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Molecular ‘bucket list’ for renal cancer

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Not to be overlooked in any of this is the importance of pathology, a point the TCGA paper drives home multiple times, says Dr. Reuter. While molecular information would appear to be steering the ship (the words “molecular characterization” are in the title, after all), morphologic context adds a much-needed anchor.

Indeed, the Cell Reports paper features, on the opening page, a graphical abstract illustrating RCC subtypes (at right). That was intentional, says Dr. Linehan. “People might say we are entering an era where genomics will make pathology less relevant. That is not the case. The role of the pathologist, armed with new genomic information, is expanding.”

Experienced pathologists, he says, will be invaluable in evaluating the genomic data as well as interpreting histology. “The more we combine those two, the better off we’ll be.” In his view, “The role of the pathologist is even more critical today than it was 15 years ago.”

Dr. Merino agrees, noting that in her quarter of a century of working with Dr. Linehan and others, “It’s been a team effort that has led to successful stories.”

As the complexity of RCC pathology grows, much of the workup is surprisingly within reach of most laboratories.

“You can get pretty far with morphology and immunostains,” says Dr. Hirsch. “But you definitely can’t get to all diagnoses in 100 percent of cases without genetic or molecular information. Even then we still use the ‘unclassified’ category in a small subset of cases. But in this day and age, immunostains are a relatively quick and inexpensive ancillary study that can get to the diagnosis in many of the cases the majority of the time.”

She suggests a “bare bones” group of stains that pathologists could have on hand: PAX8, CK7, CD10, AMACR, CA9, HNF-1beta, S-100A1, CK20, FH (for FH-deficient renal cell carcinoma), and SDHB (for SDH-deficient renal cell carcinomas). “And then I would have a TFE-3 antibody on board, with the caveat that the TFE-3 antibody is very finicky. So I use it with caution. If it’s weak or focal, it’s not contributory and I turn to fluorescence in situ hybridization.” Anything shy of strong and diffuse staining in every single tumor cell is not useful, she says.

“I wouldn’t use these for every case,” she says, “but this group of antibodies would get me to a diagnosis the majority of the time.”

She also recommends that pathologists “go with their gut. If they see a tumor that doesn’t fit into a typical category, they should seek help.”

Despite the intrigue in Anna Pavlovna’s (or is it Annette Scherer’s?) salon, Tolstoy’s story continued to unfold, its characters succumbing to love and loss, disillusionment, revolution and ruin, winter, and many chapters of battle.

Dr. Linehan is familiar with the concept of an ongoing saga. Surveying the field of renal cell carcinoma and his 35-plus years of treating patients, he says, “We have an enormous amount of work to do.” What about those four TCGA renal cell carcinoma projects? “It’s a great start,” he says.

Physicians are only beginning to grasp the complexity of hereditary tumors, for example, and pathologists need to be aware that they might be seeing an index case.
Familial tumors, it turns out, are much more common than previously thought, says Dr. Reuter. “It is fair to say that pathologists in the community will confront these cases as specimens without the clinical information that this is a patient with a hereditary syndrome.”

Some morphologies, he continues, are more likely to be associated with hereditary syndromes. There are also findings in the adjacent, supposedly normal renal parenchyma that can point pathologists toward the possibility of a tumor being associated with a hereditary syndrome.

The prototypic hereditary type is VHL, or the von Hippel-Lindau syndrome-related renal cell carcinoma, Dr. Hirsch says. Patients with VHL often develop clear cell renal cell carcinoma, but not everyone with clear cell renal cell carcinoma has VHL—in other words, the VHL gene mutations seen in the kidney tumors can be either germline or somatic.

But VHL is only one of several inheritable syndromes that affect the kidneys. Others include but aren’t limited to MET mutation with hereditary papillary renal cell carcinoma (HPRC); tuberous sclerosis (TSC); the fumarate hydratase-deficient renal cell carcinomas, which are associated with hereditary leiomyomatosis and renal cell carcinoma; and Birt-Hogg-Dubé, which involves an FLCN gene mutation.

These are a frequent topic of discussion with her clinical colleagues, Dr. Hirsch says, and labs are starting to take note. The first step, she says, is to think about the possibility of the diagnosis. If she sees a tumor that she thinks might be an FH-deficient renal cell carcinoma, for example, her next step would be to do a screen with a fumarate hydratase immunostain. “In this case we’re looking for loss of staining of the FH antibody.” If this is indeed the case, “in a note we will tell our clinical colleagues that this patient needs genetic testing to determine if this is a somatic or a germline mutation. And if it’s somatic, they just get treated for their kidney tumor. But if it’s germline, then they need to have their children and family members tested as well.”

Dr. Linehan seconds that. In the case of HLRCC, “Many times the clinician doesn’t know that’s what the patient is affected with.” This cancer spreads early, when the tumor is still quite small. Knowing the alteration status will change his surgical approach. “It’s more than invaluable; it’s essential,” says Dr. Linehan. “It really is a matter of life or death.”

In the meantime, the questions continue. Will specific genetic abnormalities or a better understanding of the immunologic landscape lead to better therapeutic interventions? Will new molecular assays help subclassify tumors even further? Will more RCC categories be helpful? Or will they become so numerous they merely create chaos, like the parade of visitors to the Marschallin in “Der Rosenkavalier”?

A common consult involves tumors with oncocytic cytoplasm, that is, tumors that enter the differential diagnosis of oncocytomas, which by definition are benign tumors. One of the morphologic and molecular limits to identifying this tumor is cytoplasmic eosinophilia. Asks Dr. Reuter: “Have we defined them too strictly in the past, and for that reason not made the diagnosis enough? Or have we used the term too liberally?” Addressing that question will require a combination of better outcomes data and improved molecular findings. “Because what happens now is, if I cannot classify a tumor as an oncocytoma, not put it into any one of those other categories that have eosinophilic cytoplasm, I end up putting it into the ‘unclassified’ category.” This is unpalatable to everyone, he says—clinician, pathologist, and patient.

And so the work continues. Echoing Dr. Linehan, Dr. Reuter takes note both of the ongoing accomplishments and the daunting task ahead. “Putting everything together is very, very difficult,” he says (possibly echoing the words of Tolstoy’s agent after hearing the writer’s War and Peace pitch).

And if it’s not clear by now, the TCGA paper—and related work in the field—is a step, but only a step, toward a better understanding of renal cancer, says Dr. Reuter. “It’s certainly not the end game.”

As readers—both actual and the merely well intentioned—of Russian novels know, the end game is a long one. (This might be a good place to point out that even when War and Peace was over, it wasn’t really over. It concludes with not one, but two—yes, two—epilogues, which add 28 more chapters to the book.)

But somehow even Dr. Linehan can manage to write a simple coda. “I’m very optimistic about the future.”

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

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