176 Discussion bone cyst, and minimal mitotic activity were observed but no cellular atypia was observed. Much controversy surrounds the CGCG. Initially, it was not distinguished from the giant cell tumor of the extra- gnathic skeleton [20], but later it was described by Jaffe as the giant cell reparative granuloma [21]. Some authorities advocate using the more neutral term ‘‘central giant cell lesion’’ to describe this process, but most accept CGCG. CGCG has been proposed to be both a reactive response, to hemorrhage or trauma, and a neoplasm [2, 3, 22]. Some have proposed that giant cell granuloma of the jaws and giant cell tumors (GCT) of the extragnathic skeleton are part of a spectrum of a single lesion, modiﬁed by anatomic site [2, 15]. However, others have viewed CGCGs and GCTs of the extragnathic skeleton as distinct lesions [21, 23, 24]. Certain histological differences exist between the CGCG and the GCT (see Table 1). The giant cells are more evenly distributed in the GCT, focal areas of necrosis exist, decreased ﬁbrous tissue is present, and an accumulation of inﬂammatory cells may be seen [25]. Histologically, CGCG resembles the giant cell lesion of hyperparathy- roidism, cherubism, and aneurysmal bone cyst, which must be excluded. Multiple central giant cell lesions have been reported in association with Noonan-like/multiple giant cell lesion syndrome, and other features of the disease include a short stature, webbed neck, cubitus valgus, pul- monic stenosis, and multiple lentigenes [26]. Immunohistochemical studies on CGCG have helped establish the lineage of the cells, but not to predict the aggressiveness of the lesion. Supporting the theory that the Table 1 Comparison of giant cell tumor and central giant cell granuloma Location Giant cells Stromal cells Osteoid No Giant cell tumor Sphenoid, temporal, ethmoid bones (endochondral ossiﬁcation, not membranous in origin) Jaws in paget disease Evenly distributed Monocytes, osteoclasts No intercellular collagen Central giant cell granuloma Jaws, anterior mandible Fewer, smaller giant cells, unevenly distributed Fibroblasts producing collagen; Numerous capillaries Yes Head and Neck Pathol (2009) 3:174–178 multinucleated giant cells are derived from macrophages is the immunoreactive response to muramidase, a-1 antichy- motrypsin, and a-1 antitrypsin [27]. Aggressive and non- aggressive CGCGs stained for antibodies to CD34, CD68, factor Xllla, and smooth muscle actin, prolyl 4-hydroxy- lase, Ki-67, p53 protein, RANK, and glucocorticoid receptor alpha have revealed no phenotypic differences between the types [28, 29]. Calcitonin receptor expression, however, has been found to exhibit a statistically signiﬁ- cant difference with more expression in the aggressive type [29]. Immunohistochemical staining for c-Src, a protein thought to be required for osteoclast activation, has yielded no quantitative difference between CGCG, GCT, or cher- ubism [30]. The SH3BP2 gene is commonly found to be mutated in cherubism, and its transcripts and proteins have been found to be expressed in GCT and CGCG. [31] The mononuclear stromal cells display strong p63 immuno- staining in GCTs, but this has not been detected in CGCGs [32, 33]. Thus, P63 is one immunohistochemical stain that may help distinguish GCT from CGCG, while also sug- gesting a differing pathogenesis. Multifocal CGCG is a challenging entity. In previous reviews of the literature, different cases have been included as multifocal CGCG [34, 35]. Previous cases of multiple giant cell lesions may represent: 1. Unusual reports of cherubism [36, 37] 2. Association with a syndrome or genetic condition [14, 15, 38] 3. A single lesion of a jaw separated by normal bone 4. Association with elevated PTHrP [39] 5. True giant cell tumors originating in the maxillofacial region, 6. Multifocality resulting from hematogenous spread due to inadequate treatment In total, we believe there are six convincing cases of multifocal CGCG of the maxillofacial skeleton previously reported and not better explained by other pathologic conditions (see Table 2). Smith et al. [40] have proposed a new term, ‘‘craniofa- cial giant cell dysplasia,’’ to describe the multifocal central giant cell of the jaws. Miloro and Quinn [34] advocate dividing multifocal central giant cell lesions into syn- chronous or metachronous lesions. They propose metach- ronous lesions are more likely to represent a recurrence due to inadequate initial treatment or tumor seeding, whereas synchronous lesions are more likely to represent true multifocality. Our case represents a clinically aggressive, multifocal, and recurrent CGCG that is quite bland histologically, and not associated with other conditions or syndromes. It dis- plays a secondary aneurysmal bone cyst component seen in 30% of CGCG [41] as well as other osseous lesions [42].