September 2018—Leo Tolstoy is not listed as a coauthor on the most recent iteration of The Cancer Genome Atlas on renal cell carcinoma, which focuses on molecular characterization of RCC. But the topic is as rich and complex as a Russian novel, and the authors’ approach is so comprehensive, it’s tempting to picture them at least holding forth at a certain soirée in Saint Petersburg (minus the after-party drunkenness and the bit with a bear, of course).
The project may not be as sprawling as War and Peace, which marches 559 characters, speaking two languages, over four volumes, 15 parts, and 333 chapters. It’s a heroic effort nonetheless. There is much to keep track of in renal cell carcinoma, both generally and in this latest document (Ricketts CJ, et al. Cell Rep. 2018;23:313–326.e5), which evaluates 843 RCCs from three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. “And remember,” says actual coauthor Victor Reuter, MD, “this is our fourth publication on kidney cancer.” The previous three each focused solely on one of the subtypes.
The most recent publication expands matters, looking at larger numbers of cases in each category and eyeing them a bit differently, says Dr. Reuter, vice chairman of the Department of Pathology, Memorial Sloan Kettering Cancer Center, and professor of pathology and laboratory medicine, Weill Cornell Medical College. “It’s a natural progression to the other three stories,” he says. “And it shows some novel information as well.” Molecular perspectives—mutations, copy numbers, RNA, microRNA expression studies, methylation, etc.—enabled researchers to look at each group and show differences as well as similarities within each “basket,” he says.
The TCGA, says coauthor Maria Merino, MD, confirms that the spectrum of kidney cancers is indeed quite ample. “And as pathologists, we need to classify these tumors as far as we can.”
Physicians don’t necessarily have to do a deep dive into the paper to realize the implications of its contents. As part of their big data dive, the researchers also looked at patient survival. Moreover, therapies will be targeted to specific tumor types, plain and simple. “If we don’t do this classification and subclassification and confirm them with the genetics, it is possible that patients may not be treated appropriately,” warns Dr. Merino, chief of translational surgical pathology and a principal investigator, National Cancer Institute. This latest installment is yet another chapter in the bigger, ongoing story of how pathologists and others are unmasking the true nature of these tumors.The work “has been humbling,” says coauthor W. Marston Linehan, MD, chief of the Urologic Oncology Branch, NCI, who has worked on all four TCGA projects. “It’s so complex.”
That complexity has been mirrored in clinical practice. “There have been a lot of changes going on in this field in general,” says Donna Hansel, MD, PhD, professor of pathology and chief of anatomic pathology, University of California, San Diego. The biggest, she says, has been the swing toward molecular diagnostics.The most recent TCGA, she says, helps explain how the various tumor types are classified and how they might be related to one another. Equally important is its emphasis on subclassification. Thirdly, she says, it offers insight into tumor biology and, broadly, the molecular changes that occur. Finally, and perhaps most importantly, in her view, it points to previously unexplored areas that could spur the development of targeted therapies, which are much needed, given that the survival rate for advanced kidney cancer has been, until recently, very dismal.
Dr. Linehan agrees. “Knowledge is power. And the first step in developing effective forms of therapy is to understand what your targets are.”
Though many of the morphological classifications and subclassifications aren’t necessarily new to pathologists, Dr. Hansel says, the paper highlights some overlapping molecular features of many of them, which haven’t been widely appreciated. That, in turn, has launched countless questions as pathologists try to connect the dots between morphologies and molecular alterations. Are there morphological clues that point to a specific mutation, translocation, or chromosomal abnormality, which would trigger further testing? And if such testing is done, what, if anything, do the results mean?
Dr. Hansel sees a large role for molecular testing. “But how far will that go?” she asks. For her, the most pressing question is whether molecular testing will become the modality for subclassifying tumors. “Or is there still a role for morphology in triaging?” she asks. “I’d like to say there’s a role for both—or else you’re going to get a lot of angry letters,” she tells CAP TODAY.
Perhaps only a fool (fun fact: the chief fool in War and Peace was Napoleon Bonaparte) would argue against any role for molecular, given the changes it has wrought in the field already.
For years, Dr. Hansel says, renal tumors generally were classified into four types of lesions. “And if you didn’t know, you’d just wave your hands and say it was unclassified,” she says, only somewhat jokingly. Over the past 15 years or so, through molecular work primarily but also improved morphology classification, “We’ve gotten much, much better at being able to subdivide these. When you take a look at what we used to call unclassified, a lot of that has shrunk away. We can now put them into very specific baskets.” And new knowledge has upended some baskets entirely.
The “unclassified” basket was “an easy out, in a way,” says Dr. Hansel. It still exists, but only after tumors have been more thoroughly worked up with molecular tools to look for either chromosomal abnormalities or translocation—two of the more common findings in renal cell carcinoma.
Knowing it’s possible to tip some tumors out of the unclassified basket, however, doesn’t mean dropping them in the right basket is a slam dunk. Immunohistochemistry isn’t foolproof. It can lack specificity. Some antibodies have been studied only in small series of tumors; others are quite finicky.
Even when IHC is firing on all cylinders, “The truth is, I continue to see renal tumors that defy classification,” Dr. Hansel says. These cancers exhibit complex and diverse histologies and comprise what Dr. Hansel calls “a maze of tumors, with a whole spectrum of immunohistochemical and molecular changes that accompany them. And trying to put them in the right bucket, and even knowing the bucket exists, has been challenging.”