer has reached the muscle, but it cannot show stages pT3 or pT4. Those stages are assigned only after the bladder is removed.
Lymph nodes are not removed during a TURBT, so most reports for high-grade papillary urothelial carcinoma do not include a nodal stage. If lymph nodes are removed during a cystectomy, the nodal stage is assigned as follows:
Tumors that start in the kidney or ureter are staged with slightly different definitions, because the wall of these organs is thinner than the wall of the bladder.
The prognosis for high-grade papillary urothelial carcinoma depends mostly on whether the cancer has invaded and how deeply. When the cancer has not reached the muscle, most people do well with treatment. However, these tumors often recur, and some later invade the muscle, which is why close follow-up is needed.
These numbers are averages for large groups of people and don’t predict what will happen to you. Features in your report that are linked to a higher chance of the cancer coming back or growing deeper include:
After a diagnosis of high-grade papillary urothelial carcinoma, your care team uses the depth of invasion and other findings in your report to plan treatment. Your urologist combines these findings with the number and size of the tumors. Most high-grade tumors that have not reached the muscle are placed in the high-risk group, which guides treatment and follow-up. A single small high-grade pTa tumor may instead be placed in the intermediate-risk group.
Drug approval and access differ by country, and your care team can explain what applies where you live. Follow-up for high-grade papillary urothelial carcinoma includes cystoscopy and urine cytology every few months at first. Checks become less frequent over time if no new tumor is found, and doctors repeat imaging of the kidneys and ureters from time to time.