title: Synchronous Metastatic Clear-Cell Renal Cell Carcinoma: A Distinct Morphologic, Immunohistochemical, and Molecular Phenotype.
abstract: Clear cell renal cell carcinomas (ccRCCs) are highly metastatic tumors with metastases detected at diagnosis (synchronous) or during follow-up (metachronous). To date, there have been no reports comparing primary ccRCC of patients with synchronous and metachronous metastases, who are different in terms of prognosis. Determining whether there is a phenotypic difference between these 2 groups could have important clinical implications.
  
  
  
  In a retrospective consecutive cohort of 98 patients with ccRCC, 48 patients had metastases, including 28 synchronous and 20 metachronous presentations, with a follow-up of 10 years. For each primary tumor in these metastatic patients, pathologic criteria, expression of vascular endothelial growth factor, partitioning-defective 3, CAIX, and programmed death ligand 1 as detected by immunohistochemistry, and complete VHL status were analyzed. Univariate analysis was performed, and survival was assessed using Kaplan-Meier curves compared by log-rank test.
  
  
  
  Compared with primary ccRCC in patients with metachronous metastases, primary ccRCC in patients with synchronous metastases were significantly associated with a poorer Eastern Cooperative Oncology Group performance (P = .045), higher pT status (P = .038), non-inactivated VHL gene (P = .01), sarcomatoid component (P = .007), expression of partitioning-defective 3 (P = .007), and overexpressions of vascular endothelial growth factor (> 50%) (P = .017) and programmed death ligand 1 (P = .019). Patients with synchronous metastases had a worse cancer-specific survival than patients with metachronous metastases even from metastatic diagnosis (median survival, 16 months vs. 46 months, respectively; P = .01).
  
  
  
  This long-term study is the first to support the notion that synchronous m-ccRCC has a distinct phenotype. This is probably linked to the occurrence of oncogenic events that could explain the worse prognosis. These particular patients with metastases could benefit from specific therapy.
authors.affiliation: Department of Pathology, University Hospital, Rennes, France; CNRS, UMR6290, Institut de Génétique & Développement de Rennes, Rennes 1 University, Rennes, France. Electronic address: jacquet.sf@gmail.com.
authors.forename: Solene-Florence
authors.initials: SF
authors.lastname: Kammerer-Jacquet
authors.affiliation: Department of Medical Oncology, Centre de Lutte Contre le Cancer, Rennes, France.
authors.forename: Angelique
authors.initials: A
authors.lastname: Brunot
authors.affiliation: Department of Epidemiology, Ecole des Hautes Études en Santé Publique, Rennes, France.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Pladys
authors.affiliation: Department of Clinical Investigation, University Hospital, Rennes, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bouzille
authors.affiliation: Department of Pathology, University Hospital, Rennes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Dagher
authors.affiliation: CNRS, UMR6290, Institut de Génétique & Développement de Rennes, Rennes 1 University, Rennes, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Medane
authors.affiliation: Department of Urology, University Hospital, Rennes, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Peyronnet
authors.affiliation: Department of Urology, University Hospital, Rennes, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Mathieu
authors.affiliation: Department of Urology, University Hospital, Rennes, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Verhoest
authors.affiliation: Department of Urology, University Hospital, Rennes, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Bensalah
authors.affiliation: Department of Medical Oncology, Centre de Lutte Contre le Cancer, Rennes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Edeline
authors.affiliation: Department of Medical Oncology, Centre de Lutte Contre le Cancer, Rennes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Laguerre
authors.affiliation: Department of Molecular Genetics, University Hospital, Rennes, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lespagnol
authors.affiliation: Department of Molecular Genetics, University Hospital, Rennes, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Mosser
authors.affiliation: Cytogenetic and Cellular Biology Laboratory, University Hospital, Rennes, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Dugay
authors.affiliation: CNRS, UMR6290, Institut de Génétique & Développement de Rennes, Rennes 1 University, Rennes, France; Cytogenetic and Cellular Biology Laboratory, University Hospital, Rennes, France.
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Belaud-Rotureau
authors.affiliation: Department of Pathology, University Hospital, Rennes, France; CNRS, UMR6290, Institut de Génétique & Développement de Rennes, Rennes 1 University, Rennes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclercq
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000071231:Carbonic Anhydrase IX; C497446:VHL protein, human
keywords: Clear cell renal cell carcinoma; Clinical outcome; Sarcomatoid component; Synchronous and metachronous metastases; VEGF; VHL gene