A subset of clear cell renal cell carcinomas (ccRCCs) exhibits various growth patterns that infiltrate
the normal renal parenchyma; however, our understanding of its association with cancer aggressiveness
is incomplete. Here, we show that the morphology of the tumor interface with normal renal
parenchyma is robustly associated with cancer recurrence after surgery, even when compared with
the TNM staging system or the World Health Organization/International Society of Urological Pathology
(WHO/ISUP) nuclear grade in nonmetastatic ccRCC. Hematoxylin and eosinestained slides
of whole tissue sections from surgical specimens were analyzed using a cohort of 331 patients with
nonmetastatic ccRCC treated with radical nephrectomy. The patients were classified into 10 subgroups
based on our classification algorithms for assessing the tumor interface with normal renal
parenchyma. Among the 10 subgroups, 4 subgroups consisting of 40 patients (12%) were identified
to have aggressive forms of nonmetastatic ccRCC associated with poor prognosis and unified as renal
parenchymal infiltration or micronodular spread (RPI/MNS) phenotypes. Multivariable analyses
showed that RPI/MNS phenotypes were robustly associated with shorter disease-free survival,
independently of existing pathological factors including the TNM staging system and WHO/ISUP
nuclear grade. The hazard ratio was highest for RPI/MNS (4.62), followed by WHO/ISUP grades 3 to 4
(2.11) and pT3a stage (2.05). In addition, we conducted genomic analyses using next-generation
sequencing of infiltrative lesions in 18 patients with RPI/MNS and tumor lesions in 33 patients
without RPI/MNS. Results showed that alterations in SETD2 and TSC1 might be associated with RPI/
MNS phenotypes, whereas alterations in PBRM1 might be associated with non-RPI/MNS phenotypes.
These data suggest that RPI/MNS may be associated with aggressive genomic backgrounds of ccRCC,
although more comprehensive analyses with a larger sample size are required. Future studies may
further elucidate the clinical implications of RPI/MNS, particularly for deciding the indication of
adjuvant treatment after nephrectomy.

JOURNAL：Modern Pathology

TITLE：Prognostic Impact and Genomic Backgrounds of Renal Parenchymal Infiltration or Micronodular Spread in Nonmetastatic Clear Cell Renal Cell Carcinoma

DOI：https://doi.org/10.1016/j.modpat.2024.100590