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Clinicopathological Characterization of Renal Cell Carcinoma in Young Adults: a contemporary update and review of literature

A continuous challenge for cancer researchers is conducting analyses in age groups where cases are limited. Renal cell carcinoma (RCC) is a kidney cancer that occurs in individuals of all ages, but is far more prevalent in older patients. Because of this, research on young adult and childhood RCC (in particular, morphological and genetic characterization studies) has been scant.

Dr. Rohit Mehra is a surgical pathologist and associate professor at Michigan Medicine. He specializes in genitourinary (GU) malignancies and is particularly interested in uncovering the genetic alterations driving these tumors. Along with his team, he conducted a recent study that sought to answer many of the questions still surrounding RCC in young people. They performed a retrospective pathological and clinical review of 68 RCC patients age 30 years or younger, diagnosed at their facility between 1986 and 2018 – the largest RCC study to date in this age group. Morphological, immunohistochemical, and genetic analyses were carried out, and results provided novel insight into the molecular and clinical course of RCC in this under-reported demographic.

I got the chance talk with Mehra about his findings. A preliminary question of mine was whether GU tumors present with any unique research and/or treatment obstacles, compared to other cancers. Mehra says they’re challenging in that “…very different organ systems (kidney, bladder, testis, etc.) with a diverse array of clinical and pathologic processes are classified under a common umbrella (GU).” Thankfully, he says, Michigan Medicine allows for plenty of interaction between different departments focused on GU disease. So, while the specialty itself can be complex, Mehra is thankful to be able to work in such a collaborative environment.

Next, I asked him to expand on his results; what were the major differences (if any) between adult and pediatric/young adult RCC? He says that, while younger patients presented with many of the same features displayed in adults, they found a few clinicopathological characteristics to be more frequent in their cohort. Firstly, while clear cell RCC, the most common subtype in adult patients, was also the most prevalent in their series, MiT-family aberrations and rare familial syndrome subtypes proved more common than in adults. Second, there didn’t appear to be a gender predilection in their series; their male: female ratio was 1:1, compared to the 2:1 ratio reported in adult RCC.

Another major finding: TFE3 and TFEB, two MiT-family genes that have previously been found altered in adult RCC, were rearranged in 13% of cases. And patients harboring these abnormalities presented with a more aggressive clinical profile, with the majority of them suffering from distant metastasis or death a few years after diagnosis. “Our study showed a lethal phenotype to be enriched within patients with TFE3 translocation in this clinical cohort.”

Previous reports about the clinical significance of MiT-family translocations in young patients have been mixed, with some even suggesting they were indicative of good prognosis. However, Mehra’s findings demonstrated a relatively aggressive trend. “Results showed that young patients with TFE3 rearrangements carry significant risk of clinical disease progression and poor outcome…It is important for pathologists, urologists and oncologists to keep MiT family aberration RCC in the differential diagnosis in the correct context, so adequate staging and treatment could be pursued for such patients.”

My final question for Mehra was what he hoped other researchers and clinicians take from the study. He says he’d like to see it help further classification of RCC in young people, as he and his team were unable to classify many of the cases in his series. “Despite applying the new WHO 2016 diagnostic criteria, we found a significant number of RCC, type unclassified, that comprise phenotypically distinct tumors, which carries potential for future subcategorization including molecular investigation and biomarker discovery.” He also hopes it inspires investigation into potential targeted treatment for patients harboring MiT-family rearrangements. “Currently, the management of metastatic MiT aberration RCC disease is not entirely different from metastatic RCC; however, the hope is that study like ours can better delineate the clinicopathologic features of this disease, and in turn trigger research for targeted therapy.”

Rachel McMahon-Eagan