PMID- 36127822 OWN - NLM STAT- MEDLINE DCOM- 20230302 LR - 20230317 IS - 2045-7634 (Electronic) IS - 2045-7634 (Linking) VI - 12 IP - 4 DP - 2023 Feb TI - Dirty necrosis in renal cell carcinoma is associated with NETosis and systemic inflammation. PG - 4557-4567 LID - 10.1002/cam4.5249 [doi] AB - AIM: Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable prognostic indicator. This study aimed to analyze the pathological and biological features of DN. MATERIALS AND METHODS: A total of 81 RCC tumors, including 33 cases of DN and 48 cases of tumor necrosis without DN features (ghost necrosis [GN]), were enrolled in this study. We compared the number of neutrophils; the activation of cell death pathways, including ferroptosis, NETosis, and apoptosis; the rate of epithelial-mesenchymal transition (EMT); and proliferation status using immunohistochemistry. We further assessed the effect of the necrosis type on systemic inflammation. RESULTS: DN tumors had a significantly higher number of neutrophils in both areas around the necrotic foci and far from the necrotic foci. Ferroptosis status did not differ between DN and GN; however, DN tumors had significantly larger areas exhibiting cell detritus with neutrophil extracellular traps (NETs) detected by citrullinated histone H3 (citH3) than GN tumors. DN tumors also had more apoptotic cells within areas around the necrotic foci. There was no significant difference between the EMT and proliferation status between DN and GN groups. Systemic inflammation markers including C-reactive protein (CRP), CRP-to-albumin ratio (CRP/Alb), platelet-to-lymphocyte ratio (PLR), and hemoglobin were significantly higher in patients with DN. In addition, some of these inflammation markers (CRP/Alb and PLR) significantly decreased after surgery. CONCLUSIONS: DN in RCC is characterized by NETs production and systemic inflammation. CI - (c) 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Kuroe, Takashi AU - Kuroe T AUID- ORCID: 0000-0002-2366-2467 AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. AD - Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. AD - Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. FAU - Watanabe, Reiko AU - Watanabe R AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Morisue, Ryo AU - Morisue R AD - Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. AD - Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Miyazaki, Saori AU - Miyazaki S AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Kojima, Motohiro AU - Kojima M AUID- ORCID: 0000-0002-6150-6545 AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. AD - Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. FAU - Murata, Shawhay Charles AU - Murata SC AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. AD - Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. AD - Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. FAU - Nakai, Tokiko AU - Nakai T AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Taki, Tetsuro AU - Taki T AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Sakashita, Shingo AU - Sakashita S AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. AD - Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. FAU - Sakamoto, Naoya AU - Sakamoto N AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. AD - Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. FAU - Matsubara, Nobuaki AU - Matsubara N AUID- ORCID: 0000-0002-9203-4245 AD - Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Masuda, Hitoshi AU - Masuda H AD - Department of Urology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Ushiku, Tetsuo AU - Ushiku T AD - Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. FAU - Ishii, Genichiro AU - Ishii G AD - Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. AD - Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220920 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - 9007-41-4 (C-Reactive Protein) SB - IM MH - Humans MH - *Carcinoma, Renal Cell/pathology MH - Inflammation/metabolism MH - Neutrophils/metabolism MH - C-Reactive Protein/analysis MH - *Kidney Neoplasms/pathology MH - Necrosis/metabolism/pathology PMC - PMC9972113 OTO - NOTNLM OT - NETosis OT - dirty necrosis OT - neutrophil extracellular traps OT - systemic inflammation OT - tumor necrosis COIS- The authors have no conflict of interest to disclose. EDAT- 2022/09/22 06:00 MHDA- 2023/03/03 06:00 PMCR- 2022/09/20 CRDT- 2022/09/21 00:42 PHST- 2022/08/24 00:00 [revised] PHST- 2022/03/05 00:00 [received] PHST- 2022/09/01 00:00 [accepted] PHST- 2022/09/22 06:00 [pubmed] PHST- 2023/03/03 06:00 [medline] PHST- 2022/09/21 00:42 [entrez] PHST- 2022/09/20 00:00 [pmc-release] AID - CAM45249 [pii] AID - 10.1002/cam4.5249 [doi] PST - ppublish SO - Cancer Med. 2023 Feb;12(4):4557-4567. doi: 10.1002/cam4.5249. Epub 2022 Sep 20.