title: Defining a new aggressiveness classification and using NFATc1 localization as a prognostic factor in cherubism.
abstract: Cherubism is a rare genetic disease characterized by bilateral giant cell reparative granuloma of the jaws consisting of a fibrotic stroma with giant multinucleated cells (GMCs) and osteoclastic features. Cherubism severity is highly variable, and recurrence after surgery is the most important risk. Currently, there are no prognostic indicators. The aims of this study were to evaluate the osteoclastogenesis phenotype by histologic examination of nuclear factor of activated T cells 1 (NFATc1) localization and tartrate-resistant acid phosphatase (TRAP) activity and to correlate the results to disease aggressiveness to define prognostic indicators. Based on cherubism evolution 1 year after surgery, 3 classes of cherubism aggressiveness were identified: mild (group A), moderate (group B), and severe (group C). Histologically, in grade A and B cherubism lesions, GMCs were negative for both TRAP activity and NFATc1 nuclear localization. In contrast, in grade C cherubism lesions, GMCs were all positive for TRAP activity and NFATc1 nuclear localization and displayed osteoclast-like features. Other histopathologic findings were not different among the 3 groups. Our results establish that TRAP activity and NFTAc1 nuclear localization are associated with aggressive cherubism and therefore could be added to routine pathologic examination to aid in prognosis and management of the disease. The finding of NFATc1 nuclear localization in aggressive tumors supports the addition of anticalcineurin treatment to the therapeutic arsenal for cherubism.
authors: INSERM, UMRS 1138, Centre de Recherche de Cordeliers, Molecular Oral Pathology, 75006 Paris, France; Université Paris Descartes, 75006 Paris, France; APHP, Necker Enfants Malades, Service de Chirurgie Maxillo-Faciale et Plastique, 75015 Paris, France; APHP, CRMR des Malformations Rares de la Face et de la Cavité Buccale, 75015 Paris, France. Electronic address: natacha.kadlub@gmail.com.
authors: Natacha
authors: N
authors: Kadlub
authors: CHU de Bordeaux, Service de Chirurgie Maxillo-Faciale, 33000 Bordeaux, France.
authors: Quentin
authors: Q
authors: Sessiecq
authors: APHP, Hôpital Armand Trousseau, Service d'Anatomopathologie et Cytologie, 75012 Paris, France; Université Pierre et Marie Curie, 75005 Paris, France.
authors: Linda
authors: L
authors: Dainese
authors: INSERM, UMRS 1138, Centre de Recherche de Cordeliers, Molecular Oral Pathology, 75006 Paris, France; Université Paris Descartes, 75006 Paris, France; APHP, Necker Enfants Malades, Service de Chirurgie Maxillo-Faciale et Plastique, 75015 Paris, France; APHP, CRMR des Malformations Rares de la Face et de la Cavité Buccale, 75015 Paris, France.
authors: Aline
authors: A
authors: Joly
authors: CHU de Dijon, Service de Génétique, 21000 Dijon, France.
authors: Daphne
authors: D
authors: Lehalle
authors: APHP, Necker Enfants Malades, Service de Génétique, 75015 Paris, France.
authors: Sandrine
authors: S
authors: Marlin
authors: Université Paris Descartes, 75006 Paris, France; APHP, Hôpital Européen Georges Pompidou, Service d'Anatomopathologie et Cytologie, 75015 Paris, France.
authors: Cecile
authors: C
authors: Badoual
authors: Université Paris Descartes, 75006 Paris, France; APHP, Necker Enfants Malades, Service d'Anatomopathologie et Cytologie, 75015 Paris, France.
authors: Louise
authors: L
authors: Galmiche
authors: CHU de Bordeaux, Service de Chirurgie Maxillo-Faciale, 33000 Bordeaux, France.
authors: Claire
authors: C
authors: Majoufre-Lefebvre
authors: INSERM, UMRS 1138, Centre de Recherche de Cordeliers, Molecular Oral Pathology, 75006 Paris, France; UFR Odontologie, Garancière, Université Paris Diderot, 75006 Paris, France.
authors: Ariane
authors: A
authors: Berdal
authors: INSERM, U1035, Université Nice Sophia-Antipolis, Microenvironment, Signaling and Cancer, 06000 Nice, France.
authors: Marcel
authors: M
authors: Deckert
authors: INSERM, UMRS 1138, Centre de Recherche de Cordeliers, Molecular Oral Pathology, 75006 Paris, France; Université Paris Descartes, 75006 Paris, France; APHP, Necker Enfants Malades, Service de Chirurgie Maxillo-Faciale et Plastique, 75015 Paris, France; APHP, CRMR des Malformations Rares de la Face et de la Cavité Buccale, 75015 Paris, France.
authors: Marie-Paule
authors: MP
authors: Vazquez
authors: INSERM, UMRS 1138, Centre de Recherche de Cordeliers, Molecular Oral Pathology, 75006 Paris, France; UFR Odontologie, Garancière, Université Paris Diderot, 75006 Paris, France; APHP, Hôpital Pitié Salpétrière, Service d'Odontologie, 75013 Paris, France.
authors: Vianney
authors: V
authors: Descroix
authors: INSERM, UMRS 1138, Centre de Recherche de Cordeliers, Molecular Oral Pathology, 75006 Paris, France; UFR Odontologie, Garancière, Université Paris Diderot, 75006 Paris, France.
authors: Amélie E
authors: AE
authors: Coudert
authors: INSERM, UMRS 1138, Centre de Recherche de Cordeliers, Molecular Oral Pathology, 75006 Paris, France; Université Paris Descartes, 75006 Paris, France; APHP, Necker Enfants Malades, Service de Chirurgie Maxillo-Faciale et Plastique, 75015 Paris, France; APHP, CRMR des Malformations Rares de la Face et de la Cavité Buccale, 75015 Paris, France.
authors: Arnaud
authors: A
authors: Picard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D015415:Biomarkers / Q000032:analysis; D002467:Cell Nucleus / Q000737:chemistry* / Q000473:pathology; D002636:Cherubism / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D015726:Giant Cells / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007568:Jaw / Q000737:chemistry* / Q000473:pathology; D008297:Male; D009154:Mutation; D050778:NFATC Transcription Factors / Q000032:analysis*; D056948:Orthognathic Surgical Procedures; D010010:Osteoclasts / Q000737:chemistry* / Q000473:pathology; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012720:Severity of Illness Index; D000071681:Tartrate-Resistant Acid Phosphatase / Q000032:analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C109073:SH3BP2 protein, human; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Cherubism; Giant cell reparative granuloma; NFATc1; Prognosis; Trap