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.