Defining a new aggressiveness classification and using NFATc1 localization as a prognostic factor in cherubism

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.