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Molecular ‘bucket list’ for renal cancer

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Complicating matters, renal cell carcinomas seem to be prone to name changes. In some cases, the same tumor is called by different names—not unlike the malleably named characters in The Brothers Karamazov (to borrow from another Russian author).

Ever since the new WHO classification came out in 2016, Dr. Hansel says, it has been apparent to her that urologists aren’t always certain of what the changes entail. “So you could be reporting on something they haven’t really heard about before,” she says. They might not know what the classification means; they might also misinterpret what it means.

Dr. Hansel has a simple strategy for this, too: Whenever she makes a diagnosis involving an uncommon category or a new classification, she picks up the phone and calls the clinician. It’s not unusual, she says, for clinicians to hear a word in the name and confuse it with something else (a concept familiar to readers trying to keep up with those Karamazov siblings, all of whom share a middle name—Fyodorovich—and are prone to nicknames as well). There is clear cell renal cell carcinoma, which is not the same as clear cell papillary renal cell carcinoma, which, in turn, is not the same as papillary renal cell carcinoma. “If you have one of those cases, you just want to have a dialogue with the urologists to make sure you’re all on the same page,” Dr. Hansel says.

Dr. Merino concurs. Practicing pathologists (and their clinical colleagues) may not need to absorb every last detail of the molecular analyses presented in the TCGA, “but they should at least see how we classify them,” she says, so they can use the same nomenclature.

Dr. Reuter

Then there are the names that vanished as subclassifications improved. Dr. Reuter alludes to the earlier RCC classifications, when the WHO defined four entities of kidney cancer: clear cell renal cell carcinoma, papillary renal cell carcinoma, granular cell-type renal cell carcinoma, and sarcomatoid renal cell carcinoma.

By the 1990s, pathologists realized neither sarcomatoid carcinoma nor granular cell-type renal cell carcinoma were true entities, and that papillary tumors were rather heterogeneous. By combining good pathology, good IHC, and good molecular biology, Dr. Reuter says, “we were able to tease out a lot of those groups, and understand the morphologic diversity that would be acceptable within each tumor type, as well as its genotype.”

But morphology alone is no longer sufficient to classify a tumor, a point driven home multiple times in the TCGA paper. “If pathologists read it with an open mind, they will see there is a good correlation between pathology and molecular,” Dr. Merino says.

Papillary renal cell carcinoma offers a good example of how matters are evolving. Since the 1990s, says Dr. Reuter, these tumors had been subdivided into Type 1 and Type 2. As it turns out, Type 1s are morphologically indistinct from papillary tumors arising in familial papillary renal cell carcinoma. The hereditary ones, however, characteristically have mutation of MET oncogene present on chromosome 7. (They also are usually diagnosed in patients at a younger age and more likely to be multifocal or bilateral.) Sporadic papillary Type 1 cancers do not have mutations of MET nearly as frequently but are likely to harbor amplifications of the same gene.

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