Doing more, doing better in bladder cancer

Karen Titus

February 2024—From her vantage at the University of Texas MD Anderson Cancer Center, Donna Hansel, MD, PhD, has a clear view of cancer’s latest frontiers. Progress and breakthroughs are the norm. But even she sounds impressed when she surveys the changes in her specialty, urothelial cancer.

“We are now thinking what we never before thought was possible: We are thinking about cures and lifelong remission from disease,” says Dr. Hansel, division head and professor of pathology and laboratory medicine.

It’s been a long time coming, says Dr. Hansel, who is also the Dr. Eva Lotzova and Peter Lotz memorial research chair. The disease historically has been caught in a sort of prepositional triangle—underfunded, overlooked, and underdiagnosed—with serious consequences. For years, she says, “We thought bladder cancer had only one treatment”—BCG, or Bacillus Calmette-Guérin, therapy. Because the field lacked a large volume of research to propel better diagnostics and treatments, “people died of this disease because it progressed.”

That has begun changing in the past dozen or so years, but the most recent developments are especially gratifying, says Arlene Siefker-Radtke, MD, professor of genitourinary medical oncology, MD Anderson. “We are seeing the strategy for how we treat urothelial cancers evolving.” Case in point: the FDA’s December approval of enfortumab vedotin (an anti-Nectin-4 antibody-drug conjugate) in combination with the immunotherapy drug pembrolizumab, which shows improved survival for people with advanced bladder cancer.

Likewise, there’s progress with sequential therapies, says Dr. Siefker-Radtke. “We have the first randomized clinical trial data that shows that erdafitinib in patients who received prior chemotherapy and immunotherapy is associated with an improved objective response rate and median overall survival, as compared to single-agent taxane.” Erdafitinib is a fibroblast growth factor receptor inhibitor, and the first approved FGFR-targeted therapy for advanced urothelial cancer.

First of two parts: part two in March issue

But much of this progress hinges on what happens earlier. None of this is academic, in any sense of the word. Early-stage bladder cancer is one of the key GU specimens in community and local/regional hospital settings, says Dr. Hansel. “Most patients are diagnosed by their local urologist or primary care physician. It will primarily be impacting their practice versus the larger academic centers.”

Dr. Siefker-Radtke agrees: “A lot of treatment is still occurring in the community.” And since urothelial cancer patients in general tend to be older (often in their 70s at the time of diagnosis) and because it’s often associated with smoking (thus bringing with it comorbidities such as type 2 diabetes, COPD, heart disease), there’s even more likelihood that patients will receive care in a local setting versus an academic center, she says. Not everyone can travel, nor wants to. “I almost feel our bladder patients need more help than ever before.”

The road ahead is clear to Dr. Hansel: more early-stage interventions and, ultimately, a decline in advanced-stage disease. “We need to diagnose this disease earlier and stratify patients based on those initial biopsies.”

For pathologists who haven’t seen this happening yet at their own institutions, “The wave is coming,” Dr. Hansel says.

Urologists have become much more aware of the differential diagnosis when a patient undergoes a tissue biopsy and are becoming well versed in morphologic subtypes and their implications, says Dr. Hansel.

(Subtypes has become the preferred term, rather than variants, which is better suited to genetic variants and molecular testing, she notes.) This includes pure subtypes such as urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and neuroendocrine carcinoma; they’re also aware of urothelial carcinoma subtypes such as micropapillary carcinoma and plasmacytoid urothelial carcinoma.

Recognizing and cataloguing the subtypes can have weighty treatment implications, Dr. Hansel notes. Some of the more aggressive ones involve equally aggressive treatments, such as early cystectomy. “That’s why it’s important for pathologists to work closely with their urologists and oncologists to understand the ramifications of their diagnosis,” she says. That’s particularly true if there’s uncertainty about a diagnosis. “You need to be really thoughtful, and maybe take some time to get a second opinion” when the impact on patients looms large.

If pathologists haven’t kept up with the array of subtypes that are now recognized by the bladder cancer community, Dr. Hansel continues, “It’s important to refresh yourself on that and have those conversations with your treating physician partners.”

Revisiting the terminology for neuroendocrine carcinoma is a good starting point. Clinicians are more used to the term “small cell carcinoma” to describe these rare malignant tumors, she says.

The term “large cell neuroendocrine carcinoma” has now been added to the terminology, “and physicians are confused,” Dr. Hansel says. “This is probably where we get the most questions—how are we approaching classification of neuroendocrine tumors. In our good efforts to try to clarify terminology, I think we’ve caused a lot of confusion on the clinical side that we need to address.”

It’s likely some confusion has been stirred up among pathologists as well, she acknowledges. “While many of the neuroendocrine tumors we see are small cell carcinomas, I think it’s good to specify this subtype when we diagnose neuroendocrine carcinomas, because it makes it much more straightforward to our treating physicians who are used to the small cell carcinoma terminology.” Likewise, she says, entities such as large cell neuroendocrine carcinoma can be confusing to pathologists as well as urologists and urologic oncologists as they try to understand how aggressive the disease is and where it fits in the classification.

The mixed carcinomas are less confusing, Dr. Hansel says. “But we have to be thoughtful about how we explain it.” Identifying a tumor as urothelial carcinoma with small cell differentiation or as urothelial carcinoma with neuroendocrine differentiation “is very confusing. I think if we were instead to be clear to call out a small cell carcinoma component, our clinical team members would be much more confident in how to approach the diagnosis.”

The more specific pathologists can be, the better, agrees Dr. Siefker-Radtke. Carcinoid tumors, for example, have lower proliferation rates and may benefit from initial surgery. Neuroendocrine tumors, on the other hand, are more appropriately treated with neoadjuvant therapy, which can give patients a chance for cure, she says. “We need to ascertain up front whether a neuroendocrine tumor is present and the type of neuroendocrine tumor. Very few patients are cured with up-front surgery when they have one of these small cell neuroendocrine or even large neuroendocrine tumors with high proliferation. So more clarity around that could be helpful.”

The biggest issue for Dr. Siefker-Radtke is the setting of node-positive disease. The challenge is that patients who have true lymph node involvement up front—even if it’s a single lymph node—are not surgically resectable, she says.

Given that, she says, “I do think that patients with lymph-node positive disease—even if it’s a single lymph node—should be in their own category.” These patients need cytoreduction of that lymph node up front to benefit from surgery. Otherwise, doing initial surgery on a known lymph node is “often fraught with positive margins and more extensive nodal disease than one can see on imaging,” she says.

Dr. Siefker-Radtke has a clear choice for the top of her pathology wish list: reporting the presence or absence of lymphovascular invasion, whether it’s invasive into the muscularis propria or not, or whether the muscularis propria is present or absent. “These are essential pieces of the path report to help us appropriately stage a patient and then determine treatment.”

Positive lymph nodes in the pelvis is a risk factor for progression and dying of disease, Dr. Hansel notes. “The lymph node dissection has to be thorough, and we need to get as many lymph nodes as possible. And any lymph node positivity has higher risk.”

Upper tract urothelial cancer throws its own set of wrenches into the works. Outside of urology, even some clinicians can find UTUC confusing, says Surena Matin, MD, the Monteleone Family Foundation distinguished professor, Department of Urology, MD Anderson.

First of all, it’s uncommon, accounting for maybe five to 10 percent of urothelial cancers, he says. It too has a language problem—the disease resides in the renal pelvis, but sometimes clinicians will speak in shorthand to their patients, referring to it as disease in the kidney—a verbal misstep Dr. Matin says even he occasionally makes, “because I’m in a rush or something.”

At a larger level, UTUC CPT coding can be mistaken, he says; moreover, the disease has frequently been misclassified in the research literature. “That has gone on for a long time. Even vital statistics, cancer statistics, will lump renal pelvis cancer with renal cell carcinoma.”

Pathologists tend not to be tripped up by these matters, but assessing depth of invasion can be challenging. “Because the biopsies we obtain for these are very superficial,” Dr. Matin says, “they’re an order of magnitude smaller than what you get with bladder biopsies.” Part of that is technical, given the limitations of the instruments. They’re long and delicate, “and we can’t get that deep. But also we’re working with an organ system that’s a couple of orders of magnitude tinier, with microscopic muscular layer,” versus the bladder’s thick muscular layer. “So it’s also not very safe to go very deeply to biopsy.”

That can lead to a different sort of language problem. “On the pathology side, there is language that can inadvertently be misleading,” Dr. Matin says. A superficial biopsy might be described as noninvasive, but if it doesn’t show the underlying tissue layers, “you can’t really say that it’s noninvasive,” he says.

Not everyone appreciates those challenges and misconceptions, he says. “Staging is incredibly difficult with this disease; if anything, we should not be mis-staging.” His preference is for pathologists to be upfront with difficult cases: This is a very superficial biopsy; we can’t assess for staging. “Then we can try to assess risk in other ways. That doesn’t leave us totally in the dark because we know that’s the case. It’s a more honest and realistic assessment of what’s there.”

Dr. Matin says he routinely has these conversations with pathologist colleagues. He suspects some are reluctant to say they’re unable to stage the tissue. “But what I want to say is, ‘That’s OK—because we’re not giving you much to stage with, so you shouldn’t be going out of your way to stage these if it’s just not possible.’”

Another common problem has to do with the heterogeneous nature of these tumors. Often the sample represents only the tip of the Titanic sticking out of the sea.

Again, there’s helpful information to be gleaned from even these small samples, Dr. Matin says. Most obviously, he and his colleagues want to know whether it’s predominantly low or high grade—nothing new for pathologists. “But the nuance is even if there is a very tiny percentage of high-grade cells, it would be helpful to know that.”

In his experience, if there’s less than five percent high grade, the tumor will be classified as low grade. “But when we’re dealing with a situation where we have very limited sampling, that little bit of information—that there may be a high-grade component present—would clue us in that there may be something going on.” If there’s even a little bit of high-grade tumor in a tiny sample, Dr. Matin says, “then I’m worried,” since there could be additional high-grade presence elsewhere in the tumor.

His pathologist colleagues have started to note this in the past year or so, he says. “We are seeing these reports that say, ‘This is predominantly low grade, but there are small foci of high grade.’ That’s helpful.”

Dr. Matin’s wish list is simple: “The best thing we can do is be better at risk stratification, i.e. staging,” he says.

“I don’t do staging for this disease,” he says. “It’s terrible. It’s incredibly inaccurate.” A discussion about risk stratification—using variables apart from what might be seen on a biopsy, such as imaging, endoscopic findings, cytology, laboratory parameters—would be much more useful, he says. “We’ve developed nomograms to help with stratifying patients into low or high risk.” The accuracy is 75 to 80 percent. “Which isn’t terrible. But it could be better.”

Tough-to-grade samples aren’t limited to upper tract urothelial cancer. All urothelial cancers can be fraught, says Andres Matoso, MD, associate professor of pathology, urology, and oncology at Johns Hopkins University School of Medicine.

Given that these cancers are small, and with testing needs in flux, pathologists should talk with their oncologist colleagues “to establish what the goals of care are before proceeding with any testing,” Dr. Matoso says.

From his perspective, distinguishing T1 from T2 muscle-invasive disease is the most problematic. “Sometimes you have cases that we call ambiguous for muscularis propria invasion.”

In those cases, he explains, some muscle fibers can be seen, but they’re thin. “We’re not 100 percent sure that the true muscularis propria of the bladder is involved by tumor.” These cases are seen in patients who almost invariably have extensive invasive disease. And even if more invasive disease doesn’t involve the muscle, if there’s too much invasion into the lamina propria, these patients have a very low percentage of response to BCG therapy. Nearly all these patients end up recurring and require radical cystectomy, Dr. Matoso says.

“Now, when you look at the cystectomy findings and the survival, those patients have a slightly worse survival than patients who have a tumor that does not involve the muscle, but it recurred, and they went to cystectomy,” Dr. Matoso continues. “But they have better survival than the patients who are diagnosed straightforward as invasive into the muscularis propria.”

In cases that are difficult to stage, “It’s always the urologist saying, ‘But I took a really deep sample—how come you cannot tell that there is no muscle?’” The situation, as Dr. Matoso explains it, is that sometimes the tumor “digests” the muscle, “so we cannot tell on the microscope. If we cannot tell, we cannot say it’s 100 percent certain.” Hence the “ambiguous” wording.

But it’s still useful to know that, Dr. Matoso notes. “In our experience, those patients have a low likelihood of responding to conservative therapy. They will fail intravesical therapy and progress to cystectomy anyway,” either because the follow-up biopsy contains more tumor indicating BCG failure/recurrence or because it shows tumor in the muscle.

As with everything in the field, this is a small percent of patients—less than five percent, says Dr. Matoso. Indeed, these diseases are more appropriately categorized into thimbles rather than buckets. As each successive thimble contains a smaller number of cases, much-needed nuance often recedes.

Adding to the difficulty, Dr. Matoso says, the emphasis is now on distinguishing between low-grade and high-grade tumors, versus using stages I, II, and III. “The tumors that are now in-between can be a little challenging to grade,” he says. “In general, a consensus is that if five percent of the tumor or less is high grade, then we call it low grade with a small proportion of high grade. In those patients, it’s unclear what the clinical outcome is going to be.”

The therapeutic implications are huge, Dr. Matoso says. Both low grade and high grade recur with similar frequency, he says, so they both need to be followed similarly, but high grade has the highest risk of progression to invasive tumors. “So they get stricter follow-up and more BCG therapy,” while a small or single low-grade tumor would not lead to BCG therapy at first-time presentation.

He and others continue to try to refine the process. “We have done some studies to try to better grade certain cases that are difficult, like tumors that have more nuclear atypia,” which tends to be more degenerative in nature, Dr. Matoso says. “And then we have shown that even though some tumors can have these large nuclei, they do not have higher proliferation, and they have molecular findings that are more in line with low-grade urothelial carcinoma. So we have done some studies to help classify those cases.”

But problems persist in clinical practice. He and his pathologist colleagues typically meet with GU experts in certain borderline cases to try to come to a consensus on whether to call a case low grade or high grade, he says. “And I would say in a very small percentage of cases we end up calling it borderline between low grade and high grade. In those situations we let the urologist know that this is a very difficult-to-grade case, and you have to decide how you’re going to manage this patient based on other features, like size of tumor and other things,” including patient age and comorbidities.

Again, the bottom line is language. “The clinicians need to know what we mean when we make a statement,” Dr. Matoso says. Using consistent language helps. “Then clinicians know, Oh, this report for Mr. Jackson is similar to Mr. Williams. So now I know where the pathologist is with these types of cases. So that is helpful to always use the same kind of terminology. And then the clinicians will get used to the way we report things. Sometimes the language in the report does not really convey how difficult that report was for us,” he adds with a laugh.

Traffic flows both ways, he says. “We work closely with urologists and oncologists and get to know each other, so that we know how they make decisions, and they understand what our limitations are with difficult cases.”

Dr. Matin sees another area for advancing standard of care: routinely assessing UTUC biopsies for Lynch syndrome and doing immunohistochemical staining for mismatch repair proteins.

He estimates that 95 percent of centers don’t do this—not that he’s pointing a finger. “We don’t do it,” he acknowledges, “although we’ve started conversations about it.”

He continues: “Mind you, this is standard of care for colon cancer and endometrial cancer, which also have high rates of Lynch syndrome.” Even though doing so would use already minimal amounts of available tissue, he says, “I think it would be good for pathologists to take a little bit of initiative there, or at least start the conversations: Should we be routinely doing this? It has huge implications for patient care.” The current thinking is that about five percent of patients with UTUC have undiagnosed Lynch syndrome, which is higher than it is for colon cancer, he points out.

The rates are not as high for bladder cancer, Dr. Matin notes. There’s an interesting relationship between the two sites, even though UTUC can look, superficially, like bladder cancer. “We call it a disparate twin,” he says. Even the distribution of mutations is quite different. With upper tract, there is a high rate of FGFR3 mutations—up to 90 percent in low-grade disease; in bladder cancer, the rate is 19 to 24 percent. On the other hand, RB1 mutations are frequently seen in bladder cancer, but are rare in UTUC.

Embryologically, the ureter and renal pelvis are derived from a different tissue than the bladder. “That might explain” the differences, says Dr. Matin, “but we haven’t fully appreciated why that is.”

As Dr. Matin notes, having bladder cancer is probably the greatest risk factor for developing UTUC, though again, it’s not common. Other risk groups include patients who have long-standing nonmuscle-invasive bladder cancer and who have received multiple rounds of intravesical treatment over a period of years.

Research indicates these are clonal, Dr. Matin says, suggesting that UTUC develops from the same cancer cell. But it’s still not clear if a similar mechanism is causing the cancer to spread in a different region. More common is for UTUC to seed the bladder and develop into new bladder disease.

Dr. Hansel draws attention to another area that has historically not been well served: urothelial cancers and urinary tract cancers in women.

The disease is diagnosed more frequently in men than women, at about a three-to-one ratio, says Dr. Siefker-Radtke. “Nobody knows why.” Some have suggested hormonal differences play a role; she suspects the different immune response between men and women could be a factor. Given that women in general have higher rates of autoimmune disease, “Perhaps there’s something different about how women generate an immune response. We know urothelial cancer is associated with the immune response. And patients on immunosuppressive therapies have higher rates of bladder cancer as well.”

It’s clear that women have worse outcomes when they receive a diagnosis of bladder cancer, says Dr. Hansel. That’s due in part to a lack of understanding about the disease; however, the problem is compounded by a lack of awareness that the disease does indeed affect women. In younger women who get bladder cancer, the disease can be misdiagnosed as a urinary tract infection that’s treated with antibiotics while the tumor progresses. In older women, intermittent bleeding can easily be attributed to changes in the menstrual cycle. “People just don’t think about it,” she says. If it walks like a duck and talks like a duck, it might not be a duck, at least not every single time.

“In our relationship with urologists—in our reads we do in cytology, which is often at the forefront of making the diagnosis—we should always keep in mind: Could there be an underlying cancer that could be present in the cytology specimen, even though it’s a younger woman?” Dr. Hansel says. “We have a role in potentially raising awareness, even in a comment in our report, that recurrent urinary tract infections may be secondary to an underlying bladder cancer” that is often overlooked in this patient population. “We often see women in their 30s and 40s go undiagnosed, often for several years, and dying of these diseases because no one ever thought to look,” she says. “This could be one way that as pathologists we could raise awareness—if we see a woman with long-standing UTI that’s not responsive to therapy, maybe we put a comment that even though we don’t see cancer in this specimen, should bladder cancer be clinically excluded from the diagnosis?”

Female urethral carcinomas have also historically been underrecognized. Dr. Hansel helped write the eighth edition AJCC; she and her coauthors observed that female urethral cancers, penile urethral cancers, and prostatic urethral carcinomas “had at one point all been lumped together in one staging system,” she says in a can-you-believe-it? voice. “Which makes no anatomic or histopathologic sense.”

When they raised the question, she recalls, it became clear there was scant literature on female urethral carcinomas, including a normal female anatomy and histopathology of the female urethra. She and others proposed staging modifications (https://bit.ly/ajsp-122020).

There is more awareness now, she says, and change is occurring related to staging, “because now we’re actually thinking about this part of the female anatomy that basically had been ignored for decades.” It’s essential, she says, for pathologists to recognize gender differences when discussing urinary tract cancers. “We’re there to help advocate for the patient in our diagnosis and to raise awareness when maybe it’s missed elsewhere. We don’t want to keep seeing women with advanced stage bladder or other urinary tract cancers just because we didn’t think they could get it.”

Dr. Hansel is firm: “As a pathologist, you feel helpless—and frustrated—when you see something that could have been treated earlier, and you’re at the point of diagnosing metastatic disease for the first time in a young woman. It’s really disheartening to have that experience.”

Granted, not every patient with a UTI can be treated as if they have a possible bladder cancer. “But if a clinical course isn’t behaving in a way we expect it to,” Dr. Hansel says, “there could be other causes. We’re part of the care team that can help raise awareness.” She’s adamant. “We need to reach out to treating physicians if we see something that doesn’t make sense or raises questions for us. It’s our obligation.”

You can almost hear Dr. Hansel puff—metaphorically, of course—on a Virginia Slim and comment that we’ve come a long way, baby.

When she began her training, she recalls, the trajectory was as straight as a Puritan sending a witch to the pond. “There was one therapy you gave to patients. If it didn’t work, the patient died.” That stark reality was, in fact, the reason she chose to specialize in this field. “We needed to do better. For me, that drove this lifelong passion to advocate for bladder cancer patients, to have better diagnostics, and to think we could do better with our treatments.”

The work has been rewarding, she says. Diagnostic and therapeutic options for bladder cancer patients have multiplied, and there’s a far better understanding of disease subtypes and which patients have been overlooked. “There’s a lot more we can do—and are doing now.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.