These discussions can help Dr. Hansel decide what comes next. “If you get an indeterminate stain, you debate whether you need to take the extra steps to further classify, understanding that that classification may or may not make a difference,” she says. Is the added TAT worth it? Is the clinician a little worried, or a lot? “Usually those are the cases I’ll call the clinician on. They may know something I don’t. Or, it may not change their management. That’s something a lot of people struggle with.”
Dr. Hirsch says her clinical colleagues at Dana-Farber Cancer Institute are keen to know the subtypes, “particularly in the metastatic setting,” in part because they can determine which clinical trials—some of which they’re designing—might help their patients.
Adds Dr. Merino: “Keep in mind, new protocols open all the time.”
In some cases, tumors once thought to be aggressive may actually be indolent. In other cases, tumors that have been considered more common in one patient population might occur in other groups more frequently.
As work in this field unfolds, researchers have made intriguing discoveries. TFE-3 translocation renal cell carcinomas were first identified in children and originally thought to be a pediatric tumor. “Over the years,” Dr. Hirsch says, “we’ve come to recognize this diagnosis in adults, and we now know that we see more cases in adults than in children.” It also appears that behavior and outcome of these tumors differ between the two patient groups as well. In children, the tumors are often confined to the kidney, and survival rates are good. In adults, these tumors not infrequently present as a metastasis before they show up as a primary kidney tumor. They also seem to show up much more frequently in middle-aged women. “I’ve had multiple cases where a TFE-3 translocation renal cell carcinoma presents in a supraclavicular lymph node,” she says. Although Dr. Hirsch can’t explain why this tumor type prefers supraclavicular lymph nodes, she does use this information to her advantage. “If I get a case of a middle-aged woman with a supraclavicular lymph node metastasis and a renal mass, in my mind, that’s a TFE-3 translocated renal cell carcinoma until proven otherwise.”
“In general, we will continue to struggle in a subset of cases where there is morphologic overlap between renal cell cancer subtypes,” Dr. Hirsch says. Without knowing the molecular makeup in all cases, “some of these kidney tumors could very well be misclassified, but this should happen with less frequency as we learn more and more about the genetic and molecular makeup of tumors.”
She and Dr. Reuter sing the same chorus: You can’t diagnose something if you’re not even thinking about it.
Then there’s the matter of clear cell papillary renal cell carcinoma. Channeling her inner Dostoyevsky, Dr. Hirsch says, “It goes by two names.” The WHO recognizes both. One is clear cell tubulopapillary renal cell carcinoma (“That’s the only terminology I use,” she says), which is synonymous with the term clear cell papillary renal cell carcinoma.
Likewise, some pathologists prefer to Type 1/Type 2 their papillary renal cell carcinomas; others (including Dr. Hirsch, Dr. Reuter, and Dr. Merino) do not. Says Dr. Merino: “I’m very opposed to saying something is papillary Type 2. Because that encompasses quite a number of different tumors.”
Along with everything else, RCC appears to have a branding issue. “Our clinical colleagues do get frustrated,” Dr. Hirsch concedes, “but I think and hope they recognize our good intentions of helping patients get the best possible diagnosis and prognostic information.”
Terminology can eventually change; obviously nothing in this field is static. As noted, sarcomatoid renal cell carcinoma is no longer used; rather, knowledge of genetics and molecular alterations have made clear that tumors with such features arose from one of the recognized RCC subtypes. “We now refer to them as renal cell carcinoma with sarcomatoid differentiation,” Dr. Hirsch says. “And we try to give the underlying subtype, whether we get that from morphology or from genetic and molecular findings: clear cell carcinoma with sarcomatoid differentiation, papillary renal cell carcinoma with sarcomatoid differentiation, etc. But sarcomatoid RCC is not its own subclassification of renal tumors.”