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 to the TNM staging system or the World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade in non-metastatic ccRCC. Hematoxylin and eosin-stained slides of whole tissue sections from surgical specimens were analyzed using a cohort of 331 patients with non-metastatic 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, four subgroups consisting of 40 patients (12%) were identified to have aggressive forms of non-metastatic 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 3-4 (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.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2024 Aug 12 [Epub ahead of print]
Hajime Tanaka, Yuki Fukawa, Kouhei Yamamoto, Kousuke Tanimoto, Akira Takemoto, Takayasu Mori, Hisashi Hasumi, Mayumi Kinoshita, Takumi Kanazawa, Asuka Furukawa, Koichiro Kimura, Hiroyuki Sato, Akihiro Hirakawa, Shohei Fukuda, Yuma Waseda, Soichiro Yoshida, Steven C Campbell, Yasuhisa Fujii
Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: ., Department of Pathology, Tokyo Medical and Dental University, Tokyo, Japan., Research Core, Tokyo Medical and Dental University, Tokyo, Japan., Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan., Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan., Department of Urology, Yokohama City University, Yokohama, Japan., Department of Pathology, Tokyo Medical and Dental University, Tokyo, Japan; Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Tokyo, Japan., Department of Radiology, Tokyo Medical and Dental University, Tokyo, Japan., Department of Clinical Biostatistics, Tokyo Medical and Dental University, Tokyo, Japan., Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan., Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH.