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Molecular ‘bucket list’ for renal cancer

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In the case of tubulo versus sans tubulo, Dr. Hirsch says using the latter term is confusing, “obviously because of the clear cell and papillary cell subtypes. The word ‘tubulo’ makes it very distinct in my mind and the clinician’s mind that this is a different subtype.”

Since this subtype was first recognized about five years ago, the cards have been reshuffled a bit, Dr. Hirsch says. The tumor can be separated from traditional clear cell and papillary renal cell carcinomas. And where traditional thinking has considered clear cell renal cell carcinoma as being the most common, followed by papillary, then chromophobe, Dr. Hirsch is convinced that the incidence of clear cell tubulopapillary is higher than that of chromophobe and might even approach that of papillary renal cell carcinoma. “We think of papillary renal cell carcinoma being 10 to 15 percent of renal cell carcinomas; I would say the clear cell tubulopapillary renal cell carcinomas [are] definitely five to 10 percent, if not more, of cases.” The majority of renal cell carcinomas—some 70 percent—are conventional/clear cell RCC.

Pathologists have learned more about the morphologic features of the tubulopapillary tumor, for starters. And whereas clear cell renal cell carcinoma has a chromosome 3p loss, and papillary renal cell carcinomas have extra chromosome copies (i.e. trisomes, often with chromosomes 7 and/or 17), none of these chromosomal changes occur in the clear cell tubulopapillary renal cell carcinoma.

“In prior years, we didn’t even realize this tumor existed,” Dr. Hirsch says. “Now I’m finding this a very frequent tumor. As I go back through my files of renal tumors, I see cases of clear cell tubulopapillary carcinoma that were originally misdiagnoses, and now we see this tumor not infrequently on a routine diagnostic basis. It’s growing in incidence, simply based on recognition.”

While these cases are labeled as carcinoma, Dr. Hirsch says, “We think clear cell tubulopapillary renal cell carcinoma is an indolent lesion. It’s a much better behaving renal cell neoplasm. For that reason, teasing it out is really important. These patients have been dubbed with a carcinoma, and that’s scary for them, and they may lose life insurance, and they may get too many CT scans during routine clinical follow-up. But in the end they really have this very low-grade, indolent, probably benign tumor. And they could have had it taken out and just been told that they’re cured. Which is a completely different emotional situation for that patient.”

Clear cell RCC is anything but clear, as it turns out. “It is a very complex disease,” says Dr. Merino. “And it’s clear we don’t know how to subclassify them according to the genetic changes. It’s possible, with clear cell carcinomas, that we have to do more molecular analysis.” Moreover, she says, “The translocation tumors are tumors that we still don’t know how to recognize very well. Because they have some clear cells, many people would just call them clear cell, when they’re not clear cell. They’re translocation tumors.”

Dr. Reuter offers another example from the TCGA study: Some genomic abnormalities present in chromophobe renal cell carcinomas—tumors that normally have a good prognosis—are associated with poor outcome. “So even within tumors that do well, we can identify features that would predict worse outcome,” he says. “But equally, if those are not present, they predict a good outcome.”


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