Grading, staging papillary urothelial carcinoma

Amy Carpenter

July 2026—Grading of papillary urothelial carcinoma can sometimes be challenging because it requires categorizing discretely a continuous spectrum of tumors.

In the view of Lara Harik, MD, discovering biomarkers that can predict progression would be an ideal solution for papillary urothelial carcinoma, especially for tumors that are difficult to grade. “Maybe the use of cell-free DNA in the near future,” she said, “could reveal which of these tumors are at risk for progression.”

Dr. Harik, associate professor in the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, spoke at CAP25 on grading and staging of bladder tumors, covering, among other things, grading papillary urothelial carcinoma, diagnosing urothelial carcinoma in situ on transurethral resection, subtypes and divergent differentiation in the urinary tract, and muscularis propria and lymphovascular invasion.

She noted the promise of antibody-drug conjugates, with the Destiny-PanTumor02 trial of trastuzumab deruxtecan opening the gates for all types of HER2-expressing tumors to be treated. Trials of another antibody-drug conjugate, disitamab vedotin, are underway.

“It’s important when you are reporting HER2/neu to pay attention to which criteria to use,” Dr. Harik said. (A CAP biomarker project team, composed of members of five CAP committees—Cancer, Pathology Electronic Reporting, Immunohistochemistry, Center Guideline, and Molecular Oncology—issued a guidebook to HER2 testing in solid tumors, including the bladder, published online June 19, 2026 in Archives of Pathology & Laboratory Medicine. doi:10.5858/arpa.2025-0593-CP. Dr. Harik is a coauthor.)

The 2022 World Health Organization classification of tumors of the urinary system and male genital organs divides papillary neoplasms into four categories: papilloma, PUNLMP, and low-grade and high-grade papillary urothelial carcinoma.

On the benign end of the spectrum is the rare papilloma. “If you’re diagnosing more than three or four a year, depending on your volume, you probably are overdiagnosing them. I diagnose papilloma only when it presents de novo,” Dr. Harik said. She would hesitate to make this diagnosis in a patient with an established history of recurrent urothelial carcinoma. Papilloma rarely recurs. “If it does recur, it is usually in the setting of a prior diagnosis of papilloma.”

The prognostic difference between a papilloma and a PUNLMP—papillary urothelial neoplasm of low malignant potential—is in the recurrence. PUNLMPs have a higher chance of recurrence but seldom progress. Dr. Harik diagnoses fewer than five per year.

“Once you get to the disorganized urothelium on a papillary stalk and loss of polarity, this is when you reach the papillary urothelial carcinoma diagnosis,” she said.

The recurrence rate for low- and high-grade papillary urothelial carcinoma is similar and ranges up to 50 percent, she said. “The difference is in the rate of progression. Low-grade papillary urothelial carcinoma will progress in about five percent of cases, whereas high-grade papillary urothelial carcinoma will progress in about 25 percent of cases.”

A papilloma should not have nuclear atypia or mitosis (Fig. 1). “If you see a mitotic figure, it should be basal. Beware,” Dr. Harik cautions, “because sometimes the umbrella cell layer, which is very common in these tumors, can look a little atypical, tricking you to believe it is a higher-grade tumor.”

A PUNLMP (Fig. 2) shows a hyperplastic urothelium with maintained polarity and can also have an umbrella cell layer, “so beware of the atypia in that as well.” There should be no nuclear atypia, loss of polarity, or disorganization. If mitotic activity is seen, it should be seen at the base.

“Once you have loss of polarity, then we are in the papillary urothelial carcinoma [category],” Dr. Harik said. Loss of polarity and mild to moderate disorganization are present in low-grade papillary urothelial carcinoma (Fig. 3). Crowding of the nuclei that leaves behind visible spaces is the first clue to disorganization. Mild to moderate nuclear atypia, mitotic activity, and apoptotic bodies all could be present in a low-grade papillary urothelial carcinoma.

Those four features are present at a much higher degree in high-grade papillary urothelial carcinoma (Fig. 4). “Nuclear pleomorphism, defined as three times the difference; mitotic activity; nuclear overlapping; and discohesion are all signs of a higher-grade tumor,” she said.

About a third of cases have histologic features that overlap between low- and high-grade papillary urothelial carcinoma and can leave room for subjective interpretation.

Since the implementation of the 1998 WHO/International Society of Urological Pathology consensus grading scheme, which is similar to the WHO 2022 classification, Dr. Harik said, “there has been a little bit of a grade migration, where our threshold for calling something high-grade papillary urothelial carcinoma has gone lower and lower, and we diagnose high grade much more readily.” This distinction is important, she said, because most of the clinical decisions depend on whether the papillary urothelial carcinoma is low grade versus high grade. The American Urological Association risk stratification table classifies papillary urothelial carcinoma as low, intermediate, or high risk, with most low-grade papillary urothelial carcinomas falling in the low-risk category and most of the high grade falling in high risk.

Papillary urothelial carcinoma can also show a spectrum of grades within the same tumor, “or what we call mixed tumors” (Fig. 5). The WHO arbitrarily designated a five percent threshold, such that a predominantly low-grade papillary urothelial carcinoma with more than five percent high-grade papillary urothelial carcinoma is automatically designated as high grade. If the tumor has five percent or less of a high-grade component, it is reported as predominantly low grade with a focal area that is five percent or less of high-grade papillary urothelial carcinoma.

Studies have shown that the prognosis of these “mixed tumors” is between low- and high-grade papillary urothelial carcinoma, and Dr. Harik prefers calling them mixed tumors and providing a percentage of the high-grade component. “Don’t we owe it to our patients and their treating urologists to share more details about what we see histologically?” she asked.

A papillary urothelial carcinoma that shows nuclear pleomorphism with disorganization and loss of polarity is definitely in the carcinoma category, Dr. Harik said. Some nuclei stand out, but the question is whether it’s sufficient to call the tumor a high-grade papillary urothelial carcinoma. Here she “channels her mentors,” she said, who taught her, “Unless you’re absolutely certain it’s a high-grade papillary urothelial carcinoma, just call it low grade.” She herself calls it low grade but notes also the slightly increased nuclear atypia. Ki-67 may be helpful in these cases. “If these tumors have a very low Ki-67 rate, I would feel more confident about grading them as a low-grade papillary urothelial carcinoma.”

Dr. Harik calls all cases of invasive urothelial carcinoma high grade. The nested variant of urothelial carcinoma shows small nests with bland cells, lacking overt nuclear atypia; however, it presents at advanced stage with invasion of the muscularis propria, she said. The nests in Figs. 6 and 7, especially at the surface, look almost like von Brunn nests. If grading based on cytology, she said, it would be low grade, “but we know these tumors are going to behave high grade,” and most are graded accordingly.

Dr. Harik shared her view on urothelial carcinoma in situ on transurethral resection. “CIS automatically classifies the patient as a high-risk patient.”

“In some cases of high-grade papillary urothelial carcinomas, we see adjacent flat lesions, and there is currently great debate about when to call these flat lesions shoulders of high-grade papillary urothelial carcinoma and when to call them flat urothelial carcinoma in situ.

“If we see a CIS or a flat high-grade lesion in a case that also has high-grade papillary urothelial carcinoma on a different fragment,” she continued, “most of us will pull the trigger for CIS.”

When a lesion looks like a high-grade papillary urothelial carcinoma and adjacent to it is a flat lining with high-grade morphology, especially in the recurrent setting, ambiguity arises, Dr. Harik said. Many would call it a shoulder lesion or extension of the papillary urothelial carcinoma onto the adjacent flat lining, she said. “For me, this is a sign it’s a little more aggressive because I’m worried about the possibility of it being able to spread sideways. And when a papillary urothelial carcinoma starts spreading sideways, it could compromise the ureteral orifices or spread inferior to the bladder neck area and involve the prostatic urethra, changing the management for the patient.”

The WHO classification of urinary and male genital tumors lists the urothelial carcinoma subtypes as nested, large nested, micropapillary, plasmacytoid, microcystic and tubular, lymphoepithelioma-like, sarcomatoid, giant cell, lipid-rich, clear cell (glycogen-rich), and poorly differentiated. “If you see something that looks like a subtype, report it and provide a rough percentage of how much of the subtype is present,” Dr. Harik said.

Also important is to identify and report divergent differentiation, defined as nonurothelial morphology (squamous and glandular are most common), and provide a percentage of the components.


Lymphovascular invasion must always be identified and reported when present, especially on transurethral resections, Dr. Harik said (Fig. 8). “Oftentimes you will see it at the edge of the invasive carcinoma.” She cautions about mimickers: Microinvasive urothelial carcinoma tends to have cleft-like spaces and may mimic lymphovascular invasion. “Sometimes the stroma on the periphery gets compressed and may look like endothelial cells.” If there is uncertainty, Dr. Harik recommends a CD31 or ERG stain, which highlights the endothelial cells in lymphovascular invasion (Fig. 9).

Dr. Harik shifted focus to urothelial carcinoma staging, beginning with pT1 substaging. “If we see a tumor that is invasive microscopically in a papillary stalk in a very large tumor and it’s only focally present, it’s intuitive that it’s probably going to behave better than a papillary tumor that is invading underneath the papillary stalk and involving the lamina propria under it, especially when it’s also a larger focus of invasion.”

Research into how to subcategorize pT1 lamina propria invasion has led to the development of various proposed systems, one of which is the histoanatomic system, which itself is divided into a two-tiered and a three-tiered system, both based on the muscularis mucosae of the bladder. The micrometric measurement system measures the size of the invasive focus, and a third system is based on whether the tumor is invading the papillary stalks versus at the base of the papillary tumor.

“The reality is that none of us is actually subcategorizing pT1 tumors because it’s very difficult to do so when the fragments are so maloriented, fragmented, and cauterized,” Dr. Harik said, noting, too, that the muscularis mucosae is a layer that is not always continuously present in the bladder.

But describing the extent of the lamina propria invasion is important, she said—for example, “very focal lamina propria invasion within the papillary stalks” or “extensive lamina propria invasion.” The lamina propria invasion seen in Fig. 10 reaches the muscularis propria and stops. “Then you have to figure out, is it really in the muscularis propria? And are these tumors going to behave like a pT1 tumor? The answer is probably not.” Dr. Harik would report the tumor as extensive lamina propria invasion, reaching the muscularis propria and abutting it but not seen infiltrating it. In most cases, she will do levels to look for muscularis propria invasion.

Also common in high-grade aggressive tumors is when the tumor replaces entire pieces of tissue, masking anatomic landmarks.

“Sometimes you don’t see a muscularis propria that is identifiable anywhere,” she said, “but deep down I know this is probably in the muscularis propria. I just can’t make that call.” She will comment that clinical and radiologic correlation is recommended for these tumor types because no muscularis propria can be seen.

“Distinguishing between pT1 and pT2 can be especially challenging in the trigone, because the trigone muscularis propria looks different than elsewhere in the bladder,” Dr. Harik said. The trigone’s large muscularis propria bundles break down into smaller fascicles that get unusually close to the mucosa, and the muscularis mucosae is not as obvious as it is in other areas.

“When tumors involve smooth muscle bundles, I ask myself: Are they large enough to be muscularis propria invasion? Are the smooth muscle cells all going in the same direction?” Dr. Harik notes that getting a desmin stain can sometimes be helpful to highlight the overall architecture of the smooth muscle bundles, ensuring a correct diagnosis.

Tumors with divergent differentiation, especially squamous, may have a prominent desmoplastic reaction associated with the tumor. “These cases tend to have a lot of desmoplasia and separate the muscularis propria bundles,” Dr. Harik said. “Make sure you’re still looking for muscularis propria.” If in doubt, she added, perform immunohistochemical stains to highlight the carcinoma on the keratin and then contrast it with the desmin that highlights the muscularis propria bundles (Figs. 11 and 12).

Involvement of adjacent organs—often seminal vesicle or prostate by direct extension—is a pT4. “Staging is performed on cystoprostatectomy specimens where you can see the tumor invading the adjacent organ,” Dr. Harik said.

She addressed what she views as the most important T4 area of confusion for the bladder: how urothelial carcinoma involves the prostate underneath. If the urothelial carcinoma invades directly through the wall of the bladder into the prostate, it would be classified as pT4—involvement of an adjacent organ. “But sometimes urothelial carcinoma will spread in an in situ fashion to involve the prostatic urethra and then continue to spread into periurethral ducts to involve prostatic glands,” she said. When it does so, it is still a noninvasive tumor because it hasn’t yet invaded into the prostatic stroma (Fig. 13). “Look for invasion into the stroma to call it pT2” of the prostatic urethra, she said, “and fill up another CAP cancer protocol for prostatic urethra.”

Finally, urachal carcinomas are staged using urachal carcinoma systems, of which there are currently four: Sheldon, Mayo, Ontario, and a novel TNM staging system from the National Cancer Data Base (Limonnik V, et al. Cancer Med. 2023;12[3]:​2752–2760). The first step is to determine whether the tumor is a urachal carcinoma and make sure it is confined to the dome or anterior wall of the bladder, where the urachal remnants are usually present. “When you have urachal carcinoma, it is limited to the urachus without the presence of carcinoma in the adjacent bladder,” Dr. Harik said. “Be sure the epicenter of the carcinoma is in the wall of the bladder when making that diagnosis.”

Amy Carpenter is CAP TODAY senior editor.